Review

Migraine and the menstrual cycle

Oestrogen and attacks of migraine with and

without aura

E Anne MacGregor
25
20
Prevalence (%)

During womens reproductive years, migraine is three times

more common than in men of a similar age. Although this
female preponderance is commonly assumed to be
associated with the additional trigger of fluctuating sex
hormones of the menstrual cycle, few studies have been
done to confirm or refute this. This review is confined to the
relation between oestrogen and attacks of migraine. The
evidence for an association between oestrogen withdrawal
and attacks of migraine without aura is presented, as well as
evidence for an association between high oestrogen states
and attacks of migraine with aura. Only clinical data are
presented here.

Male
Female

15
10
5
0
Africa
(Ethiopia)

Asia

Europe

Lancet Neurol 2004; 3: 35461

Epidemiological studies confirm the clinical impression

that migraine is mainly a disorder of women. Although
migraine is equally common in both sexes before puberty,
there is increased female prevalence in adulthood.1 This
difference between the sexes becomes greater with age,
peaking early in the fifth decade of life (figure 1)2 and then
declining.2,3 Some studies suggest that the lifetime
prevalence of migraine in women is as great as 25%,
compared with only 8% in men.4
This sex difference during the reproductive years is
generally thought to result from the additional trigger of the
fluctuating hormones in the menstrual cycle, an association
that has long been recognised. Hippocrates noted:
Shivering, lassitude, and heaviness of the head denotes the
onset of menstruation.5 In 1666, Johannis van der Linden
described a particularly severe case of one-sided headache
with nausea and vomiting associated with menstruation in
the Marchioness of Brandenburg.6
Despite evidence for a clinical association, the
underlying mechanisms remain elusive to researchers. In
1873, Liveing posed the questions: How are we to interpret
the facts; what is the character of the influence exerted and
to what extent is it the cause of the malady?7 Although
doctors in the 19th century suggested an organic cause, it is
interesting that the meaning of the terms used to describe
menstrual migraine has changed from organic to
psychogenic with the passage of time. For example,
catamenial migraine was thought to be a neurosis
meaning disorder of the nervous system. Furthermore,
because migraine was more common in women, it was
thought to be a form of hysteria (ie, arising from the womb);
the recommended cure was marriage.

354

South
and
Central
America

North
America

Figure 1. Migraine prevalence at age 40 years. Based on 18 population

studies that used IHS criteria.2

Clinical evidence: migraine and menstruation

More than 50% of women with migraine, both in the
general population and presenting to specialist clinics,
report an association between migraine and menstruation.8,9
In a community based study, Waters and OConnor10
analysed data from 117 women age 2064 years. They noted
that menstruating women experienced the highest incidence
of migraine attacks during the first few days of
menstruation. Of 42 women whose diary cards were
analysed over two menstrual cycles, there were twice the
numbers of migraine attacks during menstruation
compared with other times of the menstrual cycle.
In a study in a specialist clinic, Dalton11 assessed 52
women with menstrual migrainedefined as attacks of
severe disabling headaches always recurring at the same
phase of each menstrual cycle. Of 512 attacks recorded, 36%
were in the 4 days immediately before menstruation and
30% were during the first 4 days of menstruation. The peak
incidence was 2 days immediately before the onset of
menstruation. There was no association with ovulation.
MacGregor and colleagues12 studied a group of women
attending a specialist headache clinic. All women attending
EAM is at the City of London Migraine Clinic and the Departments
of Gynaecology and of Sexual Health, St Bartholomews Hospital,
London, UK.
Correspondence: The City of London Migraine Clinic,
22 Charterhouse Square, London, EC1M 6DX, UK.
Tel +44 (0)20 7251 3322; fax +44 (0)20 7490 2183;
email anne.macgregor@bartsandthelondon.nhs.uk

THE LANCET Neurology Vol 3 June 2004

http://neurology.thelancet.com

For personal use. Only reproduce with permission The Lancet Publishing Group.

Review

Migraine and the menstrual cycle

Follicular phase

Ovulation

Luteal phase

Pituitary
Oestrogen and
progesterone

LH

FSH and LH

FSH
Oestrogen
Ovary
Ovulation

Corpus luteum
Menstruation

Variable length

14 days

Figure 2. The pituitaryovarian axis: follicular, ovulatory, and luteal phases.

the clinic were asked to keep diary-card records of migraine

attacks and menstruation for at least three menstrual cycles
as part of their routine management.12 Incomplete records
and records from women using hormonal treatments were
excluded. In the pooled data from 55 women with a mean
age of 36 years, a notable increase in migraine attacks was
seen between 2 days before to the onset of menstruation and
the first 3 days of bleeding (day 12 days). All attacks within
day 12 days were of migraine without aura. There was no
association with ovulation.
Johannes and co-workers13 studied a group of women
who were participating in a large population-based
prevalence survey of headache. 74 young women, age
2229 years, kept diary records of all their headaches for up
to 16 weeks. The authors noted a 60% increase in attacks of
migraine without aura during the first 3 days of
menstruation. However, they did not analyse severity. All
women in the study had experienced at least one attack of
migraine with aura during their lifetime. Inclusion criteria
required that participants had at least two migraine attacks
per month, thus the study included women for whom
menstruation was not the only trigger. No increase in any
headache type was noted during the premenstrual phase or
in relation to the estimated time of ovulation; however, 22
(30%) of the 74 women were using oral contraception
during the study.
In a population-based, diary-card study, Stewart and
colleagues14 examined data from 81 women each
contributing a mean of 891 diary days (total 7219 days).
They found migraine without aura, but not migraine with
aura, was more likely to occur 2 days before the onset of
menstruation and during the first 2 days of menstruation.
They do not state whether or not any women were using
hormonal contraceptives.
In the largest study of migraine and the natural menstrual
cycle to date, my colleagues and I assessed 693 cycles from
155 women.15 Compared with all other times of the cycle,
migraine attacks were 17 times (95% CI 145210) more
likely to occur during the 2 days before menstruation and

