Review

Menstrual migraine: a review

of hormonal causes, prophylaxis
and treatment
1. Introduction Avi Ashkenazi† & Stephen Silberstein
2. Definitions Thomas Jefferson University Hospital, Department of Neurology, Philadelphia, PA, USA
3. Epidemiology
Migraine in some women is associated with changes in sex hormone levels.
4. Pathogenesis Many women suffer from increased frequency of migraine around the
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5. Management time of menses. Menstrual migraine (MM) may be more severe than
6. Expert opinion migraine that occurs at other times of the cycle. The pathogenesis of MM
is probably related to declining estrogen levels after exposure to high levels
of the hormone for several days. The acute treatment of MM is similar to
that of non-menstrually-related attacks. 5-HT1B/1D agonists (triptans), ergots,
NSAIDs, or combination analgesics may be used, although the response to
some drugs may not be as robust as that of non-menstrual attacks. Women
who suffer from frequent or debilitating MM attacks may benefit from
perimenstrual prophylaxis that can be either hormonal or non-hormonal.

Keywords: estrogen, menstrual migraine, prophylaxis, triptans

Expert Opin. Pharmachother. (2007) 8(11):1605-1613

For personal use only.

1. Intoduction

Migraine is a neurovascular disorder characterized by attacks of headache,

autonomic nervous system dysfunction and gastrointestinal symptoms [1]. Some
migraine patients experience an aura, typically manifesting as visual scotomas or
scintillations that precede the headache and last < 60 min. Less commonly, aura
symptoms may include transient tingling/numbness or dysphasia. Migraine is
a common disorder, with a prevalence of ∼ 12% in the adult population [2].
The prevalence of migraine peaks after 4 – 5 decades of life, when patients are
at their highest productivity [3]. The disease may have a significant impact on the
quality of life of the individual.
Epidemiologic data suggest a link between migraine and the female sex
hormones [4,5]. Before puberty, migraine prevalence is similar in boys and girls [6].
However, in adults migraine prevalence is three-times higher in women compared
with men (18% versus 6%). The peak incidence of migraine in women occurs at
adolescence [7]. Migraine prevalence decreases in women after the menopause,
although it remains higher than that of men [3].
Changes in headache pattern in women are probably related to changes in
estrogen levels [5]. Estrogen has diverse effects on brain function [8]. Estrogen
receptor-α (ER-α) is found mainly in the hypothalamus, whereas ER-β is more widely
distributed throughout the brain [9]. Hypothalamic endorphin levels correlate with
estradiol levels, suggesting a role for estrogen in the processing of pain perception [10].
In many women, migraine attacks are more frequent in the perimenstrual period,
and in some they occur exclusively during this time [11,12]. Migraine attacks
also appear to be more severe and less responsive to treatment compared with non
menstrually-related attacks [13].
In this review the epidemiology and pathogenesis of menstrual migraine (MM)
is discussed. Recent advances in the preventive and acute treatment of the disease
are also described.

