Researchers take a closer look at how estrogen levels may influence the release of a peptide linked with migraine. Image credit: Chelsea Victoria/Stocksy.
  • 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:

  1. women with regular menstrual cycles
  2. women taking contraceptives
  3. women who had gone through their menopausal stage.

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.”

Dr. Regina Krel, FAHS, a specialist at Hackensack University Medical Center in New Jersey who wasn’t involved in the study, said these new findings back up previous research.

“I was not surprised to see the results of this study,” she told Medical News Today. “We have long known that the drop in estrogen that occurs just prior to menstrual onset can trigger migraine attacks to come on. We have also known that patients who suffer from migraine have higher levels of CGRP and that CGRP increases during a migraine attack. This study allows us to have an explanation of why that drop in estrogen triggers migraine type headaches.”

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.

Dr. Krel said she hopes this new information will help with migraine treatment and menstruation.

“In female patients who have been identified as having menstrually related migraine or pure menstrual migraine, spot migraine prophylactic treatment may be a good option to prevent the attacks,” she said. “This means that patients can take certain migraine specific medications just prior to menstrual migraine onset and continue during their cycle to prevent the onset of headaches.”

“A more novel treatment approach may be using the newly approved CGRP blocking medications during this time to prevent a rise in CGRP levels as estrogen levels drop,” Dr. Krel added. “Alternatively, something that has already been in practice in patients, who qualify for and don’t have contraindications to, may be put on continuous estrogen birth control to prevent the drop in estrogen that occurs. This will, in turn, also prevent the rise in CGRP levels.”