Hormonal Factors in Migraine

Medically reviewed by Bronwyn Jenkins, MD. Last updated 1 July, 2020.

In this article:

  • Why do hormones matter?
  • Menstrually-related migraine
  • Pure menstrual migraine
    • How to identify menstrual migraine
  • Treatment of hormonal migraine
    • Mini prophylaxis or prevention
    • Continuous low-dose estrogen
    • Progestogen
    • Prostaglandins
    • Hysterectomy caution
  • Why menstrual migraine can be difficult
  • High oestrogen states
    • Migraine in pregnancy
    • Perimenopause and menopause
  • Case study of a 39-year-old woman
  • Summary

 


 

Why do hormones matter?

Why do hormones matter? Well, clearly there’s a difference between men and women. The incidence of migraine amongst women is much higher than in the male population.  In the graph below, the red curve represents females and the blue curve represent males.

Migraine prevalence

Overwhelmingly it seems to be the females driving the difference in migraine prevalence, particularly in their menstrual years. Hormonally migraines matter because they are: more frequent, longer lasting, more severe, more likely to relapse, and much harder to treat.

Image reference: Jensen R, Stovner L. Lancet

 

Menstrually-related migraine

Menstrually-related migraine is the most common hormonally related migraines that we see. Menstrually-related migraine is when the estrogen drops, which occurs in the two days before the period starts and then the three days after the period.  Symptomatically, there should be migraines on these days during at least two out of three cycles. It does not have to occur with every period but it has to be more than just chance. Many women are convinced they have a hormonal trigger however if it is happening just as much all the other days of the month, there may not be much success in managing the hormones.

Menstrually-related migraines are worse in just about every way. When we’re discussing migraine and headache, people often don’t even tell their neurologist about their lowest grade headaches. They often mention their “show stopper” migraine attacks. In women, these are often menstrually-related. We need to understand more about the best treatment for these sorts of headaches.

menstrual cycle

The diagram above illustrates what is happening during a menstrual cycle, from producing the follicle, ovulating, and then having the period starting from ovulation.

There are a couple of important fluctuations due mainly to estrogen, but there may be more complex interactions involved that are not yet fully understood too. For example, independent of estrogen, prostaglandins may have a role as well on sensitizing the head. And as we now know, heavy bleeding can lead to a relative iron deficiency.

A1.1.2 Menstrually-related migraine without aura

Diagnostic criteria:

  1. Attacks, in a menstruating woman1, fulfilling criteria for 1.1 Migraine without aura and criterion B below
  2. Occurring on day 1 ± 2 (ie, days −2 to +3)2 of menstruation1 in at least two out of three menstrual cycles, and additionally at other times of the cycle3.

Notes:

  1. For the purposes of ICHD-3, menstruation is considered to be endometrial bleeding resulting either from the normal menstrual cycle or from the withdrawal of exogenous progestogens, as in the use of combined oral contraceptives or cyclical hormone replacement therapy.
  2. The first day of menstruation is day 1 and the preceding day is day −1; there is no day 0.
  3. For research purposes a prospective diary is recommended, but this is not mandatory for clinical diagnosis of A1.1.2 Menstrually-related migraine without aura.

Source: ICHD-3 Criteria

Pure menstrual migraine

Pure menstrual migraine is really rare. It occurs in less than 10%, and may even be lower than 1% of women. By definition, any migraine attacks on other days of the month disqualifies this diagnosis.

A1.1.1 Pure menstrual migraine without aura

Diagnostic criteria:

  1. Attacks, in a menstruating woman1, fulfilling criteria for 1.1 Migraine without aura and criterion B below
  2. Occurring exclusively on day 1 ± 2 (ie, days −2 to +3)2 of menstruation1 in at least two out of three menstrual cycles and at no other times of the cycle3.

Notes:

  1. For the purposes of ICHD-3, menstruation is considered to be endometrial bleeding resulting either from the normal menstrual cycle or from the withdrawal of exogenous progestogens, as in the use of combined oral contraceptives or cyclical hormone replacement therapy.
  2. The first day of menstruation is day 1 and the preceding day is day −1; there is no day 0.
  3. For research purposes a prospective diary is recommended, but this is not mandatory for clinical diagnosis of A1.1.1 Pure menstrual migraine without aura.

Source: ICHD-3 Criteria

How to identify menstrual migraine

The most important tool is your diary. It is not just for the doctor’s conviction, it is also for your own personal knowledge as to what’s relevant and not relevant.

Under- and over-reporting of the role of hormones is very significant. People with migraine really need a diary. A completed diary also helps assess the response to treatment. If you can see a pattern or improvement of ≥ 50% it is easier to determine how effective or ineffective your management is.

headache diary

In the above example, there are frequent attacks in the earlier months which then become less frequent with more headache free days. The menstrually-related migraines seem to be some of the longer lasting and remaining attacks, which could not be determined without a diary noting the days of menstrual bleeding, migraine and responsiveness to treatment.