10.1517/14656566.8.11.1605 © 2007 Informa UK Ltd ISSN 1465-6566 1605

 Menstrual migraine: a review of hormonal causes, prophylaxis and treatment
2. Definitions
The International Headache Society (IHS) defines pure
menstrual migraine (PMM) as migraine attacks that occur
exclusively between days -2 and +3 of the menstrual cycle
(where day 1 is the first day of menstruation) in at least two
out of three menstrual cycles [14]. Menstrually-related migraine
(MRM) is defined by the IHS as migraine attacks that occur at
the same time period as PMM in at least two out of three
menstrual cycles and additionally may occur at other times of
the cycle. The IHS classification emphasizes that MM attacks
are of migraine without aura (MO), since attacks of migraine
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with aura (MA) do not seem to be related to menstruation.
These definitions are included in the appendix of the IHS
classification of headache disorders, meaning that more
scientific evidence is needed before they are formally accepted
as clinical entities.
3. Epidemiology
When referring to the days of menstrual cycle in this
discussion, day 1 is defined as the first day of menstruation.
An increased risk of having a migraine attack (without aura)
during the perimenstrual period has been shown in several
For personal use only.
studies [11,15-18]. However, these results need to be taken with
reservation: first, the definition of MM was not the same in
all studies; second, some of these studies were clinic-based,
causing a potential selection bias for patients with more severe
and disabling migraine compared with the general migraine
patient population.
MacGregor et al. studied the prevalence of MM in a
clinic-based study that included 55 women [15]. MM was
defined as migraine that occurs regularly on or between days
-2 and +3 of the menstrual cycle and at no other time.
The prevalence of MM in this study was 7.2% (all had MO).
A further 34% of women had an increased frequency of attacks
during the perimenstrual period. In another clinic-based study
that included 155 women, migraine was found to be 1.7-times
more likely to occur during the 2 days before menstruation
and 2.5-times more likely to occur during the first 3 days of
menstruation, compared with other days of the cycle [12].
Cupini et al. examined the association between sex-hormones
related events and the occurrence of both MA and MO in
268 women attending a headache clinic [16]. The prevalence of
MM and of MRM (defined as in the above study [15]) in
women with MO was 13.6 and 56.4%, respectively. In women
with MA, the corresponding figures were significantly lower
(3.8 and 33.3%). In another study, 20 women completed a
3-month diary of migraine and menstrual periods [17]. Of
these, 15% had MM and another 15% had MRM. All women
in both the MM and MRM groups had MO. Johannes et al.
investigated the relationship between headache occurrence and
phases of the menstrual cycle in a population-based study of
74 women [18]. The risk of having an attack of MO was elevated
during the first 3 days of menstruation (odds ratio (OR): 1.66).
1606 Expert Opin. Pharmacother. (2007) 8(11)
The risk of an MA attack was also elevated during this period,
but not significantly so. Headaches were not more frequent
during the premenstrual period or around ovulation. In
another population-based study of 81 women with migraine,
Stewart et al. found an increased risk of headache in the
perimenstrual period for MO (OR: 2.04), and for tension-type
headache (OR: 1.67) but not for MA [11]. The highest risk
was observed in the first 2 days of menses.
In a large population-based study from the Netherlands,
the prevalence of MM and MRM was assessed in a sample of
1181 women [19]. The authors found that 8% of women had
MRM and 3% had PMM, as defined by the IHS. These
figures are lower than the ones reported in clinic-based
studies, possibly due to selection bias in the latter. Recently,
MacGregor et al. studied the occurrence of migraine in
different phases of the menstrual cycle in 40 women with
MO [20]. Migraine attacks were most likely to occur on
the first day of menstruation and on the day preceding it.
Ovulation was not associated with increased risk of having
a migraine attack.
Based on these data, it appears that migraine (without aura)
is more frequent during the perimenstrual period. Pure
menstrual migraine, as defined by the IHS, is relatively
uncommon, with a prevalence of 3% in one population-based
study and 7 – 15% in clinic-based studies.
4. Pathogenesis
The pathogenesis of MM is probably related to declining
estrogen levels after exposure to high levels of the hormone
for several days [20-22]. Estrogen, given premenstrually, delays
the onset of migraine but not of menstruation [21,22]. In a
study of 38 women with MO, migraine attack frequency and
urinary levels of estrone-3-glucuronide and pregnanediol-
3-glucuronide, metabolites of estradiol and progesterone,
respectively, were recorded over three menstrual cycles.
Migraine attacks were most likely to occur during the late
luteal and early follicular phases, when estrogen levels were
falling or low, and least likely to occur when estrogen levels
were rising [20].
Estrogen and progesterone modulate receptor density and
neuronal activity of both serotonergic and opioid neurons in
the CNS [23,24]. The estrogen-sensitive changes in central opioid
tone in women with MM may relate to headache genesis.
In an immunocytochemical study, ER-α was demonstrated in
female rat trigeminal ganglia neurons in vitro [25]. Moreover,
estrogen was shown in this study to alter the expression of genes
coding for proteins that may be involved in inflammatory
pain (e.g., extracellular signal-regulated protein kinase).
In another animal study, mRNA levels of tryptophan
hydroxylase, the rate-limiting enzyme in serotonin synthesis,
were found to be more than twice as high during the proestrus
(the high estrogen phase of the cycle) compared with the
diestrus (the low estrogen phase) [26]. Thus, cyclical changes in
serotonin levels in trigeminal ganglia, which are associated

