MIGRAINE 1522–5720/05 $15.00 + .

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HORMONAL INFLUENCE ON MIGRAINE

Susan L. Hutchinson, MD

Women suffer from migraine headache at a 3:1 ratio to men. This ratio
is not established until puberty. Before puberty, boys and girls experience
migraine at an equal ratio, and some studies indicate that boys have
a higher incidence of migraine than girls before puberty. This established
3:1 ratio of women to men for migraine prevalence after puberty remains
fairly constant until menopause [1]. At menopause, two thirds of women
migraineurs experience a reduction or cessation of their migraines. Given
this prevalence data, it seems that hormones play an important role in
women with migraines. This article explores the hormonal influence on
migraine.
According to the American Migraine Study II from 1999, the annual
prevalence of migraine sufferers in the United States is 28 million
individuals over the age of 12 (21 million female and 7 million male
individuals). Migraine peaks at 25 to 55 years of age. These figures indicate
an approximate 18% annual prevalence for women and a 6% prevalence for
men [2]. However, this 18% of women is based on all women over the age of
12 across all age spans. Further analysis of epidemiologic studies indicates
an annual prevalence as high as 27% among women 30 to 39 years of age
and 26% among women 40 to 49 years of age. By 60+ years of age, the
annual incidence declines to 8% (Fig. 1) [2].
A study looking at the prevalence and characteristics of migraine in
a population-based cohort reported that migraine has affected up to 40.9%
of women by the conclusion of the reproductive years [3]. Migraine is
common among women and especially among women in their child-
bearing years. These are years involving lots of hormonal changes. How
does a woman’s hormonal milieu affect migraine?
A landmark study done by Sommerville [4] in 1972 provided support
for a specific hormonal influence on migraine. He compared the effect on

From the Headache Center, Women’s Medical Group of Irvine, Irvine, California; and the
Department of Family Practice, University of California Irvine, Orange, California

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CLINICS IN FAMILY PRACTICE familypractice.theclinics.com
Volume 7 • Number 3 • September 2005 529
530 HUTCHINSON

FIGURE 1.
Rates of migraine prevalence by age. Although the annual prevalence rate of
migraine is 18% for all women over 12 years of age, this graph shows that
migraines affect women the most during their child-bearing years. ( From
Lipton RB, Stewart WF, Diamond S, et al. Prevalence and burden of migraine in
the United States: data from the American Migraine Study II. Headache
2001;41:646–57; with permission.)

migraine by giving late luteal injections of estradiol in women who had

menstrual-related migraine versus giving late luteal injections of pro-
gesterone. Late luteal injections of estradiol delayed migraine occurrence
but not bleeding. Late luteal injections of progesterone delayed the onset
of bleeding but not migraine. Sommerville postulated that the drop in
estrogen that occurs at menses was an important migraine trigger
(Fig. 2).
Translating Sommerville’s findings to clinical practice, migraine man-
agement in women now includes hormonal strategies. Such strategies are
discussed later in this article. Falls in estrogen occur perimenstrually, with
the postpartum state, during surgical menopause, and when hormone or
contraception is cycled. This is often why many women migraineurs ex-
perience their migraines on the placebo week of their pill pack.
The relationship of changes in estrogen to migraine is only partially
understood. Estrogen is a neuromodulator and can affect receptor density
involving the serotonergic, noradrenergic, and opiatergic systems [5].
When estrogen levels decrease, monoamine oxidase levels increase in the
brain, causing a drop in serotonin level. This serotonin drop causes the
cerebral blood vessels to be more susceptible to biochemical markers,
such as calcitonin gene-related peptide, substance P, prolactin, endoge-
nous endorphins, norepinephrine, and serotonin. These biochemical
markers have been implicated in the migraine process [6–8]. Falling
HORMONAL INFLUENCE ON MIGRAINE 531

FIGURE 2.
Graph from Sommerville’s landmark 1972 study demonstrating the connection
between hormone levels and migraine attacks. (From Sommerville BW. The
role of estrogen withdrawal in the etiology of menstrual migraine. Neurology
1972;22:355–65; with permission.)

estrogen levels decrease the postsynaptic neuronal junctions for serotonin

and endogenous endorphins, priming the brain and causing it to be more
sensitive to pain. Nonmigraine pain is also experienced as more intense
perimenstrually, probably as a result of this decrease in endogenous opioid
activity [9].

