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Disclosures: Pavlovic reports no relevant financial disclosures.
April 27, 2018
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Managing migraine in women often means managing hormones

Source/Disclosures
Disclosures: Pavlovic reports no relevant financial disclosures.
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Prevalence of migraine among women is about three times that of men, and fluctuations in female sex hormones often play a role in the onset of the condition. Women are particularly vulnerable to migraine during the childbearing years, which are also generally the most active and demanding years of a woman’s life.

“The evolution of migraine in women is related to big hormonal times of change. It picks up at menarche and rapidly increases in incidence and prevalence during the teens, 20s and going into the 30s and 40s,” Jelena Pavlovic, MD, PhD, of the Montefiore Medical Center at Albert Einstein College of Medicine, told Endocrine Today. “In terms of burden, it culminates in the reproductive years, when women need to be the most productive, with young children and jobs.”

Pavlovic talked to Endocrine Today about the mechanisms of hormonal migraine, how the condition is diagnosed, and the different treatments that may benefit patients with these debilitating headaches.

What types of hormonal changes are most likely to cause migraine?

Pavlovic: Hormones affect migraine in women on two different time scales. Migraine is a disorder that manifests around menarche and is most common in the 30s and 40s. The monthly frequency of migraine will worsen during perimenopausal changes; again, it is a time of dramatic hormonal fluctuation. Postmenopausally, migraines generally improve. They are less frequent and sometimes disappear completely.

The other time scale is the monthly time scale. This involves the hormonal change that happens within a month in the menstrual cycle. These attacks tend to cluster and will occur most frequently around perimenstrual hormonal changes. About 60% to 70% of women are thought to have perimenstrual attacks. The International Classification of Headache Disorders has given these the name “menstrually related migraine.” There are two categories of these. In pure menstrual migraine, which affects a very small percentage of women, about 5% to 10%, the woman has attacks exclusively around her period. The window is about 5 days around the onset of bleeding, and generally starts about 2 days prior to the onset of bleeding.

The other diagnosis is menstrually related migraine in which the attacks occur in the 5-day window during menses but can also occur at other times. The diagnosis is common and affects 40% to 70% of women with migraine. This is very gratifying to treat because we can offer these patients medication they can take for a limited period of time. Most young women are hesitant to introduce a daily medication, but it is very easy to convince someone to take a medication every day on just those days, especially if the patient clearly recognizes that she is quite disabled during that time. It is such a small intervention, it is for a limited time, and it makes them feel much better. It’s nice to practice medicine that way.

The catch to this is that menstrually related migraine is often not recognized by those who do not specifically practice in that area of medicine. If you ask women if their migraines occur with their periods, they often may not recognize this because the headache will typically start about 2 to 3 days before the onset of bleeding. The patient might not perceive that as being associated with her period.

Migraine in general is under-recognized in clinicians’ offices and is commonly under-diagnosed. When clinical studies are done, almost anyone who actually has a diagnosis of migraine certainly does have migraine because it’s more difficult to get this diagnosis in general medical offices than it should be. The issue in many studies becomes that people may say they do not have a history of migraine, but they have frequent headaches that are migraines.

How exactly do hormones affect migraine? Which hormones are involved?

Pavlovic: What we typically consider to be the trigger of perimenstrual migraine attacks is withdrawal of estrogen, which is really the decrease in estrogen in the late luteal phase of the menstrual cycle prior to the onset of bleeding. That decrease in estrogen has been observed to precipitate a headache occurrence in those women who do have a history of migraine. It takes a sensitive central nervous system, such as that in a migraine sufferer. We presume that this is genetically predetermined in a very polygenetic, complex way.

Although the field is primarily focused on estrogen withdrawal, this may happen with progesterone decreases as well. This is a subject of research, particularly my current research. For example, my work at the Study of Women's Health Across the Nation (SWAN) has included a particular study of the ovulatory cycle (Pavlovic JM, et al. Neurology. 2016;doi:10.1212/WNL.0000000000002798). This involved women who were in their first or second year of recruitment while still having ovulatory cycles; basically, women in their 40s with ovulatory cycles. We compared the women with migraine to controls. We were not looking at headache, we were just looking at the pattern of their hormonal change during the late luteal phase, from the estrogen peak to drop prior to bleeding over 5 days. We saw that there was a faster rate of decline within women with migraine, but it was stage specific. It was late luteal phase, and it was day specific. With the first 2 days from peak, the rate of estrogen drop was faster in women with migraine than in controls.