with changes in estrogen levels, may contribute to the
pathogenesis of MM.
Prostaglandins (PGs), produced by the endometrium in
response to estrogen and progesterone, sensitize nociceptors,
promote neurogenic inflammation and cause uterine contrac-
tions, resulting in dysmenorrhea [27]. There is a high prevalence
of premenstrual syndrome (PMS) in women with MM.
Facchinetti et al. found that 64% of women with MM suffered
from PMS (compared with 33% of those with non menstrually-
related migraine) [28]. Prostoglandin E2 levels are increased
in women with MM during acute attack, supporting the
above epidemiologic data [29].
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5. Management
The management of MM includes pharmacologic treatment
for the acute attacks and, in some women, perimenstrual
prophylaxis in an attempt to decrease the frequency and
severity of attacks [5]. Perimenstrual prophylaxis may also
enhance the efficacy of acute migraine drugs. Hormonal
treatments are occasionally used to alter the duration of the
menstrual cycle, or to eliminate it altogether, thereby decreasing
MM frequency.
It has long been suggested that MM attacks are more severe
For personal use only.
and disabling compared with non-menstrually related attacks.
Recent evidence supports this notion. Granella et al. enrolled
64 women with MRM in a 2-month prospective clinic-based
diary study. Perimenstrual attacks were significantly longer,
caused greater work-related disability and were less responsive
to acute treatment compared with non-menstrual attacks [13].
MacGregor and Hackshaw found that perimenstrual migraine
attacks were 2.1 – 3.4 times more likely to be severe compared
with non-menstrual attacks [12]. Similar results were found in
a population-based study from the Netherlands [19]. Stewart
et al. found, in a population-based prospective study, that
migraine headaches were more severe during the first 2 days of
the menstrual cycle, but differences were small [11]. In a study
of 30 menstruating migraine women, MM attacks were
associated with more disability compared with non-menstrual
attacks [30]. Silberstein et al., however, did not find a significant
difference in the response to a combination of acetaminophen,
aspirin and caffeine (AAC) between patients with MM and
those with migraine not associated with menses [31].
5.1 Acute treatment
The acute treatment of MM is similar to that of non-
menstrually-related attacks [5]. Triptans (e.g., sumatriptan,
zolmitriptan), ergots (e.g., dihydroergotamine), NSAIDs
(e.g., naproxen sodium) or combination analgesics (e.g., AAC)
are used (Table 1).
5.1.1 Triptans
The 5-HT1B/1D agonists, known as triptans, have proven
safe and effective in alleviating head pain and associated
migraine symptoms [32]. The drugs presumably relieve
Expert Opin. Pharmacother. (2007) 8(11)
Ashkenazi & Silberstein
migraine-related symptoms through cranial vasoconstriction
and inhibition of neurotransmission in the trigeminovascular
system [33,34]. Several triptans have been studied as acute
treatments for MM [35].
5.1.1.1 Sumatriptan
Sumatriptan, in both injectable and oral preparations, is the
most extensively-studied triptan for the acute treatment of
MM [36-40]. However, the definitions of MM in the different
studies were not the same (Table 1).
In a placebo-controlled study, Facchinetti et al. assessed the
safety and efficacy of subcutaneous sumatriptan in 179 women
who treated two MM attacks [36]. At 2 h post-treatment,
sumatriptan injection resulted in a significantly higher rate of
headache relief compared with placebo (attack one: 73 versus
31%; attack two: 81 versus 29%). Sumatriptan was also
superior to placebo in alleviating nausea, photophobia and
phonophobia, and was well-tolerated. Solbach et al. analyzed
the data from two controlled studies on the efficacy of
sumatriptan 6 mg s.c. in the acute treatment of menstruation-
associated migraine (MAM) [37]. At 1 h post treatment with
sumatriptan, 80% of women experienced pain relief, compared
with 19% of those who were given placebo. Dowson et al.
evaluated the efficacy of oral sumatriptan 100 mg for both
menstrual and non-menstrual migraine attacks in a placebo
controlled study of 93 women [38]. Sumatriptan treatment was
associated with a 4-h headache relief in 67% of MM attacks
(versus 33% for placebo). Response to sumatriptan was
non-significantly lower for menstrual attacks compared with
that for non-menstrual attacks. In this study, however, the
definition of MM was different from that recommended
by the IHS. Nett et al. prospectively studied the effect of
sumatriptan 50 and 100 mg tablets on MAM in a placebo-
controlled trial of 349 women [39]. Patients treated a single
MAM attack within 1 h of headache onset, when pain was
mild. At 2 h after treatment, 61 and 51% of women who
used sumatriptan 100 and 50 mg, respectively, were pain free,
compared with 29% of those who used placebo. As a
comparison, in a study of 153 general migraine patients (both
men and women), 83 patients treated a single migraine attack
with oral sumatriptan 100 mg within 1 h of pain onset [41].
Seventy-one percent of patients reported being pain free
2 h after treatment. The median time from pain onset to
sumatriptan use in this study was, however, somewhat shorter
than that in the study by Nett et al. (20 versus 30 min).
In summary, sumatriptan in both injectable and oral forms
is effective as acute treatment for MM. However, the response
of MM attacks to sumatriptan may be weaker than that of
non-menstrually related attacks.
5.1.1.2 Zolmitriptan
Zolmitriptan has also been well-studied as an acute treatment
for MM [42-47]. Loder et al. evaluated the efficacy of oral
zolmitriptan for MAM in a prospective controlled study of
579 women [42]. The zolmitriptan dose range was 1.25 – 5 mg.
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 Menstrual migraine: a review of hormonal causes, prophylaxis and treatment