PRESENTATION OF MIGRAINE WITH HORMONAL

INFLUENCE

The majority of women with menstrual migraine have migraines at

other times of the month. These are referred to as menstrual-related
migraines. Approximately 60% of female migraineurs have this perimen-
strual exacerbation of their migraine headaches. A much smaller percent-
age of women migraineurs (about 7%–14%) have migraines that occur
exclusively in association with menses, occurring from 2 days before
menses through the first 3 days of the menstrual period. This is referred to
as true menstrual migraine [10].
Menstrual migraine often presents as migraine without aura; however,
many women report their menstrual-related migraine as more severe, more
prolonged, and less responsive to treatment than their other migraines.
532 HUTCHINSON

Studies indicate that menstrually associated migraines respond as well as

nonmenstrually associated migraines to triptan therapy [11,12]. In clinical
practice, many women disagree with this based on their own experience.
Even with a good response to triptan therapy, frustration with treatment
may be a result of headache recurrence due to the more prolonged nature
of menstrual migraine. A higher rate of recurrence after sumatriptan has
been observed in menstrual migraine [13]. The continued drop in estrogen
could explain the more prolonged duration of menstrual associated
migraine (ie, the triptan may relieve the acute headache, but because the
trigger [low estradiol] is still present, the headache may return). Trying to
maintain an even estradiol level may help in reducing the prolonged
duration of menstrually associated migraine. Calhoun [14] reported im-
proved migraine management when using various strategies to maintain
even estradiol levels.

DIAGNOSIS

The diagnosis of menstrual migraine is made by keeping and

reviewing a headache calendar. Tracking the frequency and severity of
the migraine in association with menses or other hormonal conditions is
the key to making the diagnosis. If the female migraine patient has
headaches only at the time of menses (ie, the true menstrual migraine),
then concentrated mini-prophylaxis can be a good approach. In most
cases, a woman experiences migraine from other triggers as well as
menses; such triggers can include stress, lack of sleep, weather change,
preservatives such as MSG and sulfites, bright light, and certain odors. In
this more common presentation, attention to the identification and
prevention of triggers other than hormonal is important in the overall
management of the female migraine sufferer.
There is no blood test or special imaging study to diagnose migraine. If
a woman presents with a disabling headache every month with her menses,
most likely it is menstrual migraine, whether she calls her headache
migraine, tension, sinus, or ‘‘just a headache.’’ If her headache pattern has
been stable for over 6 months and there are no signs of a secondary
headache, then imaging studies are probably not necessary. The history
and review of the headache diary is the key to diagnosis.

SPECIFIC HORMONAL-RELATED MIGRAINES

Menstrual Migraine

Menstrual migraine is defined as a migraine headache that begins from

2 days before a woman’s menses up to 3 days into the menses. Because
there is a predictable pattern to the headache, targeted mini-prophylaxis is
a good option. Acute and preventive approaches can be taken in the
management of menstrual migraine.
HORMONAL INFLUENCE ON MIGRAINE 533

Acute strategies can include:

