Migraine affects approximately 3 times as many women as men, with close associations with the various stages of reproduction.1 More than one-half of women with migraine have identified the time around menstruation as a trigger for attacks, with peak incidence typically occurring on the days immediately preceding and after the first day of menstruation.2 A range of research findings have shed light on the relationship between migraine and menstruation.
A population-based study published in 2000 found a significant increase in the risk for migraine without aura during the first 2 days of menstruation (odds ratio [OR], 2.04; 95% CI, 1.49-2.81), and a longer duration of migraine attacks during the 3 to 7 days before menstruation. The lowest migraine risk was observed during ovulation (OR, 0.44; 95% CI, 0.27-0.72).2
A subsequent clinic-based study found a 25% greater risk for migraine in the 5 days before menstruation, and a 71% increase in risk during the 2 days before menstruation (relative risk [RR], 1.71; 95% CI, 1.45-2.01; P <.0001). The highest risk was noted during the first 3 days of menstruation (RR, 2.50; 95% CI, 2.24-2.77; P <.0001).2 Another population-based study also reported that the highest migraine risk occurred during the first 3 days of menstruation (HR 1.96; P <.00001).2
Across multiple studies, women who experience menstrual migraine demonstrated elevated menstruation-related distress and disability.2 Less than 10% of women have pure menstrual migraine, in which there are no attacks during other times of month. Most women impacted by menstrual migraine also experience attacks at other points in time. At least 3 diary cards from consecutive cycles should be reviewed to confirm the diagnosis.2
The Role of Estrogen and Serotonin
“The very existence of pure menstrual migraine … indicates that the fall in serum estradiol values may be the most potent trigger of migraine,” as supported by the results of various studies, according to Anne H. Calhoun, MD, FAHS, partner and cofounder of the Carolina Headache Institute, and professor of both anesthesiology and psychiatry at the University of North Carolina. Estradiol may influence migraine via multiple effects of the central nervous system.3
“Sex steroids, especially estrogens, are responsible for both synthesis and secretion of neuropeptides and neurotransmitters, including serotonin, dopamine, opioid peptides, galanin, and neuropeptide Y. When estrogen levels fall, production of serotonin is reduced,” Dr Calhoun explained in a 2018 paper published in Headache: The Journal of Head and Face Pain.3 The resulting increase in monoamine oxidase activity leads to an accelerated rate of serotonin elimination, and low estrogen also leads to reduced sensitivity of 5-hydroxytryptamine1 receptors, the target of the triptans, as well as reduced endogenous opioid activity.
More research is needed to gain additional insights into the relationship between estrogen and serotonin, as well as its effects on the pathophysiology of menstrual migraine.2 “Ultimately, this clearer understanding of migraine’s response to estrogen will disprove and eliminate the traditional message that [menstrual-related migraine] MRM is historically difﬁcult to treat,” wrote Dr Calhoun.3
To further discuss the topic of menstrual migraine and related treatment recommendations, Neurology Advisor interviewed Dr Calhoun and Kevin Weber, MD, MHA, assistant professor of neurology and a specialist in headache treatment at The Ohio State University Wexner Medical Center in Columbus.
Neurology Advisor: What are some of the key takeaways regarding the relationship between menstruation and migraine?
Dr Calhoun: A drop in estrogen of about 20 μg ethinyl estradiol (EE) or greater will trigger menstrual-related migraine. Most of our oral contraceptives have drops greater than that.
Dr Weber: For many women with migraine, there is a relationship between the menstrual cycle and their migraines. Migraines can spike during ovulation and especially during menstruation. We believe this is due to the fluctuation of estrogen levels. Migraines can also fluctuate around and during pregnancy, and at and after menopause.
It is believed that estrogen fluctuations – especially reductions – can decrease serotonin levels, which in turn can cause the release of substances that play a role in migraine, such as calcitonin gene-related peptide and substance P.
Neurology Advisor: Is it possible to prevent menstrual migraines using progestin-only contraception?
Dr Calhoun: No. Progestin-only contraceptives don’t stop the drop in estrogen. I typically use continuous oral contraception with a 20-μg EE pill … at bedtime. Patients take the active pills only and don’t have periods. They can also do this with any 20 μg EE pill that they like, just active pills only. Certain patients have problems with some progestins, so there are a number of options out there to build your own pill.
Dr Weber: The available evidence is weak for oral contraceptives to prevent migraine. However, there is some evidence that desogestrel 75 μg daily can reduce migraine frequency and severity in women with migraine, although not necessarily limited to around menstruation.4
Neurology Advisor: From your perspective, what are the most important unmet needs in this area?
Dr Calhoun: I think the real need is educating physicians. We have products that work beautifully, but who knows how to use them?
Dr Weber: More studies need to be done on oral contraceptives in menstrual migraine specifically (as most studies involved women taking oral contraceptives for contraception or other medical reasons), and to investigate whether the increased risk for stroke in women with migraine with aura who are taking estrogen-containing oral contraceptives is dose-limited.
1. Gasparini CF, Smith RA, Griffiths LR. Genetic and biochemical changes of the serotonergic system in migraine pathobiology. J Headache Pain. 2017;18(1):1-24.
2. Macgregor EA. Menstrual migraine: therapeutic approaches. Ther Adv Neurol Disord. 2009;2(5):327-36.
3. Calhoun AH. Understanding menstrual migraine. Headache. 2018;58:626-630.
4. Merki-Feld GS, Imthurn B, Langner R, Seifert B, Gantenbein AR. Positive effects of the progestin desogestrel 75 μg on migraine frequency and use of acute medication are sustained over a treatment period of 180 days. J Headache Pain. 2015;16:522.