THE LANCET Neurology Vol 3 June 2004

25 times (95% CI 129313) more likely

to occur during the first 3 days of
menstruation.
These studies show that migraine
attacks are most likely to occur in the
2 days before and the first 3 days during
menstruation. Furthermore, menstrual
attacks are almost invariably without
aura, even in women who have attacks
with aura at other times of the cycle.
Despite many women reporting an
association with ovulation, no link
between migraine attacks and ovulation
has been established in any of these
studies.

Female hormones and menstrual

migraine
The menstrual cycle

The average menstrual cycle takes

28 dayscounted from the first day of one menstrual period
to the start of the nextbut the length is notoriously
variable, essentially owing to an irregular follicular phase.
The cycle can be divided into three stages: the follicular
phase, ovulation, and the luteal phase.
The follicular phase is the first part of the cycle. At the
start of each cycle, hormones from the hypothalamus
stimulate the pituitary gland to secrete follicle-stimulating
hormone (FSH). This stimulates the ovaries, and five to 20
follicles rapidly start to grow. By about day 6 of the cycle, a
single follicle in one of the ovaries grows faster and the
others regress (figure 2). The developing follicles produce
oestrogen, which instructs the pituitary gland to reduce the
secretion of FSH and trigger luteinising hormone (LH) from
the pituitary gland. Ovulation takes place as a surge of LH
causes the follicle to rupture, releasing the mature egg.
The luteal phase is the time between ovulation and
menstruation. In contrast to the variation in follicular
phase length, the luteal phase consistently lasts for about
14 days. Under the control of LH, the empty follicle
transforms itself into the corpus luteum, which produces
progesterone and a second rise of oestrogen. Therefore
progesterone is only present in the luteal phase of
ovulatory cycles. High hormone concentrations cause the
production of FSH and LH to fall. If there is no pregnancy,
the corpus luteum rapidly degenerates 911 days after
ovulation and the concentrations of oestrogen and
progesterone fall. The fall in progesterone causes the
menstrual bleed; around this time of the cycle the
incidence of migraine increases.
Menstrual migraine

In order to understand the causes of menstrual migraine it is

important to distinguish between attacks that only occur
around the time of menstruation (ie, pure menstrual
migraine) and attacks that mostly occur at the time of
menstruation in women who have additional attacks at
other times of the cycle (panel).16 This is because a pure
hormonal mechanism is likely to be involved only in women

http://neurology.thelancet.com

355

For personal use. Only reproduce with permission The Lancet Publishing Group.

Review

Migraine and the menstrual cycle

Definitions of menstrual migraine disorders16

10
Plasma progesterone (ng/mL)

Pure menstrual migraine

Attacks of migraine without aura occur exclusively on day 12 of
menstruation (ie, days 2 to 3) in at least two of three menstrual cycles.
The first day of menstruation is day 1 and the preceding day is day 1;
there is no day 0.
No migraine at other times of the cycle.
Menstrual-related migraine
Attacks of migraine occur on day 12 of the menstrual cycle in at least
two of three consecutive menstrual cycles.
Additional attacks of migraine with or without aura at other times of the
cycle.

with pure menstrual migraine. In contrast, additional nonhormonal factors are likely to be acting in women with
additional non-menstrual attacks. If studies are to uncover
the mechanisms that cause menstrual migraine, it is
necessary to study women in whom hormonal events are the
only association.
With this in mind, researchers have considered how
normal or abnormal female hormonal function might be
associated with migraine. Oestrogen and progesterone are
the main hormones that have been studied in relation to
migraine attacks but studies of these hormones in women
with menstrual migraine compared with women who do not
have migraine have found no convincing differences.
Researchers have, therefore, focused on the naturally falling
concentrations of oestrogen and progesterone during the
luteal phase of the menstrual cycle, coinciding with the onset
of menstrual attacks of migraine.
Progesterone and migraine

Insufficient progesterone in the luteal phase was first

thought to cause menstrual attacks of migraine. However,
no studies confirm this association.1719 Somerville,19
considering progestogen withdrawal to be a likely
mechanism, used progesterone supplements to treat six
women who had attacks of migraine during the late luteal
phase. Menstruation was delayed in four of these women
but, despite this, five had migraine attacks at their customary
time, unrelated to plasma concentrations of progesterone
(figure 3). In a later study, two women with ovulatory failure
developed migraine attacks associated with declining
concentrations of oestrogen after depot oestradiol.20 In both
women, the plasma concentrations of progesterone did not
exceed 1 ng/mL throughout the study.
When continuous progestogen treatments have been
effective in preventing menstrual migraine, it has been
through suppression of the menstrual cycle.21 Somerville and
Carey22 reported that 41% of women in their study
improved. However, treatment-associated effects of
polymenorrhoea and breakthrough bleeding limit
acceptability.
Oestrogen withdrawal and migraine

Evidence is generally in favour of menstrual attacks being

associatedat least in some womenwith falling
concentrations, or withdrawal, of oestrogen. The clinical