• Over-the-counter (OTC) analgesics or nonsteroidal anti-inflamma-
tory drugs (NSAIDs)dIf the patient is using these medications,
recommend setting a limit, such as !12 tabs per week during the
week of menstruation to avoid rebound headache. If O12 tabs are
needed, consider preventive therapy.
• Prescription NSAIDS such as naproxen; ibuprofen; ketorolacd
Ketorolac comes in oral and injectable formulations; the 60 mg IM
dose can be useful in the ER setting or if the headache is associated
with significant nausea or vomiting.
• TriptansdIt is okay to dose BID up to 5 days in a row if necessary;
sumatriptan injection 6 mg is especially good for severe menstrual
migraines (those that are rapidly escalating or accompanied by
nausea and vomiting). Sumatriptan 20 mg and zolmitriptan 5 mg
nasal spray formulations are nonoral alternatives to sumatriptan
injection but are not as efficacious and take longer to take effect.
The injection begins taking effect in 10 minutes; the nasal sprays 15
minutes. The sumatriptan injection can be repeated in 1 hour to
a maximum of two injections in 24 hours. Both nasal sprays may be
repeated in 2 hours to a maximum of two sprays in 24 hours. For less
severe migraines, the oral formulations of the seven different
triptans can be used. Sumatriptan, zolmitriptan, and rizatriptan are
as effective in treating menstrual migraine as they are in treating
nonmenstrual migraine [12]. In addition to treating the headache
pain, the triptan class can also control the nausea and vomiting
associated with migraines, including menstrual migraines.
• Triptan/NSAID combinationdAdding an NSAID such as naproxen
500 mg to the triptan treatment can help achieve greater pain-free
results for some women. In addition, the NSAID can help with
associated menstrual cramps.
• DihydroergotaminedDihydroergotamine is an ergot alkaloid and is
not available in an oral formulation. It is available as a nasal spray
and as other nonparental routes of administration, such as IV or IM.
In some women, it may work better than the triptans. Both classes
of drugs are considered ‘‘migraine specific.’’
For all acute treatments, the desired clinical end-point is for the
patient to be headache and symptom free in 2 hours. Other desirable
attributes of acute headache medication include little to no side effects and
a low chance of headache recurrence.

Preventive Treatment
Continuous contraception. Continuous contraception, ideally with
contraceptive formulations containing 35 mg or less of estradiol, can be
effective preventive treatment. Any formulation with 35 mg or less of
estrogen is considered ‘‘low dose.’’ Continuous contraception can be in the
form of the oral birth control pill, the transdermal patch (Ortho Evra), and
534 HUTCHINSON

the vaginal contraceptive ring (Nuvaring). The woman should have the
estrogen/progesterone contraceptive dose delivered every day into her
blood system, thereby maintaining a more even estradiol level, which,
theoretically, can help with menstrual migraine control [15–18]. It is widely
accepted in the OB-GYN community that women do not have to cycle off
and have a withdrawal bleed every 4 weeks. This continuous contraceptive
technique has been in wide use for the treatment of endometriosis. In
addition, the FDA has approved Seasonale, a 35-mg estradiol-containing
oral contraceptive, as an extended contraceptive. For Seasonale, the pill
pack has 12 weeks of active contraceptive hormone and then a placebo for
7 days on week 13. Women taking Seasonale have a period every 13 weeks.
This same concept can be applied to other available contraceptive pills and
to the new nonoral formulations. To be able to convert from cyclical to
continuous contraception, it is advisable to use a monophasic contracep-
tive in which the estrogen and progesterone amounts are the same for the
first 3 weeks of pill pack. This same continuous contraceptive approach to
minimizing menstrual migraine can be applied to the transdermal patch
and the vaginal ring. The traditional cyclical method for the contraceptive
patch is for the woman to wear and change the patch every week and then
on week 4 to not wear a patch and experience a withdrawal bleed. To
convert to continuous method, the woman is instructed to continue to use
the patch every week until she and her health care provider decide to cycle.
Most typically, this is every 3 months; however, some OB-GYN MDs do not
feel it is necessary to cycle off that often in the absence of breakthrough
bleeding. For the vaginal contraceptive ring, the ring is left in place for 4
weeks instead of 3 weeks; the ring is replaced after week 4. These nonoral
contraceptive formulations may provide more steady-state levels of
estradiol and could be an advantage over the oral contraceptives for some
female menstrual migraine sufferers. In addition, they are especially suited
for women who often forget to take their oral pill and thereby run the risk
of breakthrough bleeding and migraine headache due to the drop in
hormone levels. More research needs to be done in this area exploring the
relationship of continuous contraception and menstrual migraine control.
However, clinical experience indicates that it is a good approach to taking
in preventing menstrual migraine.
Estradiol. Estradiol can be effective as migraine prevention if it is
taken the week of the placebo if the patient is on contraception or the week
of menses if the patient is not on contraception. Transdermal estradiol
0.1 mg is the recommended dose. The concept behind the supplemental
estradiol is to prevent the drop in estradiol that occurs at the time of
menses.
Continuous transdermal estradiol patch in the symptomatic
perimenopausal women. This patch is a form of estrogen replacement
therapy (ERT). It contains no progesterone and does not provide
contraception protection. It can be useful in female migraine patients
who have vasomotor symptoms, such as hot flashes and night sweats, and
in patients who often experience an exacerbation of headaches and mood
disorders due to the hormonal fluctuation characteristic of perimenopause.
HORMONAL INFLUENCE ON MIGRAINE 535

