Oestrogen Lancet 2004

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

THE LANCET Neurology Vol 3 June 2004 http://neurology.thelancet.com354

Review Migraine and the menstrual cycle

During women’s reproductive years, migraine is three timesmore common than in men of a similar age. Although thisfemale preponderance is commonly assumed to beassociated with the additional trigger of fluctuating sexhormones of the menstrual cycle, few studies have beendone to confirm or refute this. This review is confined to therelation between oestrogen and attacks of migraine. Theevidence for an association between oestrogen “withdrawal”and attacks of migraine without aura is presented, as well asevidence for an association between high oestrogen statesand attacks of migraine with aura. Only clinical data arepresented here.

Lancet Neurol 2004; 3: 354–61

Epidemiological studies confirm the clinical impressionthat migraine is mainly a disorder of women. Althoughmigraine is equally common in both sexes before puberty,there is increased female prevalence in adulthood.1 Thisdifference between the sexes becomes greater with age,peaking early in the fifth decade of life (figure 1)2 and thendeclining.2,3 Some studies suggest that the lifetimeprevalence of migraine in women is as great as 25%,compared with only 8% in men.4

This sex difference during the reproductive years isgenerally thought to result from the additional trigger of thefluctuating hormones in the menstrual cycle, an associationthat has long been recognised. Hippocrates noted:“Shivering, lassitude, and heaviness of the head denotes theonset of menstruation.”5 In 1666, Johannis van der Lindendescribed a particularly severe case of one-sided headachewith nausea and vomiting associated with menstruation inthe Marchioness of Brandenburg.6

Despite evidence for a clinical association, theunderlying mechanisms remain elusive to researchers. In1873, Liveing posed the questions: “How are we to interpretthe facts; what is the character of the influence exerted andto what extent is it the cause of the malady?”7 Althoughdoctors in the 19th century suggested an organic cause, it isinteresting that the meaning of the terms used to describe“menstrual” migraine has changed from organic topsychogenic 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 wasthought to be a form of hysteria (ie, arising from the womb);the recommended cure was marriage.

Clinical evidence: migraine and menstruationMore than 50% of women with migraine, both in thegeneral population and presenting to specialist clinics,report an association between migraine and menstruation.8,9

In a community based study, Waters and O’Connor10

analysed data from 117 women age 20–64 years. They notedthat menstruating women experienced the highest incidenceof migraine attacks during the first few days ofmenstruation. Of 42 women whose diary cards wereanalysed over two menstrual cycles, there were twice thenumbers of migraine attacks during menstruationcompared with other times of the menstrual cycle.

In a study in a specialist clinic, Dalton11 assessed 52women with menstrual migraine—defined as attacks ofsevere disabling headaches always recurring at the samephase of each menstrual cycle. Of 512 attacks recorded, 36%were in the 4 days immediately before menstruation and30% were during the first 4 days of menstruation. The peakincidence was 2 days immediately before the onset ofmenstruation. There was no association with ovulation.

MacGregor and colleagues12 studied a group of womenattending a specialist headache clinic. All women attending

EAM is at the City of London Migraine Clinic and the Departmentsof Gynaecology and of Sexual Health, St Bartholomew’s 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 [email protected]

Oestrogen and attacks of migraine with andwithout aura

E Anne MacGregor

Prev

alen

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%)

0Africa

(Ethiopia)

15

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Asia Europe

Male

Southand

CentralAmerica

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Figure 1. Migraine prevalence at age 40 years. Based on 18 populationstudies that used IHS criteria.2


THE LANCET Neurology Vol 3 June 2004 http://neurology.thelancet.com 355

ReviewMigraine and the menstrual cycle

the clinic were asked to keep diary-card records of migraineattacks and menstruation for at least three menstrual cyclesas part of their routine management.12 Incomplete recordsand records from women using hormonal treatments wereexcluded. In the pooled data from 55 women with a meanage of 36 years, a notable increase in migraine attacks wasseen between 2 days before to the onset of menstruation andthe first 3 days of bleeding (day 1±2 days). All attacks withinday 1±2 days were of migraine without aura. There was noassociation with ovulation.

Johannes and co-workers13 studied a group of womenwho were participating in a large population-basedprevalence survey of headache. 74 young women, age22–29 years, kept diary records of all their headaches for upto 16 weeks. The authors noted a 60% increase in attacks ofmigraine without aura during the first 3 days ofmenstruation. However, they did not analyse severity. Allwomen in the study had experienced at least one attack ofmigraine with aura during their lifetime. Inclusion criteriarequired that participants had at least two migraine attacksper month, thus the study included women for whommenstruation was not the only trigger. No increase in anyheadache type was noted during the premenstrual phase orin relation to the estimated time of ovulation; however, 22(30%) of the 74 women were using oral contraceptionduring the study.