Table 1. Acute treatment of menstrual migraine.

Drug Dosage and Study design n* Results Reference

route of
administration

Sumatriptan 6 mg s.c. Prospective, randomized, PC 179 Drug superior to placebo [36]

6 mg s.c. Retrospective analysis of two 157 Drug superior to placebo; no [37]

PC trials difference between MRM and
non-MRM
100 mg PO Prospective, randomized PC 93 Response of MRM to drug ns [38]
crossover lower than that of non-MRM
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50 or 100 mg PO Prospective, randomized PC 349 Drug superior to placebo [39]

Zolmitriptan 1, 2.5 or 5 mg Prospective, randomized PC 579 Drug superior to placebo but [42]
PO response rates low
2.5 mg PO Prospective, randomized PC 334 Drug superior to placebo; [47]
response rates similar to those
reported for non-MM
1 – 2.5 mg PO Retrospective analysis of 530 Drug similarly effective for MRM [43]
eight PC trials and for non-MRM
2.5 mg PO Subset analysis of a PC trial 49 Response of MRM to drug ns [44]
lower than that of non-MRM
1 – 10 mg Subset analysis of a PC trial 999‡ Response of MRM to drug ns [45]
higher than that of non-MRM
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5 mg PO Open label 2058 Response of MRM to treatment [46]

similar to that of non-MRM
Rizatriptan 5 or 10 mg PO Retrospective analysis of two 335 Drug superior to placebo; [48]
PC trials efficacy similar for MRM and for
non-MRM
10 mg PO Retrospective analysis of 95 Drug superior to placebo; [49]
long-term data efficacy similar for MRM and for
non-MRM
Naratriptan 2.5 mg PO Prospective, randomized PC 229 Drug superior to placebo [50]

Almotriptan 12.5 mg PO Retrospective analysis of a 136 Almotriptan and zolmitriptan [51]

randomized comparative trial similarly superior to placebo
AAC (acetaminophen 2 tabs PO Retrospective analysis of 966 Drug superior to placebo; no [31]
250 mg, aspirin 250 mg, three PC trials difference between MRM and
caffeine 65 mg) non-MRM

Modified from: ASHKENAZI A, SILBERSTEIN SD: Curr. Headache Rep. (2006) 5:207-212.
*n = number of patients.
‡This is the total number of patients in the study. Number of patients with MRM was not provided.

AAC: Acetominpohen, asprin, caffeine; MRM: Menstrually-related migraine; ns: Not significant; PC: Placebo controlled; PO: Per os.