ERT does not stop ovulation; therefore, the woman experiences hormonal
fluctuation from her ovaries.
NSAIDs. Beginning an OTC or prescription NSAID such as naproxen
or ibuprofen several days before the menses and the expected menstrual
migraine and continuing the NSAID several days into menses can be a cost-
effective method of menstrual migraine prevention. However, for many
women, NSAIDs do not provide sufficient protection, and these patients
may still experience menstrual migraine.
Long-acting tripans. Long-acting tripans, such as naratriptan (1 mg
or 2.5 mg) or frovatriptan (2.5 mg), dosed daily for 3 to 5 days in a row
during the vulnerable menstrual migraine time frame can be effective as
migraine prevention. Frovatriptan has a longer half-life than naratriptan
and can be dosed as 2.5 mg once daily or 2.5 mg twice daily. In a study
looking at frovatriptan for menstrual migraine prophylaxis, patients were
randomized to frovatriptan 2.5 mg QD, frovatriptan 2.5 mg BID, or placebo
for 6 days perimenstrually. Frovatriptan 2.5 mg once daily and frovatriptan
2.5 mg twice daily were superior to placebo in reducing the frequency,
severity, and impairment of the menstrually associated migraine [18]. For
naratriptan, the recommended dosage is 2.5 mg taken as one half tablet
twice a day for 3 to 5 days. Studies on naratriptan showed good
effectiveness with the 1 mg and with 2.5 mg [19]; therefore, it is econom-
ical to have the female migraineur break the 2.5 mg tablet in half when
taking naratriptan for menstrual migraine prevention.
Shorter-acting oral triptans. Shorter-acting oral triptans, such as
sumatriptan 50 to 100 mg, rizatriptan 5 to 10 mg, zomitriptan 2.5 to 5 mg,
almotriptan 6.25 to 12.5 mg, or eletriptan 20 to 40 mg, can be effective as
treatment for menstrual migraine prevention. For most women, the higher
oral dose of tripan is more likely to render them headache free. If the
medication is taken early, there is little difference in side effects.
Therefore, to start with the highest available dose of the oral triptan is
preferable in the treatment of menstrual migraine for most women. All oral
triptans can be redosed in 2 hours to a maximum of 200 mg daily for
sumatriptan, 30 mg daily for rizatriptan, 10 mg daily for zolmitriptan, 25 mg
daily for almotriptan, and 80 mg daily for eletriptan.
Progesterone-only oral contraceptives. Progesterone-only oral
contraceptive can be effective in women who are sensitive to estrogen and
for whom the previously described methods are ineffective for menstrual
migraine. It is best to avoid Depo-Provera in women migraineurs because it
may cause headache as a side-effect that could last 3 months due to the
3-month duration of action of Depo-Provera.
GnRH agonist. A GnRH agonist (Depo-Lupron) given IM should be
used for refractory cases only. It suppresses ovarian hormone production.
This treatment causes medication-induced menopause; therefore, the
question of increasing risk of osteoporosis and giving add-back estrogen
needs to be addressed.
In most cases, a combination of acute and preventive treatment is
ideal. If the female migraine patient has no or few headaches other than
with her menses, then targeted mini-prophylaxis is an option. In some
536 HUTCHINSON