356

9
Migraine

8
7

Progesteronetreated cycle

6
5

Migraine

4
3

=progesterone injection

Normal cycle

1
0
5

4

3
2
1
1
2
Days from onset of menstruation

Figure 3. The role of progesterone in menstrual migraine. Reproduced

with permission from Lippincott, Williams & Wilkins.19

evidence suggests that ovulation is not a necessary precursor

to menstrual attacks because migraine occurs in other
hormonal situations when oestrogen concentrations fall in
the absence of ovulationeg, women taking the combined
oral contraceptive pill who experience migraine attacks
during the pill-free week, when amounts of oestrogen fall
after 21 days of high concentrations.23 In women using
hormone-replacement therapy, migraine attacks occurred
during the oestrogen-free week in the regimen of 21 days on
treatment, 7 days off.24 In a placebo-controlled double-blind
crossover study of hysterectomised women with bilateral
oophorectomies, increased frequency of headache was
reported after courses of oestrogen.25 Migraine attacks also
occur directly after giving birth, a time when oestrogen
concentrations plummet.26
Somerville20,27,28 did several studies in a small group of
women who had a history of pure menstrual migraine in the
preceding six menstrual cycles. He noted that oestrogen
priming with several days of exposure to high oestrogen
concentrations is necessary for migraine attacks to result
from oestrogen withdrawal, such as that in the late luteal
phase of the menstrual cycle. This effect would explain why
migraine attacks are not associated with ovulation. In
contrast to sustained high oestrogen concentrations in the
luteal phase, oestrogen concentrations are low in the
follicular phase and do not prime the system sufficiently for
the drop in oestrogen immediately after ovulation to have an
effect.
Several other studies support Somervilles oestrogen
withdrawal theory. Epstein and co-workers29 noted that the
extent of decline from peak to trough oestrogen was greater
in 14 women with migraine compared with 8 women in the
control group who did not have migraine. They concluded
that variation in hormonal activity might be a relevant factor
in all women with migraine; factors additional to the
hormonal environment could account for the development
of menstrual attacks. Lichten and colleagues30 studied 28
postmenopausal women challenged with oestrogen. They
confirmed that, in women with a history of premenopausal

THE LANCET Neurology Vol 3 June 2004

http://neurology.thelancet.com

For personal use. Only reproduce with permission The Lancet Publishing Group.

Review

Migraine and the menstrual cycle

Menses

E1G
PdG
Migraine

Menses
30

20

50

PdG ng/mL

E1G ng/mL

100

likely to occur in association with

falling oestrogen in the late luteal or
early follicular phase of the menstrual
cycle and less likely to occur during the
subsequent part of the follicular phase
during which oestrogen concentrations
rose (figure 5). No association was seen
between migraine attacks and urinary
concentrations of progestogens.
Supplementation of oestrogen

If the oestrogen withdrawal theory is

correct, the maintaining of high, stable
concentrations of oestrogen should
prevent migraine attacks. Somerville20
showed that migraine attacks could be
0
0
postponed by intramuscular injection
of long-acting oestradiol valerate in
oil; migraine attacks later occurred
Follicular phase
Luteal phase
when the concentration of oestradiol
Figure 4. Incidence of migraine versus urinary oestrogen and progesterone metabolites (E1G and
in
the plasma fell (figure 6). This
PdG) in a single cycle in one woman. Note the longer duration of migraine associated with
finding also supports Somervilles
menstruation versus non-menstrual attacks. Reproduced with permission from Lippincott, Williams &
Wilkins.
previous research showing a lack of
effect of progesterone on migraineif
menstruation-related migraine, a drop in oestrogen progesterone was an important factor, the timing of
concentrations in the plasma could precipitate migraine menstrual attacks would have been unaffected by the use of
attacks, and that a period of oestrogen priming was oestrogen supplements. Somerville further attempted to
necessary.
control oestrogen fluctuations with oral oestrogens and
My colleagues and I31 studied 40 women with pure oestrogen implants. Both of these routes of delivery failed
menstrual or menstruation-related migraine age 2949 years to provide stable concentrations of oestradiol and so, not
(mean 43 years). Urine was collected daily for assay over surprisingly, were of no benefit.28 The fact that short-acting
three menstrual cycles and analysed for LH, oestrone-3- oestrogen did not produce the same results as the longglucuronide, pregnanediol-3-glucuronide, and FSH. Data acting supplements confirms the hypothesis that long-term
from individual women showed migraine associated more oestrogen exposure is necessary for withdrawal to trigger
with decreasing concentrations of oestrogen than with rising migraine attacks.
More recent trials with more stable routes of delivery
concentrations. Furthermore, menstrual attacks lasted
longer than non-menstrual attacks (figure 4). In an analysis have shown efficacy. de Lignires and co-workers32 studied
of pooled data, the incidence of migraine attacks was 18 women with strictly defined menstrual migraine who
inversely associated with urinary oestrogen concentrations completed a double-blind, placebo-controlled crossover trial
across the menstrual cycle: an attack was significantly more with 15 mg oestradiol gel or placebo daily for 7 days during
three consecutive cycles.32 Treatment was started 48 h before
the expected attack of migraine. Only eight menstrual
Menses
Menses
attacks occurred during the 26 oestrogen-treated cycles
(308%) compared with 26 attacks during the 27 placebo
cycles (963%). Attacks during oestrogen treatment were
milder and shorter than during placebo. 18 women also
completed a similar trial by Dennerstein and colleagues33 in
which 15 mg oestradiol gel or placebo was used daily for
7 days, beginning at least 2 days before the expected
migraine attack, for four cycles.33 The difference between
oestradiol gel and placebo was highly significantfavouring
the use of oestradiol geland less of the treatment was used
during active treatment. However, the results were not as
impressive as the study by de Lignires and co-workers.32
Migraine incidence
Dennerstein and colleagues comment that this might be
Oestradiol
because women in their study had menstruation-related
Progesterone
migraine rather than pure menstrual migraine. Therefore
Figure 5. Graphical representation of incidence of migraine versus plasma
migraine in their participants was only partly hormone
concentrations of oestrogen and progesterone in a group of women with
dependent.
migraine.
10

31

30

THE LANCET Neurology Vol 3 June 2004

http://neurology.thelancet.com

357

For personal use. Only reproduce with permission The Lancet Publishing Group.