The things to note in menstrually-related migraine is how predictable, reliable and regular the periods are. If they are all over the place, it is difficult to predict when the estrogen drop is going to occur and thus difficult to treat early or even preemptively.

It is also important to ask about associated symptoms. Are there any perimenstrual symptoms of bloating or period pain? It’s not so much that you are being asked about how bad your pain is, it is  more if you have other uterine symptoms, there could be other factors such as prostaglandins at work. If heavy bleeding is experienced, then you can have a relative iron deficiency later on in the period cycle.

Another factor to consider is whether aura is present or not during an attack. Auras are usually visual but they can be sensory or motor symptoms. They are symptoms that gradually progress usually before or at the start of a migraine and they usually last 20 minutes but they can be shorter or longer.

There are several main considerations when determining how to manage menstrually-related migraine. To begin, it’s important to recognize menstrually-related migraine is the most important subgroup because it’s so severe and common. So what can be done about it?

Treatment of hormonal migraine

1) Mini prophylaxis or prevention

If the periods are regular in their timing related to the period, you can use treatments in a way that we call mini-prophylaxis or mini prevention.

A long acting treatment such as a non-steroidal anti-inflammatory medication Naproxen (once daily) or triptan Naratriptan or Zolmitriptan, can be started on the day before you reliably wake up with an established, untreatable, menstrual migraine, and continued regularly  for the duration of that high risk time.


Starting before the expected onset of menstrual migraine:

Level A evidence (highest)

  • Naratriptan (1mg; Australian dose is 2.5mg) twice a day
  • Zolmitriptan 2.5mg twice a day for 6 days

Level B evidence

  • Naproxen 550mg, twice a day taken for 7-14 days, starting during the week before expected onset of menstruation.

Note: there is a risk of a withdrawal headache on the day after stopping.


As you can see, this means that some people might be using 5 to 7 days of naratriptan, which for anyone who is wanting to avoid medication overuse gets tricky if they have more than 3 other days of migraine the rest of the month as well. It is therefore worth noting that this strategy is for a very specific subgroup with severe menstrual migraine.

2) Continuous low-dose estrogen

The second, and probably the most useful thing to do if there are no contraindications, is to use a continuous low-dose estrogen combination pill to suppress ovarian function and the estrogen changes.

When you take this low-dose estrogen combination pill you can choose the timing of when you have your period. i.e. when you take the sugar pill. This allows you to help navigate through times when you have significant triggers and minimise your vulnerability at important times in your life like your wedding day, or your end of financial year at work.

Over time, you can also gradually skip the sugar pill on subsequent cycles until you are having less periods without breakthrough bleeding. You can get down to 2 to 4 withdrawal periods a year instead of 12. This can greatly reduce the burden and frequency of menstrual migraine if attacks occur with each cycle.

You will need to work with your doctor and monitor your body so that you know how many cycles your body is telling you it needs. If there are too few it can cause breakthrough bleeding, still with headaches. Women need to have some menstruation during their reproductive years but you don’t have to have twelve a year. Suppressing the hormones is not felt to reduce fertility later.

Similarly, even just shortening how long you take the sugar pill can make a difference.  Taking the sugar pill for seven days may not be necessary and possibly only four or five days may be sufficient.  As long as you have had enough menstrual bleeding, you can then reduce those high risk weeks when you are prone to a migraine attack.

Coming back to aura, the reason doctors ask about aura is that there is an increased risk of stroke in migraine with aura that we don’t want to worsen.

risk of stroke

Image Reference: 1) Headache: The Journal of Head and Face Pain, 2013. 2) Calhoun A, Batur P, Cleveland Clinic J Med, 2017


Migraine without aura is not a significant risk for stroke but migraine with aura has a twofold increase in risk without any other factors such as smoking or the combined estrogen containing contraceptive pill.

The frequency of aura may also increase risk – one study showed a fourfold risk if aura was more frequent than once per week and a twofold increase if it is greater than one aura per month.


It is important to identify if you have aura. Some people get a bit of blurred vision before they feel a bit faint at the peak of the pain. This is not aura. Some aura is irregular and it happens in the middle of the headache, but aura is generally a distinct neurological stereotypical event that happens, usually before the headache.