cases, a patient may be on a prophylactic headache medication but still

experiencing breakthrough migraine at the time of her menses. Increasing
the dose of the prophylactic treatment around the time of menses may be
helpful. Medications such as a tricyclic antidepressant or a selective
serotonin reuptake inhibitor (SSRI) can be increased around the time of
menses to achieve better headache control.
In rare cases, estrogen can aggravate migraines in a female patient. In
these cases, it may be necessary to stop any estrogen and consider, for
example, the progesterone-only pill. Anytime hormones are prescribed or
the hormonal regimen or dose is changed, close attention to any change in
headache is warranted. The best way to track any change in headache
pattern is by having the patient keep a headache diary and report to you
any worsening of her headache after hormone treatment is instituted.
Occasionally, a woman may develop new-onset aura or worsening of her
headache on contraception. In these cases, stop the hormone and watch
for improvement in the headache pattern. In some cases, imaging and other
evaluations to rule out a secondary headache may be necessary.
The safety of prescribing hormones and contraception is often a topic
of concern for practicing clinicians. Migraine patients younger than 45
years of age have a slightly higher risk of stroke than the general
population. There is no increased risk of stroke in female migraine patients
over 45 years of age compared with the general population over 45 years
of age [20]. For the majority of female migraineurs, hormones and
contraception are not contraindicated. If the female patient has migraine
without aura, her risk of stroke is less than if she has migraine with aura.
Her risk increases with the use of contraception. The greatest risk of stroke
is if the patient, in addition to having migraines, smokes and has other
cardiac risk factors (Table 1).
There is ongoing debate and lack of consensus among headache
experts on whether it is safe for a female patient who has migraine with
aura to go on contraception. Most female migraine patients have migraine
without aura, which carries a smaller risk of stroke (Table 1) [20]. Many
headache clinicians allow a female patient who has migraine with aura to
go on contraception if the aura is predictable and uncomplicated. A more
dense aura, any worsening of aura, or new-onset aura while the patient is
on contraception necessitate a cessation of contraception. These at-risk
patients should, in most cases, be placed on aspirin. Some headache
experts also suggest using vitamin B2 (riboflavin) daily.

PREGNANCY AND MIGRAINES

According to epidemiologic data, most female migraine patients

report improvement in their migraines, especially by the second and third
trimesters [20]. Such improvement is considered to be secondary to the
sustained high levels of estradiol that occur during the second and third
trimester. However, some women experience their first migraine during
pregnancy [21]. Also, many women experience migraine headaches the
HORMONAL INFLUENCE ON MIGRAINE 537

TABLE 1.
Comparison of Odds Ratios and Risk Factors for Stroke

Risk Factor Odds Ratio

Migraine 3
Migraine with aura 6
Migraine plus OCs 5–17
Migraine and OCs 34
and smoking

Note: Look for risk factors such as smoking, hypertension, and migraine with dense aura to
determine if OCPs are appropriate.
Abbreviations: OC, oral contraceptive; OCP, oral contraceptive pill.