At 2 h post treatment, headache response was achieved in
48% of zolmitriptan-treated attacks compared with 27% of
placebo-treated attacks. Zolmitriptan was well tolerated, with
most adverse events being transient and of mild or moderate
intensity. Although zolmitriptan showed efficacy in treating
MAM in this study, response rates were lower that those
reported in studies on the efficacy of the drug in migraine
attacks of any type [43,44]. Placebo response rates in this
study were also low, suggesting that this study population
may have been more difficult to treat than those in other
studies. In another placebo-controlled study of 334 patients,
Tuchman et al. examined the efficacy of oral zolmitriptan
2.5 mg in MM treatment [47]. A total of 67% of patients who
used zolmitriptan had headache response, compared with 33%
of placebo-treated patients. These results are similar to efficacy
data with zolmitriptan for non-menstrual migraine. Schoenen
et al. reviewed the data from eight studies constituting the
zolmitriptan clinical trial program [43]. Data for 530 women
with MRM was analyzed. Headache response rate for
MRM attacks was similar to that of non-MRM attacks
(65% for both types of attacks with the zolmitriptan 2.5 mg
dose; 69 versus 64%, respectively, with the 5 mg dose).
Solomon et al. conducted a controlled trial to assess the
efficacy of oral zolmitriptan 2.5 mg in the acute treatment

1608 Expert Opin. Pharmacother. (2007) 8(11)


of migraine [44]. A subset analysis of the data for 49 women
who had MAM showed a headache response rate of 56%,
compared with 41% for placebo. The corresponding rates
for non-MAM attacks were 63 and 33%. Different results
were obtained by Rapoport et al., who showed a slightly
higher headache response rate to zolmitriptan in women
with MRM compared with those with non-MRM (72 versus
67% with zolmitriptan 2.5 mg and 69 versus 64% with
zolmitriptan 5 mg, respectively) [45]. In an open label long-term
study of oral zolmitriptan 5 mg, data from 31,579 migraine
attacks experienced by 2058 patients were analyzed [46].
Headache response rates were not affected by association of
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migraine attacks with menstruation.
In summary, oral zolmitriptan appears to be effective and
well-tolerated as an acute treatment for MM. Available data do
not show a significant difference in response to the drug
between MM and non-MM attacks.
5.1.1.3 Other triptans
There is little data on the efficacy of other triptans in the
treatment of MM. In two retrospective studies, rizatriptan
10 mg was found to be as effective for MM as it was for
non-MM attacks [48,49]. In a prospective study of 229 women,
naratriptan 2.5 mg was superior to placebo in relieving MM
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headache [50]. Allais et al. performed a retrospective comparative
analysis of the efficacy of almotriptan 12.5 mg versus
zolmitriptan 2.5 mg in MM [51]. Both drugs were equally
effective for this indication.
5.1.2 Dihydroergotamine
Although used clinically for acute MM attacks, no data from
controlled studies on the efficacy of dihydroergotamine in the
acute treatment of MM are available.
5.1.3 Other analgesics
Silberstein et al. looked at data from three randomized
controlled trials to assess the efficacy of AAC combination
for both MAM and non-MAM [31]. Of the 1220 patients,
185 women treated a MAM attack and 781 treated a non-MAM
attack. AAC was superior to placebo in providing headache
relief for both types of attacks, with no significant difference
between the two types (headache response at 2 h post dose:
MAM 61%, non-MAM 58%; pain free at 2 h: 25 versus 21%,
respectively). In this study, however, patients with incapacitating
headaches were excluded, causing a potential selection bias.
5.2 Prophylactic treatment
Short-term drug prophylaxis is given for several (usually 5 – 7)
days each month, beginning before the anticipated time of
menstrual headache, in an attempt to prevent menstrually-
related attacks. This may be achieved with either hormonal or
non-hormonal treatments (Table 2). When a woman uses a
perimenstrual migraine prophylaxis, drugs that do not interact
with the prophylactic medication should be used as acute
treatment for breakthrough attacks (e.g., when a triptan is
Expert Opin. Pharmacother. (2007) 8(11)
Ashkenazi & Silberstein
used for perimenstrual prophylaxis, drugs from the same
class, or an ergot, should not be used for acute migraine attacks
at that time; an NSAID would be an appropriate choice for
acute treatment in these circumstances).
5.2.1 Non-hormonal prophylaxis
Drugs that have been used for MM prophylaxis include
triptans, ergots and NSAID’s [52,53].
5.2.1.1 Triptans
Several triptans have been studied as prophylactic treatment
for MM, including sumatripan, naratriptan and frovatriptan.
5.2.1.1.1 Sumatriptan Newman et al. treated in an open
label study 20 women migraineurs with oral sumatriptan
(25 mg t.i.d.) perimenstrually (Table 2) [52]. Headache was
absent in 52% of treated cycles and significantly reduced
in severity in 42%.
5.2.1.1.2Naratriptan Naratriptan (1 or 2.5 mg b.i.d. for
5 days) was evaluated in MRM prophylaxis in 206 women [53].
Naratriptan 1 mg treatment was associated with a significantly
lower number of MRM attacks (2.0 versus 4.0) and MRM
days (4.2 versus 7.0) compared with placebo. The 2.5 mg dose
was not effective.
5.2.1.1.3Frovatriptan Silberstein et al. evaluated the efficacy
of frovatriptan (2.5 mg once or twice daily) in the prevention
of MRM in a placebo-controlled study of 546 women [54].
Treatment was started 2 days before the anticipated onset
of MRM headache, and lasted for 6 days. The incidence of
MRM headache was 67, 52 and 41% for placebo, frovatriptan
2.5 mg once daily and frovatriptan 2.5 mg b.i.d., respectively.
5.2.1.1.4 Zolmitriptan Tuchman and Emeribe evaluated the
efficacy of oral zolmitriptan (2.5 mg twice or three times daily)
in MM prevention in a placebo-controlled study of
244 women [55]. Zolmitriptan treatment was started 2 days
prior to the expected day of menses and continued for a
total of 7 days. Zolmitriptan at both treatment regimens
was significantly superior to placebo in decreasing the
frequency of MM attacks (proportion of patients with ≥ 50%
decrease in MM frequency: 59, 55 and 38% for
zolmitriptan 2.5 mg t.i.d., zolmitriptan 2.5 mg b.i.d. and
placebo, respectively).
5.2.1.2 NSAIDs
Naproxen sodium 550 mg b.i.d. given perimenstrually, was
shown to be associated with a significant decrease in headache
intensity, headache duration and the number of days with
headaches in a controlled study of 35 women with MM [56].
5.2.2 Hormonal prophylaxis
Hormonal manipulation, usually with estrogen, may also
be effective in the short-term prophylaxis of MM (Table 2).
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 Menstrual migraine: a review of hormonal causes, prophylaxis and treatment