There is an increased risk of stroke in migraine with aura if given an estrogen containing oral contraceptive pill, which is in the order of three fold (3x) of the natural history of migraine with aura. Even though the absolute level of risk is low, it is the opposite of what many of us as clinicians go to work to do each day. My aim in life is not to triple the risk of young women for stroke. It’s to do the opposite and improve health and wellbeing. It is still a very small risk, it’s a tripling of a tiny risk, but it is still an increased risk to the point that most guidelines are aligned and will advise against giving the combined pill to anyone with aura. The latest treatment guidelines are from Europe, and support the previous one from the World Health Organisation. They said that all women with migraine with aura should be on only permanent methods or progestogen containing contraceptives rather than using estrogen supplements. They suggest actively seeking out these patients and switching to non-hormonal contraception.

Whereas in migraine without aura, if there are no additional risk factors, patients can take what they wish.

It is important to note that estrogen may help most people but does not work for everyone and for some people, estrogen may worsen symptoms of migraine. For example, in pregnancy, estrogen can exacerbate headache symptoms. This underscores the importance of tailoring treatment for the individual and working in partnership with your doctor.

3) Progestogen

The third thing that can be done is to use progestogen.  It is not fully understood why progestogen may help or result in changes in estrogen or headache frequency.  T The progestogen only pill has been shown to reduce the number of migraine days, intensity and duration and also the amount of pain killers or triptans that people need. There are certainly some suggestions from pooled analysis of four studies indicating at the very least, more study is warranted.

4) Prostaglandins

The fourth option is targeting the prostaglandins. If there are perimenstrual symptoms like bloating or cramps, then using something targeting the prostaglandins like Naproxen can be effective in helping the triptans be more effective.

During the luteal phase of the menstrual cycle, uterine prostaglandin levels increase threefold with a further increase during the first 48 hours of menstruation.

NSAIDS (non steroidal anti-inflammatories) can affect prostaglandins such as Naproxen in particular. The dose is 550mg twice a day for 7-14 days starting in the week before the expected onset of menstruation according to level B evidence from current treatment guidelines.

Hysterectomy caution

Many patients ask for a hysterectomy (a surgical operation to remove all or part of the uterus) or to just ablate the estrogen fluctuations with a hysterectomy? However, a hysterectomy with or without oophorectomy (removing the ovaries as well) actually increases the risk of migraine.  Generally a hysterectomy is not recommended unless it is required for other gynaecological reasons.

Rarely a medically induced menopause can be suggested. However it needs to be under the care of a very subspecialist gynecologist. There are many important considerations before initiating this procedure because you need to consider bone density, vascular resource and a number of other factors, as well as the potential to worsen symptoms before they improve.

Estrogens are important in a healthy woman’s life and it can be a pretty turbulent road initially if you are medically ablating it too quickly.

Why menstrual migraine can be difficult

Menstrual migraine is one of the most difficult migraine conditions to manage for patients as well as for clinicians. Both require a good diary to understand how relevant it is and how much focus should be put on the hormones. It is often the ongoing small estrogen drops that are targeted but prostaglandin might further sensitize the head so these should also be considered to target.

Using estrogen is not a simple matter and is not always successful. We particularly avoid it in migraine with aura due to the risk of stroke. It requires careful consideration, usually with a headache specialist or a gynecologist with an interest in the area of menstrually related migraine and hormones.

High oestrogen states

Migraines can also increase in other hormonal states, for instance when using IVF,  contraceptives or during pregnancy.

Migraine in pregnancy

The good news is that most people, perhaps around 70%, with migraine during pregnancy improve.

Unfortunately it is typically only in the second and third trimesters (ie ignoring the first 12 weeks). The improvement is more likely in migraine without aura. The migraine attacks with aura ones are the type which may flare up.

If migraine in pregnancy occurs, it is usually experienced in those with menstrual migraine and migraine that began at the onset of their periods.

Some people can get worse during pregnancy. This is important to note because pregnancy is an abnormally high hormone state that clinicians may exclude underlying causes if the headache suddenly shifts into a more sinister headache. It’s important to make sure there’s no high pressure states like clotting, that might be hidden because it is attributed to the pregnancy.

Sometimes an MRI is required during pregnancy, if things are behaving irregularly. The problem with treatment during pregnancy are the medications allowed and what doses are permitted and what to try next if the initial treatment is ineffective.

The guidelines shown below are taken from the updated Australian therapeutic guidelines, which really means that every doctor who has access can provide you with  details of what medications are allowed,  suggested doses and what to move onto next if treatment does not work.

Therapeutic Guidelines

The guidelines recommend few medications during pregnancy.

There is a strong preference for simple strategies such as having days off work, resting or using a cool pack. They now permit the use of an anti nausea tablet (such as metoclopramide).

The first line treatment is paracetamol, which is believed to be one of the safest risk profiles. Codeine can be used if needed, which is very different to our usual outlook on migraine, because we usually try to get everyone off codeine. If you need treatment there is long term experience about its safety however we still have to try and avoid medication overuse with codeine.