first trimester; often, some may not even know they are pregnant early in
the first trimester. Therefore, the choice of acute and prophylactic
medication is important in the child-bearing years for female migraine
sufferers.
Most OB-GYN providers prefer no medication treatment during
pregnancy and often recommend nonpharmacologic measures. These
nonpharmacologic measures may include biofeedback; acupuncture;
physical therapy; hot/cold packs; massage; relaxation exercises; regular
sleep; avoidance of caffeine, alcohol, and nicotine; and regular meals.
Nonpharmacologic treatment may not be enough for most pregnant
migraine patients. When medication is needed, most OB-GYNs recommend
Tylenol (category B), Tylenol with codeine (category C), Vicodin (category
C), metoclopramide (category B), and NSAIDs. Most OB-GYNs do not
recommend NSAIDs during the first trimester due to organogenesis (most
OB-GYNs prefer no NSAIDS at any time during pregnancy). No NSAIDs
should be taken after week 32 to prevent premature closure of the patent
ductus arteriosus.
Metoclopramide (Reglan) is an anti-dopaminergic agent and can exert
anti-migraine action in addition to relief of the nausea and vomiting that
may be associated with migraine. It may be useful to try 5 to 10 mg
metoclopramide slow IVP in a pregnant woman with a severe migraine.
This can be done in an emergency room setting or in the doctor’s office.
The class of triptans is category C for pregnancy. Category C indicates
that the risk of the medication has to be weighed against the benefit for the
female pregnant patient. All the triptan manufacturers have a Pregnancy
Registry. The combined Sumatriptan and Naratriptan Pregnancy Registry is
the largest to date. A review of the International Interim Report covering the
period of January 1, 1996 through April 30, 2004 reveals the following [22]:
• A total of 449 pregnancy exposures to sumatriptan or naratriptan
• The proportion of pregnancies with birth defects after earliest
exposure in the first trimester is 4.3%; the proportion with birth
defects with any trimester of exposure is 4.5%.
538 HUTCHINSON

• Registry findings do not suggest a greater proportion of birth defects

among these prospectively reported pregnancies when compared
with that expected in the general population of pregnant women.
There is no consistent pattern of defects among the birth defects
reported to the Registry.
In conclusion, there is no evidence suggesting teratogenicity
associated with sumatriptan or naratriptan use; however, sample size is
insufficient to lead to definitive conclusions regarding such risk [22].
The pregnancy registries for the other triptan manufacturers show no
increased risk; the numbers in the other registries are smaller than the
Sumatriptan/Naratriptan Pregnancy Registry. It is important to report
pregnancy exposures to the respective registries. The phone numbers are
as follows:
• GlaxoSmithKline (sumatriptan/naratriptan) 800-336-2176
• Merck (rizatriptan) 800-986-8999
• Astra-Zeneca (zomitriptan) 302-886-8494
• OrthoMcNeil (almotriptan) 800-682-6532
• Pfizer (eletriptan) 800-438-1985
• Endo (frovatriptan) 800-462-3636

Migraine Prophylaxis in Pregnancy

As with acute pharmacologic treatment, it is preferable for the female

pregnant patient not to take medication unless absolutely necessary. If the
female pregnant patient is experiencing frequent or severe migraines, then
medication may be necessary. The following categories may be used:
• Beta blockers, such as propanolol and timolol (category C)
• SSRIs, such as fluoxetine, sertraline, and paroxetine (category C)
• Bupropion (category B)
• Gabapentin or topiramate (category C)
Many pregnant women have relief of their migraines by the second
trimester; therefore, it is recommended that a trial taper-off of a preventive
headache medication be done during the second trimester.

Lactation and Migraines

For many pregnant women, there is marked improvement in their

migraine headaches during the second and third trimesters, in part due to
the sustained high levels of estradiol. For many migraine sufferers, their
migraines return soon after delivery due to the precipitous drop in
estrogen. For postpartum migraineurs who want to breastfeed, the issue of
safety arises. Which medications are safest for the breastfeeding woman
who needs acute migraine medication? Prescription and OTC NSAIDs are
considered safe; however, they may not provide sufficient relief. Triptans
HORMONAL INFLUENCE ON MIGRAINE 539

are classified by the American Academy of Pediatrics (AAP) as ‘‘use with

caution.’’ For many postpartum women, a triptan was the drug of first
choice before pregnancy and lactation. The commonly accepted practice
has been to allow the female migraine patient to take her normal triptan
but to then discard her breast milk for the next 6 to 8 hours. The AAP
recently concluded that sumatriptan is compatible with breastfeeding;
therefore, it seems that it is no longer necessary to pump and discard the
breast milk if sumatriptan is used [23].
Some women suffer postpartum depression and migraines. Supple-
mental transdermal estrogen may be helpful in the treatment of both
conditions during the postpartum period. Providing supplemental estrogen
can help treat the precipitous drop in estrogen that occurs after delivery;
a more even level of estradiol may help both conditions. The transdermal
route may be preferable to the oral route because it provides a more steady
level of estradiol. For women who require a preventive agent during the
postpartum period because of the severity or frequency of her migraine
attacks, beta-blockers and SSRIs are often used. Most migraine patients
who want to breastfeed are able to do so with appropriate and effective
treatment. Therefore, migraine treatment and breastfeeding are compat-
ible for the majority of female migraineurs.