Review

Migraine and the menstrual cycle

with a pretreatment cycle.36 They found that the 100 g dose

gave a better clinical result than the 25 g patches, raising the
question of a critical concentration.

Plasma oestradiol (ng/100 mL)

200
100

Oestrogen
injection
Oestrogentreated cycle

50
20
10

Is there a critical threshold?

Migraine
Normal cycle

Migraine

5
2
1
6 5 4 3 2 1 1 2 3 4 5
Days from onset of menstruation

Figure 6. The role of oestradiol withdrawal in menstrual migraine.

Reproduced with permission from Lippincott, Williams & Wilkins.31

We31 used 15 mg oestradiol gel in a double-blind,

placebo-controlled study to prevent perimenstrual migraine
attacks in 27 women with regular menstrual cycles and
menstrual migraine or menstrually-related migraine.31 Each
woman was treated for up to six menstrual cycles (three
cycles percutaneous oestradiol and three placebo). Women
used the Clearplan Easy Fertility monitor to identify
ovulation, doing a test each day as required by the monitor,
using a sample of early morning urine. Oestradiol gel or
placebo was first used on the tenth day after the first day that
the monitor signified ovulation and continued daily until,
and including, the second day of menstruation. Use of
percutaneous oestradiol was associated with a significant
reduction in the the number of days with migraine and
attack severity. No clinically relevant adverse events were
reported during the study. However, as Somerville had
found, there was a significant increase in migraine attacks
immediately after cessation of active gel compared with
placebo. Possible reasons for this post-gel oestrogenwithdrawal migraine are that the dose of oestradiol was
inadequate, the duration of treatment was too short, or
perhaps that exogenous oestrogen delays the normal rise of
endogenous oestrogen. This migraine shift associated with
delayed oestrogen withdrawal in the absence of progesterone
further refutes the importance of progesterone in the
development of menstruation-related migraine.
Oestrogen patches have not been as successful as
oestrogen gel in the prevention of migraine attacks.
Pfaffenrath34 studied 41 patients completing a trial of 50 g
oestradiol patches versus placebo used daily from 2 days
before and up to the expected onset of an attack, during
treatment phase of 4 months. No significant differences were
seen, although oestradiol was slightly better than placebo in
all parameters. Smits and colleagues35 also studied 50 g
patches versus placebo over three cycles in 20 women and
found no difference between oestradiol and placebo.
Pradalier and co-workers36 studied two groups of 12 women
using either 25 g or 100 g patches on day 4 and day 1 (two
patches per cycle) over two cycles, and compared the results

358

The suggestion from these studies is that the 25 g and 50 g

patches are not effective in the prevention of menstrual
attacks of migraine as they result in suboptimal doses,
achieving serum oestradiol concentrations of 25 pg/mL and
40 pg/mL respectively. A study of migraine in the pill-free
interval of combined oral contraceptives with an oestrogen
patch on the last day of the pill cycle, replaced on the fourth
day of the pill-free interval, also suggested that 50 g patches
are a suboptimal dose to prevent oestrogen-withdrawal
attacks.37 Lichten and co-workers30 noted the mean oestradiol
concentration on the day of oestrogen-withdrawal migraine
was 464 pg/mL (SD 56).30 de Lignires and Bousser38
reported that at least 60 pg/mL is needed to prevent
oestrogen-withdrawal migraine attacks, as well as 15 mg
percutaneous oestrogen gel daily.38 Similarly, the 100 g patch
leads to concentrations of oestradiol of about 75 pg/mL.
Is there a critical duration of oestrogen exposure?

In all prospective studies migraine was not associated with

ovulation, despite high concentrations of oestrogen followed
by an immediate drop at this time of the cycle. Somerville
suggested that a period of sustained oestrogen exposure is
necessary for oestrogen withdrawal to provoke migraine
attacks. When Somerville studied two women with ovulatory
failure, they experienced migraine attacks 9 days and 10 days
after 5 mg depot delivery of oestradiol valerate.20 In both
patients, oestrogen concentrations had decreased for 7 days
after treatment.
Lichten and co-workers30 gave postmenopausal women
5 mg depot oestradiol and noted that migraine attacks
occurred between 14 days and 21 days after treatment and
were associated with a decline in oestradiol concentrations.30
Mean oestradiol concentrations were above baseline at day 7
but had declined to below baseline by day 14.
Suppression of endogenous oestrogen cycle

Suppression of cyclical ovarian activity is generally effective

for the management of menstrual migraine. Notably,
women who have amenorrhoea report improvement in
migraine. However, even when ovulation is suppressed,
breakthrough bleeding can occur and is commonly
associated with migraine attacks. Somerville hypothesised
that because fluctuations in oestrogen concentrations can
occur even when ovulation is suppressed, oestrogen
withdrawal will still be a migraine trigger.22
Continuous hormonal treatments are particularly useful
if cycles are irregular or when the above strategies prove
ineffective despite a convincing hormonal link. Magos and
colleagues39 showed that implant doses large enough to
suppress ovulation and produce constant oestrogen
concentrations in the plasma achieved a 96% response rate
in 24 patients.39
Analogues of gonadotropin-releasing hormone seem
effective,40,41 although adverse effects of oestrogen deficiency

THE LANCET Neurology Vol 3 June 2004

http://neurology.thelancet.com

For personal use. Only reproduce with permission The Lancet Publishing Group.