The third line treatment is the triptans. The triptans with the most experience over the last 30 years is sumatriptan. Even if you have experience with another type of triptan you are still likely to be referred to going back to sumatriptan.

Other options are common anti-inflammatories that many people rely on such as aspirin, Nurofen, Voltaren or indomethacin. These are only permitted after the first trimester because of danger to the baby if you take it when the neural tube is forming and also before 30 weeks.

If the pregnant patient is really in a dire situation, they may be admitted for hydration, magnesium is felt to be safe, and even a short burst of prednisolone. Fortunately, 70% of people are better in pregnancy and most people will not need to worry about any of that.

If prevention is used and attacks become too frequent and severe during pregnancy then propranolol is a migraine preventive medication with a high level of safety for first line use. Amitriptyline would be considered as a second line if propranolol was not tolerated or effective.

It’s important that you understand the safety risks. This is still very important for the person to have informed consent that they’re happy to proceed, rather than suffering with the headache during pregnancy.

Perimenopause and menopause

Hormones fluctuate significantly during adolescence and for many years around menopause. This fluctuating hormonal state around menopause can go on for five years, maybe even ten years. This time around menopause is referred to as perimenopause. Menopause is just a neat medical term defined as 12 months after your last period. Even if they have been present every six months before that.

Irregular periods suddenly make a predictable treatment with mini-prophylaxis difficult. There is an increased risk of migraine during these years. For most people, migraine will improve during menopause. But not necessarily for everyone.

If there is major sleep disruption from night sweats and other symptoms then an antidepressant with sedative side effects like amitriptyline to have a good solid sleep. Sleep is important for brain health and in migraine management.

Some clinicians may suggest  serotonergic antidepressants (SSRIs). Gabapentin can be used to reduce flushing and related symptoms, as well as migraine frequency/severity. Sometimes you can kill two birds with one stone with multiple symptoms addressed by the one treatment.

Certain treatments that are complementary such as evening primrose oil may also be helpful in this instance.

Hormone replacement therapy can be considered whether or not you have aura. The medically designed variants of hormone replacement therapy are designed to have a more physiological (close to our usual levels) dosing of estrogen rather than having a higher dose like contraceptive pills. It is usually used for more gynecological factors and it has to be carefully balanced alongside personal and family history, especially with any history of breast or ovarian cancers, and those sorts of things.

Case study of a 39-year-old woman

Let’s finish with a case study. This is the story of a 39 year old female. Her migraine attacks started in high school (this is a typical age when the migraine begins). She has had progressively severe attacks, particularly around her period. She has blurred vision with dizziness at the peak of the pain, but does not have loss of vision, sparkling lights or any distinct positive or negative visual symptoms. She is sleeping well and  does not have jaw or neck pain. Being a non caffeine drinker, she does not suffer caffeine withdrawals. She has a normal full diet without deficiencies, has regular, normal periods without any suggestion of premenstrual symptoms and  does not  take any regular medications. Generally she is well and leads a relatively busy working life in two high level roles.

This is what her headache diary looks like.

On these headache days, we underline the days of the menstrual period and we circle the days of any significant headaches. Her headache typically starts the day before, or in this case, two days before. This kind of timeline is spot on for what you’d recognize as menstrually-related migraine.

Now, for this woman, for some reason the headache days go on for quite long. Due to this, her treating physician considered whether her neck was locked up by this stage. It is not clear why her attacks continued for this duration because usually that would have a more classic pattern. After trying prevention medications including topiramate, amitriptyline, and sodium valproate, she experienced side effects and the treatments did not improve her attacks.

The woman found her migraine attacks very difficult to treat and as a consequence she lost time from work and other activities. This was despite trying all five of our available triptans in Australia as well as trying the Naratriptan morning and night.

She then started the low dose continuous oral contraceptive pill. Within three months she was 90% better with just three migraine days each month that would now actually respond to treatment. Over the next two years she was able to reduce the frequency of her menstrual cycles to just three times per year. She can now choose the timing to avoid her busy times at work. She can predict when the headache is starting with the sugar pill, and she can also reduce the number of menstrual exacerbations she has to have each year.

In her case it was really important to make sure she did not have aura as this could have tripled her  risk of stroke. The small amount of blurred vision at the peak of the headache was not specific enough for an aura.

Summary

Migraine as a whole is an important debilitating disorder.  Menstrual and perimenopausal migraine are often more severe and challenging to treat. It is still important to treat other factors, since there is rarely only one trigger for migraine attacks. Further research must advance clinician’s ability to do good whilst doing no harm such as minimizing the risk of stroke. Even regular migraine treatments should be tested with rigor as to whether or not they also help the menstrually related subgroup. Such evidence would certainly benefit this significant group of people living with migraine.

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