Perimenopause and Migraine

Perimenopause is characterized as a time of ‘‘change’’ in which

hormones, including estradiol and progesterone, fluctuate widely. The age
of onset of perimenopause varies but typically begins around the 47 years
of age and lasts for approximately 4 years until menopause, at which time
the ovaries no longer function. For many women, this time of hormonal
fluctuation is characterized by troublesome vasomotor symptoms, such as
hot flashes and night sweats, exacerbation of her migraine headaches, and
often the onset or exacerbation of mood disorders such as depression or
anxiety. Hormone blood test results are difficult to interpret because the
levels fluctuate widely, even in a given day. Menses are often unpredict-
able, further complicating migraine treatment, including mini-prophylaxis
regimens. Successful mini-prophylaxis of menstrual migraines requires
a predictable menstrual pattern that is often absent in the perimenopausal
woman.
Clinically, some women in this ‘‘change before the change’’ (which
perimenopause is often referred to) may benefit from low-dose supple-
mental estrogen. Estrogen can be given in an oral form, as a transdermal
patch, or as a topical gel or cream. If the woman does not need
contraception, then the estrogen would be a form of hormone replacement
therapy (HRT) and, as such, would not suppress ovarian function. In this
case, the woman’s ovaries would still create hormonal fluctuation;
however, the low-dose supplemental estradiol can often help the
vasomotor symptoms, including disrupted sleep, which may be exacerbat-
ing migraine control. In addition, the supplemental estrogen may help with
540 HUTCHINSON

migraine control and with mood disorders. The patient should be instructed
to keep a headache diary and to watch for any change in headache pattern
as the HRT is instituted. A non-oral route, such as the transdermal patch,
may provide a more steady level of estradiol than the oral route.
Transdermal estradiol is available in a patch as low as 0.014 mg/d of
estradiol. In most cases, the initial dose should be low; then the medication
should be titrated to the therapeutic dose as the headache pattern is
watched. If the woman is still having menses, then progesterone is usually
not needed, but that decision should be made by the treating gynecologist. If
the perimenopausal female migraine patient needs contraception, then
a low-dose monophasic form of birth control can be instituted if she is
a nonsmoker and is felt to be a good candidate for contraception.
Because of the exacerbation of migraine attacks that many perime-
nopausal women experience, preventive medication may be needed. If
appropriate intervention is not taken to prevent the frequent headache
pattern that many women in perimenopause experience, then trans-
formation from episodic migraine to chronic daily headache may be the
result. In this age group, there can be an increase in depression, in part due
to the hormonal fluctuations. Attention to the frequent comorbidity of
depression and migraine in this population can help in overall management
of this population of female migraineurs. Understanding that hormonal
fluctuation can aggravate migraine control can help in treating this
population of women.

Menopause and Migraine

Menopause is often defined as no menses for 1 year or by a follicle

stimulating hormone (FSH) level O30. Normal ranges for blood tests can
vary among laboratories, but, in general, an elevated FSH with a low
estradiol characterizes the menopausal state. For many menopausal
women, migraine headaches improve or go away. For others, there can
be a change in their migraines, such as experiencing migraine equivalents
(the aura without the headache). In menopause, the ovaries no longer
produce estrogen or progesterone; this can dramatically help a woman
who had migraines aggravated by hormonal fluctuation before menopause.
Many menopausal migraine patients want to go on HRT to help
alleviate moderate to severe vasomotor symptoms, such as hot flashes,
night sweats, and insomnia. Patients may be concerned that the HRT will
aggravate their migraines. In these patients, it is recommended to start on
a low dose of HRT and titrate up carefully to achieve relief of menopausal
symptoms while watching any change in headache pattern. Often, HRT
does not aggravate migraine headaches. The transdermal estradiol patch
and topical estrogen may be less likely to aggravate headaches [24,25]. In
women who need estrogen and progesterone, use both drugs daily.
Otherwise, when the estrogen is stopped, migraine may occur. The patient
should be instructed to watch any change in headache pattern as HRT is
instituted.
HORMONAL INFLUENCE ON MIGRAINE 541