Review

Migraine and the menstrual cycle

Table 1. Odds ratios (OR) for ischaemic-stroke risk in

women with migraine with and without aura

Table 2. Additional risk factors and odds ratios (OR) for

risk of ischaemic stroke in patients with migraine

Study

Additional risk factor

Tzourio et al53
Carolei et al54
Chang et al55

Migraine without aura

OR (95% CI)
30 (1258)
10 (0520)
297 (066135)

Migraine with aura

OR (95% CI)
62 (21180)
86 (175)
38 (127115)

(eg, hot flushes) restrict their use. The hormones are also
associated with a reduction in bone density and should not
typically be used for more than 6 months without regular
monitoring and bone densitometry. Add-back continuous
combined oestrogen and progestogen can be given to
counter these difficulties.41,42
Clinical and research data support an association
between attacks of migraine without aura and withdrawal of
either endogenous or exogenous oestrogen, after oestrogen
priming. This can be prevented by the maintenance of
constant concentrations of oestrogen, with or without
suppression of the natural menstrual cycle.

Oestrogen and migraine with aura

In contrast to oestrogen withdrawal associated with attacks
of migraine without aura, high plasma concentrations of
oestrogen seem to be associated with attacks of migraine
with aura.
High concentrations of oestrogen have been reported in
women with migraine with aura during the normal
menstrual cycle: mean oestradiol concentrations in women
with migraine with aura during the normal menstrual cycle
(944 pg/mL [SD 283]) were double those of the control
group (506 pg/mL [SD 89]) and women with migraine
without aura (416 pg/mL [SD 71]).43 Whether women
diagnosed with migraine with aura also had attacks without
aura was not clear.
Migraine without aura commonly improves with use of
combined oral contraceptives. By contrast, migraine with
aura worsens or attacks with aura develop for the first time.44
Granella and colleagues45 studied 100 women with migraine
with typical aura, with no history of attacks of migraine
without aura. Women were age-matched to controls with
migraine without aura and no history of attacks with aura.
They found worsening of migraine was more likely to occur
with use of combined oral contraceptives in the women with
pre-existing migraine with aura. These women were also
more likely to continue to have attacks during pregnancy.
Women with pre-existing migraine without aura may
develop aura for the first time during pregnancy.46,47 Also, if a
woman has her first ever migraine attack when pregnant, it is
likely to be with aura.48
In four case studies of women developing aura associated
with starting hormone-replacement therapy,49 two women
had no previous history of attacks with aura, and two had a
past history of migraine with and without aura but had had
no migraine attacks with aura for several years before
starting hormone-replacement therapy. In all cases, a
lowering of oestrogen dose or change to the route of delivery
was associated with loss of aura.

THE LANCET Neurology Vol 3 June 2004

None
Combined oral contraceptives
Smoking
Smoking and combined oral
contraceptives

Tzourio et al53
OR (95% CI)
35 (1864)
139 (55351)
102 (35299)
Not analysed

Chang et al55
OR (95% CI)
354 (1396)
659 (08548)
3739 (21255)
344 (327361)

Kaiser and Meienberg50 reported on 10 women seen in an

ophthalmology clinic who were using transdermal oestrogen
patches 50 g daily.50 Six women had a history of migraine
(three migraine with aura, three migraine without aura)
before use of replacement therapy. If any of the women with
aura also had attacks without aura is unknown. All six
women developed increased headache severity and
accompanying visual scintillations. One woman with no
previous history of migraine developed visual scintillations
with no accompanying headache. Withdrawal of oestrogens
and additional prophylactic antimigrainous therapy led to
improvement in all women, with complete loss of migraine
in four patients.
There may be a critical concentration of oestrogen above
which aura may be triggered. Oestrogen concentrations
fluctuate throughout the menstrual cycle, with large
interindividual and intraindividual variations in serum
concentration, exposing susceptible women to this
additional migraine trigger. With respect to oestrogen
replacement therapy, peak plasma concentrations of
oestradiol vary with dose and route of delivery.51 This could
account for the development of aura with some routes and
not with others. There are also large interindividual and
intraindividual variations in plasma concentrations after the
use of natural oestrogens irrespective of route of
administration.51 Furthermore, some women continue to
produce significant amounts of oestrone and oestradiol in
extraovarian sites such as adipose tissue after menopause.52
Therefore not all women are deficient in oestrogen after the
menopause and, for some, standard doses of oestrogen
replacement might be more than they require.
Migraine with aura and ischaemic stroke

Why should we be concerned with the development of aura in

women using oestrogens? It depends on whether or not aura
is truly associated with an increased risk of stroke. Results of
several studies suggest that, in young women, migraine with
aura is associated with a greater risk of ischaemic stroke than
migraine without aura (table 1).5355 Stroke risk is substantially
increased by smoking and use of combined oral
contraceptives (table 2).53,55 To date, no study has been able to
assess the separate risks associated with migraine with aura
and migraine without aura in women taking combined oral
contraceptives, because the low absolute risk of ischaemic
stroke in this population results in numbers too small for
subgroup analysis. Migraine may only be a risk factor for
ischaemic stroke in women whose migraine is a symptom of
an unidentified disorder that predisposes to stroke. For

http://neurology.thelancet.com

359

For personal use. Only reproduce with permission The Lancet Publishing Group.