From there, we came up with this two-hit hypothesis of migraine triggering around menses, because if you interview women with migraine, it doesn’t occur with every menstruation. Even the diagnostic criteria state that the headaches should occur in at least two of the last three menstrual cycles. Women will not have a reliable menstrual migraine attack with every menstruation. Also, during ovulation, there is a decrease in estrogen that is commonly large, even in absolute value. The magnitude of it is greater than the magnitude of the late luteal drop. So, if it were only estrogen withdrawal, if estrogen was the only mechanism, why wouldn’t the migraines occur at other times of estrogen decrease, such as ovulation? The study we did in SWAN suggests that there is a faster rate of decline only in women with migraine and only in the late luteal phase, not in the periovulatory phase.

This suggests that we need another trigger to come along and tip an already sensitive system over into migraine.

How should hormone-related migraine be treated during the different phases of a woman’s reproductive life?

Pavlovic: The perimenstrual migraines are specifically treated with something called mini-prophylaxis, or mini-prevention therapy. In general, for migraine treatment, patients who have one to two migraine attacks per month can take a medication such as Aleve or Advil, NSAIDs or triptans. If these medications work well enough, that’s it for those patients. For those who have more than about four to five headache attacks per month, we will suggest preventive treatment, which is a daily preventive medication. These might be antidepressants, anticonvulsants or beta-blockers, such as propranolol and nadolol.

Women with premenstrual migraine, even if they have migraine at other times, will be offered mini-prophylaxis during those days, especially if their periods are regular and predictable. Patients are advised to keep a headache diary. A physician can then study the headache diary and identify a clear window of perimenstrual attacks and advise accordingly. Through this mini-preventive treatment, the patient takes daily medication prior to the onset of the attack, but only for these 5 to 7 days. This can be done either with NSAIDs, such as Naprosyn 550 mg twice daily, or with a triptan, such as naratriptan. We like longer-lasting medications, so we can offer coverage for most of the day. Naratriptan is one of the longest-acting triptans. If the patient’s period is due to arrive on Saturday and the headache typically starts on Thursday morning, she can take the first pill on Wednesday night at bedtime and continue that for 5 to 7 days.

Another option is to bridge the estrogen drop with something like a transcutaneous estrogen patch. Lastly, patients can opt to use a 3-month contraception, such as Depo-Provera. One issue with hormonal treatment is that although it works very well for a lot of women, it can actually worsen headaches in others. This is always the risk, and we don’t have a diagnostic screen for this.

Also, the women who typically come to us are usually already in a pickle — the classic is a 24-year-old graduate student who is studying and needs something to get her through it. They come in when they’re having difficulty, and they don’t want to take a risk at that time that it may worsen their headache.

An additional caveat is that estrogen-containing compounds are contraindicated in women who have migraine. There is an absolute contraindication in the WHO and American College of Obstetricians and Gynecologists guidelines. It’s been suggested that this is probably dose-dependent. The American Headache Society recommends that this should probably be decided on a case-by-case basis. However, these situations are challenging. There is a perception, both by practitioners and patients, that hormones are contraindicated or somehow dangerous in migraine, which is untrue. They are generally very safe, with a few caveats. However, this perception adds an extra layer of hurdles for a woman with migraine to actually obtain hormonal treatment.

Are there any other approaches to alleviating hormonal migraine?

Pavlovic: There is increasing evidence that we need multimodality treatments, such as behavioral intervention like biofeedback, cognitive behavioral therapy, relaxation and so on. A lot of non-headache neurologists are under the impression that you just give the patient an effective drug and it’s fixed. This is truly a mind and brain disorder. Although women may be started on appropriate medication therapy, they may also benefit from an integrated approach that includes exercise, relaxation and biofeedback.

Also, new therapies are on the horizon. CGRP antibodies that inhibit calcitonin gene-related peptide are making their way through the FDA and are expected to be on the market in 2019. Neuromodulation therapies, such as vagal nerve stimulation and transcranial stimulation, are also recently emerging treatments for this population. – by Jennifer Byrne

For more information:

Jelena Pavlovic, MD, PhD, can be reached at 1250 Waters Place, Bronx, NY 10461-2720; email: jpavlovi@montefiore.org.

Disclosure: Pavlovic reports no relevant financial disclosures.