Hormonal treatments of menstrual migraine

Timothy C. Hain, MD, Chicago IL. • Page last modified: January 30, 2019 You may also be interested in our many other pages on migraine on this site

It should be noted here that no hormonal treatment regimen has FDA approval for migraine or headache indication. Thus all of the use of these treatments is "off label". MacGregor (2010) reviewed this subject in detail.

The general goal of most hormonal treatments of menstrual migraine is to stabilize estrogen. One method is to avoid or blunt the drop in estrogen around menstruation. Another possible approach, especially to situations where aura predominates, might be to attempt to decrease the overall level of estrogen or to block its receptor, both to reduce aura as well as to reduce the dynamic range of fluctuation.

Some approaches attempt to stabilize estrogen levels in the blood by adding more estrogen. Basically one can provide higher doses of estrogen in an attempt to drown out the normal fluctuation of estrogen with external estrogen, or just provide estrogen during the times when it usually falls (such as prior to menstruation). The large dose of estrogen approach is not done much because high doses of estrogen are generally now avoided due to worry about increasing the risk of blood clots and breast cancer. Also, estrogen can increase aura. Nevertheless, there is a role for clinical judgment in situations where the benefits are large. There are many ways that estrogen can be administered -- basically pills, patches, and implants. See the next section for more comments about providing hormones.

Risks of adding estrogen: The  use of oral contraceptives is generally contraindicated in women with migraine with aura (Allais, Gabellari et al. 2009). The risk of stroke is roughly 2-fold increased (Schurks, Rist et al. 2009). Non-estrogen containing birth control pills can be used safely  in migraine with aura, according to Dodick (Dodick 2009).  In other words, additional estrogen is to be avoided when possible in women with migraine with aura. As aura may be increased by estrogen, this is also another reason to avoid estrogen containing medications.

One can also "shut off" estrogen using a gonadatrophin agonist such as lupron, while also providing a constant amount of external estrogen/progesterone, such as with a transdermal patch. This method just gets rid of the body's cycling of estrogen. More about this is below.

Removing hormonal treatments to treat migraine.

Fertility clinics often use strong medications to manipulate hormones. These are prone to cause headaches. Lupron "cycling" therapy, associated with drastic drops in estrogen, often aggravates migraine, and if practical considering the entire health picture, it should be stopped. Lupron is also used in endometriosis.

Oral hormones:

Birth control pills -- unlikely to work for menstrual migraine.

As estrogen drops trigger migraine, and most birth control pills (OCP) contain 21 days of estrogen and 7 days of a "blank", it follows that birth control pills might reasonably increase migraine. Birth control pills also contain a progestin. Accordingly, in women with migraine that occurs just pre-menstruation, ideally birth control pills that cause estrogen to fluctuate (i.e. with spacers) should be stopped. If hormones cannot be stopped, say because of endometriosis, then they should be changed to a constant amount every day. It often takes 2-3 months for the beneficial effects of hormonal manipulations to take effect.

Our impression is that this strategy is generally not effective, perhaps due to the smaller amounts of estrogen in current birth control pills.

In the 1970s OCPs contained 50 to 100 mcg of ethinyl estradiol, while more recent pills contain 15 to 35 mcg. (Martin et al, 2006). Variant OCP pills include monophasic, triphasic and extended release. Triphasic OCP change the dose of hormone on a weekly basis followed by a placebo. Extended release OCPs contain a fixed dose of hormones for 3 months followed by a placebo week. Progestin-only pills have a fixed dose of progestin for 4 weeks.

Birth control pills modified to reduce frequency of periods

Menstrual periods can also be stopped entirely or reduced in number. As of 2017, the most common method of doing this is to use estrogen containing birth control pills that "omit the spacer" for 2 out of every 3 months. This strategy has roughly the same health risk as estrogen containing birth control pills, but can theoretically reduce hormonal migraines by a factor of 3. As current formulations of birth control pills now contain less estrogen than in the past, this strategy may also be not be entirely effective. There have also been experiments where the spacer was reduced in days (i.e. from 21/7 to 24/4). This seems reasonable enough, but less likely to work.

Calhoun (2004) reported an open trial of an oral contraceptive in 11 women, containing 20 ug ethinyl estradiol on days 1-21, supplemented with 0.9 mg of conjugated equine estrogens on days 22-28. Calhoun reported a 50% reduction in headaches days/cycle, and also stated that migraine could be prevented if "the decline in estradiol is limited to the equivalent of 10 ug". While we are willing to consider this, we are doubtful that this conclusion can be reasonably established from such a small study.

Inducing artificial menopause combined with HRT

A more drastic method of stopping hormonal fluctuations is to combine Leuprolide (Lupron) to stop internal estrogen with HRT to avoid bone loss, eventually followed by oopherectomy. There are reports of excellent responses (Loder et al, 2007). Obviously this is not a rational treatment option if one is hoping to have children. Leuprolide (Lupron) without HRT causes a precipitous drop in estrogen, and would be likely to trigger migraines rather than reduce them. MacGregor et al (2010) commented that gonadotrophin releasing hormone analogs are effective, but can provoke adverse effects of estrogen deficiency, and should be combined with "add-back" combined continuous estrogen and progestogen.