Table 2. Perimenstrual prophylaxis for migraine.

Drug Dosage and route Study design n* Results Reference

of administration

Sumatriptan 25 mg PO t.i.d. Open label 20 Headache absent in 52% of treated cycles and [52]
significantly reduced in 42%
Naratriptan 1 mg PO; 2.5 mg Randomized PC 206 Significantly lower number of MRM attacks with 1 mg; [53]
PO 2.5 mg dose not effective
Frovatriptan 2.5 mg PO qd or Randomized PC 546 Decrease in incidence of MRM attacks with both doses, [54]
b.i.d. more so with the b.i.d. regimen
Zolmitriptan 2.5 mg bid or t.i.d. Randomized PC 244 Decrease in frequency of MM attacks with both [55]
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regimens
Naproxen 550 mg PO b.i.d. PC 35 Decreased headache intensity and duration [56]
sodium
Estradiol 1.5 mg, transdermal Randomized 20 Decreased frequency, severity and duration of MRM [57]
(gel) PC, cross-over
Estradiol 1.5 mg, transdermal Randomized PC 35 A 22% reduction in MM days when using the drug, but [59]
(gel) cross-over an increase in headache after cessation of treatment
*n = number of patients.

MM: Menstrual migraine; MRM: Menstrually-related migraine; PC; Placebo controlled; PO: Per os.

The transdermal estrogen preparation is convenient and 6. Expert opinion

effective. However, withdrawal headaches with cessation of
For personal use only.

