Menstruation and migraine – it’s time to find the link

A new research-based theory suggests an answer: a woman’s “migraine brake” eases off in the lead up to menstruation.

Around one billion people – approximately one in seven the world over – are affected by migraine to varying degrees. And migraines are three times more common in women of child-bearing age than in men.

It has been assumed in scientific circles for a long time now that this uneven distribution between the sexes is largely due to the reproductive cycle of women – and that female hormones play a major role.

There has been much speculation about the precise link, but specific answers have remained elusive.

However, a Swedish-Danish research team now gives a potential explanation. They believe their theory holds water, and they intend to investigate it further.

The theory, which focuses on a kind of “migraine brake” in a woman’s hormonal cycle, was recently published in the scientific journal Nature Reviews.

The team is led by one of the world’s leading migraine researchers, Professor Lars Edvinsson from Lund University.

Edvinsson – one of the four recipients of the Lundbeck Foundation’s 2021 brain research prize, The Brain Prize – is also a professor of clinical pharmacology at the University of Copenhagen.

There are many facets to the theory described by Professor Edvinsson and colleagues in Nature Reviews. Basically, however, it concerns factors linked to the release of CGRP, a natural neurotransmitter that is one of the main villains when it comes to migraine.

CGRP conveys a pain response to the brain, and the protein expands the blood vessels in the meninges – which can provoke a migraine attack.

Over the course of their decades-long research, the four recipients of the 2021 Brain Prize have revealed the details of this link, paving the way for the development of the medical treatment with CGRP inhibitors that, today, benefits many patients with severe, chronic migraine.

‘But we still have a long way to go before we understand the science behind the excess incidence of migraine in women of child-bearing age compared with the incidence in men of the same age,’ says Professor Edvinsson.

This is where the theory about a “migraine brake” in the female hormonal cycle comes in.

And then the storm rolls in!

Migraine follows a fairly set pattern in women of child-bearing age. The wicked headache starts one to two days before menstruation begins – blowing in like a storm. Professor Edvinsson explains:

‘This is when the oestrogen and oxytocin hormones fall to their lowest level in the hormonal cycle – and it is the biochemical signal that heralds the start of menstruation. The question is how we should interpret this hormonal drop in terms of the headache that sets in at this exact time.’

The CGRP neurotransmitter – which sends messages of pain to the brain – is released in the trigeminal nerve, which is located in the trigeminal region of the brain.

This is a sensory nerve that sends impulses to the head and face, and as Lars Edvinsson and his colleagues found a few years ago when they took a closer look at the trigeminal nerve, it differs in one very significant respect from many of the other structures in the brain.

They discovered that the blood vessels in the trigeminal system lack the blood-brain barrier. This barrier keeps most chemical substances out of the brains of humans and other mammals, ensuring a stable biochemical environment within the brain.
Professor Edvinsson explains that if a region of the brain does not have this barrier, substances can pass from the bloodstream into the brain:

‘This means that the oestrogen and oxytocin circulating in a woman’s bloodstream can pass unchecked into the trigeminal system – where specific receptors cause the two hormones to affect the neurons. We were able to detect these oestrogen and oxytocin receptors when we examined the trigeminal region.’

This is the theory recently published by the research team in Nature Reviews, in simple scientific terms:

• We must assume that oestrogen and oxytocin act as a kind of “migraine brake” in women of child-bearing age.
•  When oestrogen and oxytocin levels drop as menstruation approaches, these hormones are no longer able to keep the CGRP neurotransmitter on a tight leash, and this is when migraines occur.

Professor Edvinsson and his colleagues will now test this hypothesis on animals in the laboratory.

‘We will also look at genetic factors that potentially play a role. This is highly complex territory, because – fortunately – not all women of child-bearing age experience migraines in the lead up to menstruation.

‘We hope that the scientific understanding we gain will form the basis for new therapies to help the women who, month after month, are plagued by menstrual migraine,’ says Professor Edvinsson.

The Migraine Specialist

• Lars Edvinsson, born 1947, is one of four researchers sharing The Brain Prize (TBP) 2021.
• The prize, which is awarded by the Lundbeck Foundation, is worth DKK 10 million, making it the largest brain research prize in the world.
• Lars Edvinsson is a Swedish citizen, and graduated as a doctor from Lund University in 1980.
• He has spent over 40 years researching the two areas in which he specialises: migraine and the circulatory system of the brain, particularly in the context of understanding and preventing stroke.
• He is Professor of Internal Medicine at Lund University, Professor of Clinical Pharmacology at the University of Copenhagen, and the founder and director of Glostrup Research Park.
• Lars Edvinsson, along with the three other recipients of the TBP 2021, is being rewarded for many years of research that has led to the development of effective medical treatment for migraine using so-called CGRP inhibitors.
• Throughout his scientific career, Lars Edvinsson has received a number of honours. He is an honorary member of the British Pharmacology Society and the Stroke Council (American Heart Association).
• He has also been president of the International Headache Society.