Review

Migraine and the menstrual cycle

Search strategy and selection criteria

Data for this review were identified by a search of MEDLINE
with
the
terms
(o)estrogen,
ethinyl(o)estradiol,
(o)estradiol, (o)estrogen replacement therapy, migraine.
184 articles were identified by this means but many had limited
relevance. The search strategy identified 17 clinical trials of
which eight were relevant to this review. In addition, references
from the authors own files and peer-reviewed presentations at
International Congresses were considered.

example, many of the cases in the study by Tzourio and

colleagues53 had underlying pathology and controls did not
undergo the same investigations. However, the results are
sufficient evidence for some authorities to caution against, or
to contraindicate, use of combined oral contraceptives by
women with migraine with aura.5658
Because ischaemic stroke is rare in women of
reproductive age, the odds ratios should be interpreted in
the context of absolute risk. In Europe annual incidence
rates range from one to three strokes per 100 000 for all
women younger than 35 years, rising to ten per 100 000 in all
women over 35 years.59 Hence, age is significant in the
assessment of risk.
In older women transient ischaemic attacks are
commonly misdiagnosed as aura.60 There is also concern
about the potential influence of hormone-replacement
therapy on the risk of stroke in women with migraine.
Unfortunately, to date no studies have assessed the relation
of migraine, hormone-replacement therapy, and stroke. It
would be very interesting if future studies looked at migraine
as a possible marker for ischaemic stroke. The true effect of
hormone-replacement therapy on ischaemic stroke is
unclear. Past observational studies that suggested a beneficial
effect of hormone-replacement therapy have been hampered
by healthy-user bias. Data from randomised, placebocontrolled studies suggest that 1 mg oral 17-oestradiol daily
has no significant effect on ischaemic stroke in
postmenopausal women with previous cerebrovascular
disease (relative risk 11 [95% CI 0814]).61 0625 mg oral
equine oestrogen combined with 25 mg medroxyprogesterone acetate daily did not increase ischaemic risk in
postmenopausal women with previous cardiovascular
disease (relative hazard 109 [088135]).62,63 By contrast,
studies of healthy postmenopausal women taking 0625 mg
oral equine oestrogen combined with 25 mg
medroxyprogesterone acetate daily show increased risk of
ischaemic stroke compared with those taking placebo
References
1
2
3

4
5

Bille B. Migraine in school children. Acta Paed Scand

1962; 51 (suppl 136): 1151.
Scher A, Stewart W, Lipton R. Migraine and
headache: a meta-analytic approach. In: Crombie I,
ed. Epidemiology of Pain. Seattle: IASP Press, 1999.
Stewart W, Lipton R, Celentano D, Reed M.
Prevalence of migraine headache in the United
States: relation to age, income, race, and other
sociodemographic factors. JAMA 1992; 267: 6469.
Rasmussen B, Jensen R, Schroll M, Olesen J.
Epidemiology of headache in a general population: a
prevalence study. J Clin Epidemiol 1991; 44: 114757.
Bronfen E. The knotted subject: hysteria and its
discontents. Princeton: Princeton University Press,
1998.

360

(hazard ratio 144 [109190].64 An equivalent outcome has

been reported in healthy postmenopausal women taking
0625 mg oral equine oestrogen daily.65
Oestrogen has favourable long-term effects on
cardiovascular markersit raises plasma concentrations of
high-density-lipoprotein cholesterol while lowering
concentrations of low-density-lipoprotein cholesterol and
improving endothelial vascular function.66 However,
oestrogen also has adverse physiological effects, particularly
on thrombotic markers and can induce a hypercoagulable
state in susceptible individuals.67 This differential effect has
not been seen with oral hormone-replacement therapy used
in the above studies but whether or not similar results apply
to more physiological non-oral routes of delivery or with
lower oestrogen doses is unknown.
Clinical data support an association between attacks of
migraine with aura and increased risk of ischaemic stroke in
young women. This risk is increased by use of combined oral
contraceptives. Although there are no data to suggest that
migraine with aura is associated with an increased risk of
stroke in older women using hormone-replacement therapy,
no studies to date have included migraine as a parameter for
stroke risk.

Future research
Clinical trial evidence supports an association between
oestrogen withdrawal and attacks of migraine without aura
after a period of sustained oestrogen exposure of no more
than 7 days. However, the minimum necessary duration of
exposure to oestrogen is unknown. Studies suggest the
existence of a critical oestrogen threshold, although future
research is needed to confirm this.
Clinical evidence implies an association between high
concentrations of oestrogen and attacks of migraine with
aura. However, further research is needed to establish the
exact relation. The potential association between migraine
with aura and increased risk of stroke also needs
confirmation, with clarification of the role of oestrogen.
Perhaps a more fundamental question is why does oestrogen
affect migraine in some women and not others?
Conflict of interest

I have no relevant conflicts of interest to declare.

Role of the funding source

No funding source had a role in the preparation of this review or the

decision to submit it for publication.

Van der Linden J. De Hemicrania Menstrua.