Transdermal hormones:

Use of transdermal preparations: Use of oral estrogen supplements has not generally shown as large a benefit as transdermal gels (Loder et al, 2007). The reason for this is not entirely clear. A trial of 50 ug estrogen patches during the pill-free interval of oral contraceptives was modestly effective (MacGregor and Hackshaw, 2002). This may have been too small a dose. Larger doses of patches seem a bit more successful. Estrogen patches (100 ug) was reported helpful (Pradalia et al, 1994).

Macgregor (2015) suggests using 1.5mg patches starting between days -5 and 02 of menstruation for 7 days (a total of 7 days). A 1.5 mg patch is a relatively large amount. Patches used as replacements for low dose estrogen pills may provide relatively more estrogen causing other risks and side effects.

According to Martin et al (2006), a 100 mcg estradiol patch results in serum estradiol levels of 45-75.

Implants:

Estrogen implants (the most popular IUD is a progesterone device), were reported as very effective by Magios et al. (1983).

It is our impression from our clinical practice that the progesterone containing implants are a "wash" with respect to migraine. Implants, like "ablations", add to the difficulty of diagnosis as it is no longer easy to tell when the woman is cycling (or even if she has any estrogen fluctuations). We think they are a bad idea.

Estrogen blockers:

This approach is a less drastic version of the Lupron/hormone add-back approach discussed above. '

Bromocriptine, a dopamine agonist, inhibits gonadotrophin-releasing hormine and LH, and can reduce peak estradiol levels. Bromocriptine is often used to treat small pituitary adenomas, without much adverse effect. According to MacGregor (2010), 2 studies have suggested efficacy for menstrual migraine. One would think that if dopamine agonists are helpful for menstrual migraine, why would dopamine blockers work for migraine ? Perhaps this is a double-edged sword.

Estrogen blockers such as tamoxifen or danazol are used in clinical situations where there are estrogen sensitive cancers or in men who are attempting to become more muscular. These drugs are occasionally used in migraine in women, particularly menstrual migraine. (Allais et al, 2005; Granella et al, 1997). Presumably the reason that this works is because they lowers the overall effect of estrogen. Although this approach has been discussed for roughly 25 years, it is rarely used. Perhaps combining these agents with estrogen supplements might result in the desired reduction of fluctuations without hot flashes.

Medications used in a special way to prevent MM include:

  • Bromocriptine (see above).
  • Diamox 250 mg: Twice a day, 3-4 days prior to menses. We are dubious. Tingling in the fingers and toes can be a side effect as well as increased urination.
  • Magnesium (360 mg/day) was reported helpful in a small study (Facchinetti et al, 1991), and is generally accepted as useful in migraine in general. More recently, 500-600 mg is recommended. We think this is a good idea. For menstrual migraine, it need only be taken during the last 15 days of the menstrual cycle (i.e. counting day 1 as the last day of bleeding).
  • Nsaids:
    • naproxen (550 mg) can be started on menstruation day -5 and continued for 5 days. This approach obviously runs the risk of some stomach irritation The efficacy of this approach was not impressive. (e.g. see MacGregor et al, 2010).
    • Aspirin or Motrin, use a small dose for 3 days prior to anticipated menses (Sances et al, 1990)
    • mefenamic acid (Ponstel) : (250 every 6 hours, not to exceed one week)
    • We think cox-2 inhibitors might work but we would advise against them because most have been withdrawn from the market due to cardiac risk.
  • Triptans -- most are taken twice or 3 times/day, starting 4 days before the anticipated headache. These were reviewed by Hu et al (2013).
    • Frovatriptan 2.5 mg-- this 24 hour triptan is also used similarly to Amerge. Recently, extremely high pricing has made frovatriptan unaffordable to many. Most protocols involve 6 days of medication, starting 4 days prior to flow. Twice/day treatment is more effective than once/day, but why not just use 5 mg once/day as the drug lasts a very long time. We think this is often a good idea.
    • Naratriptan (Amerge) -- this triptan is sometimes used off-label to prevent menstrual migraine. Safety is not known. Twice/day is the usual frequency.
    • Sumatriptan 25 mg 3 times/day 2-3 days before expected headache and continued for 5 days (Newman et al, 1998). Interestingly, sumatriptan is a generic medication and far less expensive than frovatriptan for most. However, this regimen seems less convenient and also more "up/down" in blood levels than frovatriptan. We think this is a "fall back" for those whose insurance won't cover frovatriptan.
    • Zolmitriptan (2.5mg times/day) also has been studied and is somewhat effective. We see this as similar to sumatriptan.

Abortive medications: These medications are used identically for migraine in general, look here for a discussion. Triptans on a one time basis may not be as durable in women with premenstrual headaches however (Bhambri et al, 2014).

References regarding treatment of menstrual migraine.