treatment may occur.
5.2.2.1 Estrogens
Percutaneous estradiol gel (1.5 mg in 2.5 g gel), started
2 days before the menses and continued for 7 days, was
associated with a reduction in frequency, severity and
duration of MM [57]. These positive results were confirmed in
other trials [58]. Recently, MacGregor et al. examined the
efficacy of estardiol (1.5 mg) gel in MM prevention in a
placebo controlled study [59]. Women treated six cycles
in a cross-over design. Gel was applied daily from the
10th day after ovulation to the second day of menses.
During the time of gel application, estradiol treatment
was associated with a 22% reduction in migraine days,
compared with placebo. However, an increase in migraine
in the estardiol group occurred during the 5 days
following cessation of gel application, compared with the
placebo group.
5.2.2.2 Gonadotropin-releasing hormone agonists
In few studies, the efficacy of gonadotropin-releasing hormone
(GnRH) agonists in MM prevention was examined, with
inconsistent results. In one study, five women with severe
MM were treated with the GnRH agonist leuprolide
acetate, alone and in combination with transdermal estrogen
and oral medroxyprogesterone acetate. Both treatments
resulted in significant headache relief [60]. In another study
of 21 women with migraine, treatment with the combination
of GnRH agonist goserelin and transdermal estradiol,
was effective in migraine prevention, but goserelin alone
was not [61].
There is convincing evidence, both from epidemiologic data
and from basic science research, for the association between
female sex-hormones and migraine. Changes in estrogen levels
that occur around the time of menses appear to trigger migraine
attacks in susceptible women. There is still a debate on whether
MM is a separate clinical entity or the same disease process
as non-menstrual migraine with a propensity to occur at a
specific time. There is no specific biologic marker for MM
that would distinguish it from non-menstrual migraine. More
research is needed to address this question. Current data is
insufficient to support the hypothesis that MM is a separate
disease. MM attacks seem to be more severe and possibly
less responsive to some migraine drugs, compared with
non-menstrual attacks. This may be due to the effect of changes
in hormonal (most importantly estrogen) levels on cranial
nociception and does not prove that MM is fundamentally
different from non menstrually-related migraine.
Some clinical observations support common mechanisms
for both MM and non-MM:
• The symptomatology of both types of migraine is similar,
with the exception of aura that does not seem to be associ-
ated with MM.
• Both types respond to the same classes of acute-treatment
drugs (e.g., triptans, ergots, NSAIDs).
• MM severity and frequency may decrease with the
use of preventive drugs that are also effective in the
prevention of non-menstrual migraine (e.g., antidepressants,
anticonvulsants).
Future research may help in finding more specific drugs
for MM treatment. This may be accomplished once the

1610 Expert Opin. Pharmacother. (2007) 8(11)

 Ashkenazi & Silberstein

exact mechanisms of the interactions between estrogen and
the trigeminal system are elucidated. Until then, the mainstay
of MM treatment will consist of drugs used for migraine at
any other time of the cycle.
When treating MM attacks, the general principles of acute
migraine treatment should apply. The triptans are effective
in the acute treatment of MM and should be considered a
first line treatment for this indication, although the response
of MM to some triptans may not be as robust as that of
non-MM attacks. Other treatment options include NSAIDs
and combination analgesics. There are no established guidelines
for the prophylactic treatment of MM and MRM. Women
Expert Opin. Pharmacother. Downloaded from informahealthcare.com by University of Pennsylvania on 07/13/13
for 5 – 7 days, starting 2 days before the anticipated headache
day) is effective for this purpose in the majority of women
and is used by the authors as a first choice treatment, unless
contraindicated. If this fails, a triptan (e.g., frovatriptan
2.5 mg b.i.d. for 6 days, starting 2 days before the anticipated
day of the headache) may be used. We use hormonal prophylaxis
(e.g., percutaneous estradiol) if the above drugs are contra-
indicated or ineffective, or if the patient prefers it. Giving a
3-month cycle hormonal contraceptive (e.g., Seasonale®,
Duramed Pharmaceuticals, [ethinyl estradiol 30 µg plus
levonorgestrel 0.15 mg]) may also be considered. This will
result in decreased frequency of menses and thereby of

who suffer from frequent or debilitating migraine attacks in menstrually-related migraine. This option may be particularly
the perimenstrual period should be considered for short-term appealing to women whose MM attacks are severe and
prophylaxis. An NSAID (e.g., naproxen sodium 550 mg t.i.d. difficult to treat.

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Affiliation
Avi Ashkenazi†1 MD &
Stephen Silberstein2 MD FACP
†Author for correspondence
1Assistant Professor of Neurology,
Thomas Jefferson University,
Department of Neurology,
111 South 11th Street, Suite #8130,
Philadelphia, PA 19107, USA
Tel: +1 215 955 2032; Fax: +1 215 955 2060;
E-mail: avi.ashkenazi@jefferson.edu
2Professor of Neurology,
Director, Jefferson Headache Center,
Thomas Jefferson University Hospital,
Philadelphia, Pennsylvania
1613
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For personal use only.