How do sex hormones influence migraine?

On the occasion of the Migraine Awareness Week 2019, we’ve invited Dr. Bianca Raffaelli Junior Fellow of the European Federation School of Advanced Studies (EHF-SAS) to tell us about the influence of sex hormones on migraine and her current research project.

Migraine affects women three times more often than men. This sex gap is most pronounced in the age group between 35 and 45 years, where migraine has a prevalence of 25-30% in females but only 8% in males. This results in approximately 500 million women worldwide who are severely impaired in their most productive years because they suffer from migraine. The huge associated health and social burden makes this topic highly relevant and has motivated me to do research in this field.

Menstrual and menstrual-related migraine

Hormonal changes during life stages and the regular menstrual cycle can affect the course of migraine. Read a detailed, systematic review on this topic in The Journal of Headache and Pain that I co-authored as a Junior Fellow of the European Headache Federation School of Advanced Studies (EHF-SAS).

Somerville’s ‘Estrogen withdrawal hypothesis’ [states that] decreasing estrogen levels may trigger migraine attacks.

The first migraine attack in females often occurs at the onset of puberty along with the beginning of cyclic hormonal fluctuations. Women are much more likely to develop migraine attacks during the perimenstrual period and these attacks tend to be severe, long-lasting and difficult to treat. The International Headache Society (IHS) classifies migraine as purely menstrual if migraine attacks occur only between two days before to three days after the onset of menstruation, and as menstrually-related if attacks occur mainly in this period but may also occur at other time points.

Estrogen fluctuations cause migraine through complex genomic and non-genomic mechanisms. According to the (simplified, yet leading) ‘Estrogen withdrawal hypothesis’ by Somerville (1972), decreasing estrogen levels, for example before menstruation, may trigger migraine attacks.

Exogenous hormones: cause or therapeutic option?

The use of oral contraceptives and the occurrence of migraines are closely related.
© terovesalainen

The most common oral contraception in the Western World is combined oral contraceptives (CHC), used for 21 consecutive days followed by a pause of 7 days in order to mimic a normal menstrual cycle. The course of migraine with CHC varies individually, both improvement and worsening are possible. Migraine attacks under CHC occur mostly in the ‘pill-free’ time, consistent with the ‘Estrogen withdrawal hypothesis.’

Following this hypothesis, elimination of cyclic hormonal fluctuations through long-term hormonal therapy has been proposed as possible prophylactic treatment of menstrual migraine. However, the evidence is scarce and contraindications as well as possible side effects must be considered.

Migraine during pregnancy

In a second systematic review published in The Journal of Headache and Pain on behalf of the EHF-SAS, my colleagues and I focused on headache during pregnancy. Migraine improves during pregnancy in up to three quarters of cases, but a new migraine onset is also possible. In a recent retrospective study, I analysed headache characteristics of 151 pregnant women who presented at the Charité, Berlin between 2010 and 2016 with headache as the leading symptom. Approximately 40% of them were diagnosed with migraine, for over half of these patients this was the first migraine episode in life occurring during pregnancy.

A relevant number of women experience migraine recurrence after childbirth, even with increased headache intensity and attack duration, providing further support for the ‘Estrogen withdrawal hypothesis.’

Migraine and endometriosis: outlook on current research

Migraine prevalence is twice as high in women with endometriosis compared to the general (female) population.

Endometriosis is a frequent gynecological disease, in which endometrial-like cells grow outside the uterine cavity. Like migraine, endometriosis episodes are influenced by ovarian hormones. Migraine prevalence is twice as high in women with endometriosis compared to the general (female) population. Comorbid patients report greater headache frequency and intensity and significantly lower quality of life. Calcitonin Gene-Related Peptide (CGRP), a neuropeptide prominently involved in migraine pathophysiology, could play a crucial role in the pathogenesis of endometriosis-related pain. Endometriotic lesions are innervated through CGRP positive nerve fibers and endometrial CGRP levels fall after hormonal treatment.

I am currently conducting a project to assess CGRP levels in peripheral blood in patients with migraine and endometriosis throughout the menstrual cycle. Results are expected in the first quarter of 2020. We are very excited about the outcomes and hope that we will contribute to better understand the mechanisms of migraine- and endometriosis-related pain and the common pathophysiological features of both diseases.


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