London, 1666.
7 Liveing E. On Megrim, sick-headache, and some
allied disorders: a contribution to the pathology of
nerve-storms. London: J & A Churchill, 1873.
8 MacGregor EA, Igarashi H, Wilkinson M. Headaches
and hormones: subjective versus objective
assessment. Headache Quarterly 1997; 8: 12636.
9 Couturier E, Bomhof M, Knuistingh Neven A, van
Duijn N. Menstrual migraine in a representative
Dutch population sample: prevalence, disability and
treatment. Cephalalgia 2003; 23: 30208.
10 Waters W, OConnor P. Epidemiology of headache
and migraine in women. J Neurol Neurosurg
Psychiatry 1971; 34: 14853.
11 Dalton K. Progesterone suppositories and pessaries

12
13

14
15
16

in the treatment of menstrual migraine. Headache

1973; 13: 15159.
MacGregor EA, Chia H, Vohrah RC, Wilkinson M.
Migraine and menstruation: a pilot study.
Cephalalgia 1990; 10: 30510.
Johannes C, Linet M, Stewart W, Celentano D,
Lipton R, Szklo M. Relationship of headache to the
phase of the menstrual cycle among young women: a
daily diary study. Neurology 1995; 45: 107682.
Stewart W, Lipton R, Chee E, Sawyer J, Silberstein S.
Menstrual cycle and headache in a population
sample of migraineurs. Neurology 2000; 55: 151723.
MacGregor EA, Hackshaw A. Prevalence of migraine
on each day of the natural menstrual cycle.
Neurology (in press).
Headache Classification Subcommittee of the

THE LANCET Neurology Vol 3 June 2004

http://neurology.thelancet.com

For personal use. Only reproduce with permission The Lancet Publishing Group.

Migraine and the menstrual cycle

17
18
19
20
21

22
23
24
25
26
27

28
29
30

31

32

33

34
35

International Headache Society (IHS). The

international classification of headache disorders,
2nd edn. Cephalalgia 2004; 24 (suppl 1): 1160.
Gray L. The use of progesterone in nervous tension
states. Southern Med J 1941; 34: 100405.
Singh I, Singh I. Progesterone in the treatment of
migraine. Lancet 1947; 1: 74547.
Somerville BW. The role of progesterone in
menstrual migraine. Neurology 1971; 21: 85359.
Somerville BW. The role of estradiol withdrawal in
the etiology of menstrual migraine. Neurology 1972;
22: 35565.
Bradley WG, Hudgson P, Foster JB, Newell DJ.
Double-blind controlled trial of a micronized
preparation of flumedroxone (Demigran) in
prophylaxis of migraine. BMJ 1968; 3: 53133.
Somerville B, Carey M. The use of continuous
progestogen contraception in the treatment of
migraine. Med J Aust 1970; 1: 104345.
Whitty CW, Hockaday JM, Whitty MM. The effect
of oral contraceptives on migraine. Lancet 1966;
1: 85659.
Kudrow L. The relationship of headache frequency
to hormone use in migraine. Headache 1975;
15: 3640.
Dennerstein L, Laby B, Burrows GD, Hyman GJ.
Headache and sex hormone therapy. Headache 1978;
18: 14653.
Stein G. Headaches in the first post partum week and
their relationship to migraine. Headache 1981;
21: 20105.
Somerville BW. Estrogen-withdrawal migraine, I:
Duration of exposure required and attempted
prophylaxis by premenstrual estrogen
administration. Neurology 1975; 25: 23944.
Somerville BW. Estrogen-withdrawal migraine, II:
attempted prophylaxis by continuous estradiol
administration. Neurology 1975; 25: 24550.
Epstein MT, Hockaday JM, Hockaday TD. Migraine
and reproductive hormones throughout the
menstrual cycle. Lancet 1975; 1: 54348.
Lichten EM, Lichten JB, Whitty A, Pieper D. The
confirmation of a biochemical marker for womens
hormonal migraine: the depo-oestradiol challenge
test. Headache 1996; 36: 36771.
MacGregor EA, Frith A, Ellis J, Aspinall L. Estrogen
withdrawal: a trigger for migraine? A double-blind
placebo-controlled study of estrogen supplements in
the late luteal phase in women with menstruallyrelated migraine. Cephalalgia 2003; 23: 684.
de Lignires B, Vincens M, Mauvais-Jarvis P, Mas JL,
Touboul P, Bousser MG. Prevention of menstrual
migraine by percutaneous estradiol. BMJ 1986;
293: 1540.
Dennerstein L, Morse C, Burrows G, Oats J, Brown J,
Smith M. Menstrual migraine: a double-blind trial of
percutaneous estradiol. Gynecol Endocrinol 1988;
2: 11320.
Pfaffenrath V. Efficacy and safety of percutaneous
estradiol vs. placebo in menstrual migraine.
Cephalalgia 1993; 13: 244.
Smits MG, van der Meer YG, Pfeil JP, Rijnierse JJ,

