Migraine and periods: Study looks at the mechanisms

  • A new study has found that migraine attacks experienced by cisgender women during menstruation may be the result of an increase in the peptide CGRP, which has been linked to migraines.
  • This increase corresponded in the study to a reduction in estrogen that occurs during menstruation.
  • The study did not find an increase in CGRP in people taking contraceptives or who had gone through menopause, although they may still experience migraine episodes.

Experts have known for decades that a drop in the hormone estrogen is associated with the onset of menstruation-related migraine episodes. However, the mechanics behind this connection have remained unclear.

A new study has found that, as hormonal levels fluctuate throughout the menstrual cycle, levels of a peptide associated with migraine also rise and fall.

During the drop in estrogen that occurs at the onset of menstruation, there is an increase in levels of calcitonin gene-related peptide, or CGRP.

While the reason a reduction in estrogen might trigger a release of CGRP remains unknown, the pilot study may offer an important clue regarding the cause of menstrual migraine.

It may also explain why menstrual migraine attacks occur during menstruation, and why they decline in frequency after menopause.

The study appears in Neurology.

CGRP and menstrual stages

The study was a cross-sectional, matched-cohort study conducted at the Headache Center, Department of Neurology, Charité Universitätsmedizin Berlin in Germany.

The study cohort consisted of 180 cisgender women who had had at least three episodic migraine attacks in the month leading up to the study.

The researchers divided the participants evenly divided into three groups:

Age-matched women who did not get migraines served as a control group.

To assess levels of CGRP, the researchers analyzed blood and tear samples taken from study participants. They took samples from participants with regular menstrual cycles during menstruation and ovulation, when hormone levels are lowest and highest, respectively.

For women on birth control, they collected samples at roughly day 4 of the participants’ hormone-free intervals, and again during days 7–14 of their hormone intake.

Samples were taken just once from women post-menopause, on a random day.

Women with migraine and regular menstrual cycles had significantly more CGRP — 5.95 picograms per milliliter (pg/ml) — in their blood during menstruation than women who did not get migraines — 4.61 pg/ml.

During ovulation, the time at which hormone levels are at their highest, CGRP levels decreased, aligning with the cessation of migraine attacks that typically occurs after menstruation.

The same patterns held true for tear samples, an experimental form of CGRP measurement. Women with migraine who had regular menstrual cycles had 1.20 nanograms of CGRP per milliliter (ng/ml), while women without migraine had 0.4 ng/ml.

Participants who were taking contraceptives and women post-menopause did not exhibit the same increase in CGRP levels, whether or not they experienced migraine. This suggests that migraine attacks experienced by the women in these groups are likely not triggered by CGRP.

Lead study author Dr. Bianca Raffaelli told Medical News Today:

“Our hypothesis is that, in those patients, other pain pathways play a more important role than CGRP. In fact, there are several neuropeptides that can provoke migraine attacks in humans. This is only speculative at this stage and should be examined in further studies.”

Tear sampling

Tear sampling is still considered experimental, with Dr. Raffaelli telling the American Academy of Neurology that the study supports its further use and exploration.

Tear sampling offers a non-invasive means of measuring CGRP.

In addition, Dr. Raffaelli explained to MNT, “[d]ue to the anatomical proximity to the trigeminal nerve, CGRP in the tear fluid is more likely to reflect the trigeminovascular release of CGRP, while CGRP in blood could also come from other sources.”

Hormones and CGRP

Neurologist Dr. Shazia Afridi, not involved in the research, described the study as “helpful in trying to understand the role of female hormones in migraine, in particular in the menstrual exacerbation of migraine.”

“Animal studies have previously suggested that estrogen can influence CGRP expression in the trigeminovascular system, but there are very few human studies,” she noted.

Dr. Afridi suggested that there may be a clue as to the connection between hormone levels and CGRP in that “estrogen receptors are found in nerve cells, which also express CGRP in the trigeminal system.”

Migraine and contraception

While it appears that being on contraception may affect the occurrence of migraine attacks, both Dr. Raffaelli and Dr. Afridi describe the outcomes as complicated.

Different types of contraception behave differently in relation to migraine, said Dr. Afridi. “There is some evidence that desogestrel can improve migraine in some cases,” she added.

Desogestrel is the active ingredient in the progestogen-only contraceptive pill, also known as the “mini-pill.”

Dr. Raffaelli said that, for women taking oral contraceptives, “about one-third of patients with migraine experience improvement, one-third worsening, and one-third no change.

Oral contraceptives taken in a 21–7 cycle — 3 weeks of contraception followed by a week without — Dr. Raffaelli reported, most often produces a worsening of migraines. Long-cycle oral contraceptives appear to be associated with migraine improvements.

“It is also important to note that both estrogen-containing preparations and migraine with aura are associated with a slightly increased risk of stroke, whereby the risk depends significantly on the dosage of the estrogen,” she added.

“Accordingly, estrogen-free contraceptive strategies should be used primarily in patients with migraine with aura,” Dr. Raffaelli advised.

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