If a woman requiring estrogen replacement therapy develops an

increase in her headaches, there are several empirical strategies that may
be used, including reducing the dose of estrogen or changing from
a conjugated estrogen to pure estradiol, to synthetic ethinyl estradiol, or to
a pure estrone [26]. Migraineurs have sensitive nervous systems and
benefit from the most pure medications, especially with hormonal therapy.
Avoidance of drugs like conjugated estrogen, which is likely to trigger
migraine, seems prudent.
If a menopausal migraine patient has a uterus, then progesterone is
necessary in addition to estrogen to prevent uterine cancer. Some non-oral
forms of HRT, such as the transdermal patch, have progesterone with
estradiol in the same patch. Some menopausal women cannot tolerate
supplemental estrogen; in these women, even low doses may exacerbate
migraine, and non-estrogen products may be needed to treat vasomotor
symptoms.
Acute migraine treatment in the menopausal woman can include the
triptan class in most cases. Attention to cardiac risk factors becomes
especially important in this population of migraine sufferers to ensure that
the triptan class of medication is safe. An alternative could be a NSAID
such as naproxen if triptans are contraindicated.
Migraine prevention in the menopausal woman should take into
account coexisting conditions such as hypertension, fibromyalgia, de-
pression, and insomnia. Choosing a preventive medication that can treat
more than one condition is desirable because this population of aging
women is often on multiple medications.

RED FLAGS IN THE FEMALE MIGRAINEUR

• New-onset aura in a patient who previously only experienced
migraine without aura
• A change or worsening in the pattern of the headache
• Complex or dense aura
• New-onset migraine O50 years of age (it is rare to have migraines
develop as a new condition over the age of 50)
In addition to the red flags listed above, look for temporal arteritis in
the female menopausal patient presenting with headache. Be on alert for
secondary headache, even in established migraine patients. Keep in mind
that migraine patients can also develop a secondary headache. If there is
suspicion of a secondary headache, consider imaging studies or referral to
a headache specialist.

SUMMARY

Hormones play a role in 60% to 70% of female migraineurs who report

exacerbation of migraine headaches perimenstrually. For many of these
women, exacerbation of migraines can occur at other times of hormonal
change, such as pregnancy, postpartum, and perimenopause. Attention to
542 HUTCHINSON

a woman’s hormonal status can help in the management of the female

migraine patient.
More research is needed to provide evidence-based medicine for
much of what we do clinically for our female migraine patients. In the
meantime, trying to maintain an even estradiol level can help in many
women with hormonally related migraine headaches. Understanding that
hormones influence migraine headaches can help the health-care provider
and patient achieve optimal headache management.

Key Points
• Identifying times of hormonal change in the female migraine patient is
important.
• Correlating hormonal changes with a woman’s migraine headache pattern
can help in determining if there is a hormonal connection for that particular
female patient. The best way to do this is for the female migraine patient to
keep a headache diary.
• Consider strategies to minimize hormonal fluctuation, especially estrogen;
this may help prevent hormonally related migraines.
• Targeted mini-prophylaxis is a good treatment option for menstrual
migraine.
• For most female migraineurs, contraception and HRT are not contra-
indicated.

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Address reprint requests to

Susan L. Hutchinson, MD
Headache Center, Women’s Medical Group of Irvine
16300 Sand Canyon Avenue, Ste 311
Irvine, CA 92618

e-mail: wbfpd@cox.net