THE LANCET Neurology Vol 3 June 2004

36

37

38
39
40

41

42

43
44
45

46
47
48

49
50

51
52

Vos AJ. Perimenstrual migraine: effect of Estraderm

TTS and the value of contingent negative variation
and exteroceptive temporalis muscle suppression
test. Headache 1994; 34: 10306.
Pradalier A, Vincent D, Beaulieu P, Baudesson G,
Launey J-M. Correlation between estradiol plasma
level and therapeutic effect on menstrual migraine.
In: Rose F, ed. New advances in headache research.
London: Smith-Gordon, 1994: 12932.
MacGregor EA, Hackshaw A. Prevention of migraine
in the pill-free week of combined oral contraceptives
using natural oestrogen supplements.
J Fam Plann Reprod Healthc 2002; 28: 2731.
de Lignires B, Bousser MG. Migraine. Lancet 1992;
340: 6162.
Magos AL, Zilkha KJ, Studd JW. Treatment of
menstrual migraine by oestradiol implants.
J Neurol Neurosurg Psychiatry 1983; 46: 104446.
Holdaway IM, Parr CE, France J. Treatment of a
patient with severe menstrual migraine using the
depot LHRH analogue Zoladex.
Aust NZ J Obstet Gynaecol 1991; 31: 16465.
Martin V, Wernke S, Mandell K, et al. Medical
oophorectomy with and without estrogen add-back
therapy in the prevention of migraine headache.
Headache 2003; 43: 30921.
Murray SC, Muse KN. Effective treatment of severe
menstrual migraine headaches with gonadotrophonreleasing hormone agonist and add-back therapy.
Fertil Steril 1997; 67: 39093.
Nagel-Leiby S, Welch KM, Grunfeld S, DAndrea G.
Ovarian steroid levels in migraine with and without
aura. Cephalalgia 1990; 10: 14752.
Bickerstaff E. Neurological complications of oral
contraceptives. Oxford: Oxford University Press,
1975.
Granella F, Sances G, Pucci E, Nappi RE, Ghiotto N,
Nappi G. Migraine with aura and reproductive life
events: a case control study. Cephalalgia 2000;
20: 70107.
Wright G, Patel M. Focal migraine and pregnancy.
BMJ 1986; 293: 155758.
Chancellor AM, Wroe SJ, Cull RE. Migraine
occurring for the first time in pregnancy. Headache
1990; 30: 22427.
Cupini L, Matteis M, Troisi E, Calabresi P, Bernardi G,
Silvestrini M. Sex-hormone-related events in
migrainous females: a clinical comparative study
between migraine with aura and migraine without
aura. Cephalalgia 1995; 15: 14044.
MacGregor A. Estrogen replacement and migraine
aura. Headache 1999; 39: 67478.
Kaiser HJ, Meienberg O. Deterioration of onset of
migraine under oestrogen replacement therapy in
the menopause. J Neurol Neurosurg Psychiatry 1993;
240: 19597.
Kuhl H. Pharmacokinetics of oestrogen and
progestogens. Maturitas 1990; 12: 17197.
MacDonald PC, Edman CD, Hemsell DL, Porter JC,
Sitteri PK. Effect of obesity on conversion of plasma
androstenedione to estrogen in postmenopausal
women with and without endometrial cancer.

http://neurology.thelancet.com

Review
Am J Obstet Gynecol 1978; 130: 44855.
53 Tzourio C, Tehindrazanarivelo A, Iglsias S, et al.
Case-control study of migraine and risk of ischaemic
stroke in young women. BMJ 1995; 310: 83033.
54 Carolei A, Marini C, de Matteis G, and the Italian
National Research Council Study Group on Stroke
in the Young. History of migraine and risk of
cerebral ischaemia in young adults. Lancet 1996;
347: 150306.
55 Chang C, Donaghy M, Poulter N, and World Health
Organization Collaboration Study of Cardiovascular
Disease and Steroid Hormone Contraception.
Migraine and stroke in young women: casecontrol
study. BMJ 1999; 318: 1318.
56 MacGregor EA, Guillebaud J. Recommendations for
clinical practice. Combined oral contraceptives,
migraine and ischaemic stroke. Br J Fam Plann 1998;
24: 5360.
57 World Health Organization. Improving access to
quality care in family planning: medical eligibility
criteria for initiating and continuing use of
contraceptive methods, 2nd edn. Geneva: WHO,
2000.
58 Bousser MG, Conard J, Kittner S, et al.
Recommendations on the risk of ischaemic stroke
associated with use of combined oral contraceptives
and hormone replacement therapy in women with
migraine. Cephalalgia 2000; 20: 15556.
59 World Health Organization Collaborative Study of
Cardiovascular Disease and Steroid Hormone
Contraception. Ischaemic stroke and combined oral
contraceptives; results of an international,
multicentre, case-control study. Lancet 1996;
348: 498505.
60 Bousser MG, Conard J. TIAs, migraine and platelets.
Headache 1987; 27: 522.
61 Viscoli CM, Brass LM, Kernan WN, Sarrel PM,
Suissa S, Horwitz RI. A clinical trial of estrogenreplacement therapy after ischaemic stroke.
N Eng J Med 2001; 345: 124349.
62 Simon JA, Hsia J, Cauley JA, et al. Postmenopausal
hormone therapy and risk of stroke: the Heart and
Estrogen-progestin Replacement Study (HERS).
Circulation 2001; 103: 63842.
63 Grady D, Herrington D, Bittner V, et al.
Cardiovascular disease outcomes during 6.8 years of
hormone therapy: Heart and Estrogen/progestin
replacement study follow-up (HERS II). JAMA 2002;
288: 4957.
64 Wassertheil-Smoller S, Hendrix SL, Limacher M,
et al. Effect of estrogen plus progestin on stroke in
postmenopausal women. JAMA 2003; 289: 267384.
65 Barbara Alving. NIH asks participants in Womens
Health Initiative Estrogen-Alone Study to stop study
pills. http://www.nhlbi.nih.gov/new/press/04-0302.htm (accessed March 12, 2004).
66 Mendelsohn ME, Karas RH. The protective effects of
estrogen on the cardiovascular system. N Eng J Med
1999; 340: 180111.
67 Judd HL, Meldrum DR, Deftos LJ, Henderson BE.
Estrogen replacement therapy: indications and
complications. Ann Int Med 1983; 98: 195205.

361

For personal use. Only reproduce with permission The Lancet Publishing Group.