How Progesterone May Increase Susceptibility to Migraines

Migraines are pulsating headaches that commonly occur alongside nausea and heightened sensitivity to light, sound and touch. Nearly 30 million people in the US live with migraines, with almost 1 in 4 experiencing at least four serious attacks every month.

Women are affected by migraine headaches three times more often than men. This difference is particularly marked during the reproductive years.

Migraines frequently develop around the menstrual cycle, when reproductive hormones including progesterone and oestrogen fluctuate. Both hormones are at low levels during the perimenstrual phase.

For some people, headaches occur only during menstruation; these are known as menstrual migraines. Such migraines are often more intense and harder to manage than attacks that happen before or after menstruation.

Recurring migraine attacks raise the likelihood of chronic migraines. Poorly controlled migraines may also heighten the risk of headaches caused by medication overuse.

We investigate the ways progesterone controls neuronal function in both health and disease. Over recent years, our work has examined how this hormone and its receptors influence the brain. In recently published mouse research, we found that progesterone could make people who menstruate more vulnerable to migraines.

Progesterone and pain sensitivity

We first examined whether female mice experience changes in pain sensitivity over the course of their reproductive cycle. Female mice undergo recurring hormonal shifts during estrous cycles, which last four to five days.

We tested touch sensitivity by placing fine wires of progressively greater weight against the animals’ hind paws. A mouse indicated discomfort by pulling its paw away.

Mice at the end of the cycle, when reproductive hormone concentrations are low, showed greater pain sensitivity than mice in the middle of the cycle, when these hormone levels are high.

We then assessed whether progesterone itself raises pain sensitivity. To remove hormone changes driven internally, we removed the mice’s ovaries. Because a rise in oestrogen comes before progesterone release during female reproductive cycles, we gave the mice oestrogen followed by either progesterone or saline. Only the animals treated with progesterone developed increased sensitivity to touch; those given saline did not.

Progesterone partly works by activating proteins known as progesterone receptors in the brain, which gradually alter the expression of various genes. It can also rapidly change neuronal activity after being broken down into a molecule called allopregnanolone.

Our findings indicate that progesterone receptors may contribute to progesterone’s gradually developing effect of promoting pain.

After identifying progesterone receptors in neurons that are part of the brain’s migraine pain pathways, we investigated whether these receptors control susceptibility to migraine.

In mice whose brains lacked progesterone receptors, progesterone did not lower the pain threshold. By comparison, pain susceptibility rose when progesterone receptors were activated with a drug designed to target them specifically. Progesterone altered sensitivity to mechanical and cold stimuli, but not to heat or light stimuli.

Lastly, we used nitroglycerin to model migraines. Nitroglycerin causes symptoms resembling those experienced by migraine patients, and many medicines used for migraine treatment also relieve these symptoms in animals. Stimulating the mice’s progesterone receptors made them more susceptible to migraines. Conversely, mice without these receptors were resistant to pain induced by nitroglycerin.

Progesterone receptors and migraine susceptibility

Our research identifies progesterone receptors in the brain as one factor behind women’s susceptibility to migraines. Fluctuations in progesterone levels across the menstrual cycle activate these receptors, potentially triggering migraines.

Potential targets for migraine treatment

The progesterone receptor may therefore offer a possible drug target for preventing or treating migraines. As our team continues exploring how progesterone receptors heighten pain sensitivity, we hope to identify new approaches for treating migraine headaches.

Suchitra Joshi, Research Associate Professor of Neurology, University of Virginia and Jaideep Kapur, Professor of Neuroscience and Neurology, University of Virginia

This article is republished from The Conversation under a Creative Commons licence. Read the original article.