In a population-based, diary-card study, Stewart andcolleagues14 examined data from 81 women eachcontributing a mean of 89·1 diary days (total 7219 days).They found migraine without aura, but not migraine withaura, was more likely to occur 2 days before the onset ofmenstruation and during the first 2 days of menstruation.They do not state whether or not any women were usinghormonal contraceptives.

In the largest study of migraine and the natural menstrualcycle to date, my colleagues and I assessed 693 cycles from155 women.15 Compared with all other times of the cycle,migraine attacks were 1·7 times (95% CI 1·45–2·10) morelikely to occur during the 2 days before menstruation and

2·5 times (95% CI 1·29–3·13) more likelyto occur during the first 3 days ofmenstruation.

These studies show that migraineattacks are most likely to occur in the2 days before and the first 3 days duringmenstruation. Furthermore, menstrualattacks are almost invariably withoutaura, even in women who have attackswith aura at other times of the cycle.Despite many women reporting anassociation with ovulation, no linkbetween migraine attacks and ovulationhas been established in any of thesestudies.

Female hormones and menstrualmigraineThe menstrual cycle The average menstrual cycle takes

28 days—counted from the first day of one menstrual periodto the start of the next—but the length is notoriouslyvariable, essentially owing to an irregular follicular phase.The cycle can be divided into three stages: the follicularphase, ovulation, and the luteal phase.

The follicular phase is the first part of the cycle. At thestart of each cycle, hormones from the hypothalamusstimulate the pituitary gland to secrete follicle-stimulatinghormone (FSH). This stimulates the ovaries, and five to 20follicles rapidly start to grow. By about day 6 of the cycle, asingle follicle in one of the ovaries grows faster and theothers regress (figure 2). The developing follicles produceoestrogen, which instructs the pituitary gland to reduce thesecretion of FSH and trigger luteinising hormone (LH) fromthe pituitary gland. Ovulation takes place as a surge of LHcauses the follicle to rupture, releasing the mature egg.

The luteal phase is the time between ovulation andmenstruation. In contrast to the variation in follicularphase length, the luteal phase consistently lasts for about14 days. Under the control of LH, the empty follicletransforms itself into the corpus luteum, which producesprogesterone and a second rise of oestrogen. Thereforeprogesterone is only present in the luteal phase ofovulatory cycles. High hormone concentrations cause theproduction of FSH and LH to fall. If there is no pregnancy,the corpus luteum rapidly degenerates 9–11 days afterovulation and the concentrations of oestrogen andprogesterone fall. The fall in progesterone causes themenstrual bleed; around this time of the cycle theincidence of migraine increases.

Menstrual migraineIn order to understand the causes of menstrual migraine it isimportant to distinguish between attacks that only occuraround the time of menstruation (ie, pure menstrualmigraine) and attacks that mostly occur at the time ofmenstruation in women who have additional attacks atother times of the cycle (panel).16 This is because a purehormonal mechanism is likely to be involved only in women

Pituitary

Ovulation

FSH

Oestrogen

Ovary

FSH and LH

Menstruation

Follicular phase Ovulation

Variable length 14 days

Corpus luteum

Luteal phase

Oestrogen andprogesterone

LH

Figure 2. The pituitary–ovarian axis: follicular, ovulatory, and luteal phases.




with pure menstrual migraine. In contrast, additional non-hormonal factors are likely to be acting in women withadditional non-menstrual attacks. If studies are to uncoverthe mechanisms that cause menstrual migraine, it isnecessary to study women in whom hormonal events are theonly association.

With this in mind, researchers have considered hownormal or abnormal female hormonal function might beassociated with migraine. Oestrogen and progesterone arethe main hormones that have been studied in relation tomigraine attacks but studies of these hormones in womenwith menstrual migraine compared with women who do nothave migraine have found no convincing differences.Researchers have, therefore, focused on the naturally fallingconcentrations of oestrogen and progesterone during theluteal phase of the menstrual cycle, coinciding with the onsetof menstrual attacks of migraine.

Progesterone and migraineInsufficient progesterone in the luteal phase was firstthought to cause menstrual attacks of migraine. However,no studies confirm this association.17–19 Somerville,19

considering progestogen “withdrawal” to be a likelymechanism, used progesterone supplements to treat sixwomen who had attacks of migraine during the late lutealphase. Menstruation was delayed in four of these womenbut, despite this, five had migraine attacks at their customarytime, unrelated to plasma concentrations of progesterone(figure 3). In a later study, two women with ovulatory failuredeveloped migraine attacks associated with decliningconcentrations of oestrogen after depot oestradiol.20 In bothwomen, the plasma concentrations of progesterone did notexceed 1 ng/mL throughout the study.

When continuous progestogen treatments have beeneffective in preventing menstrual migraine, it has beenthrough suppression of the menstrual cycle.21 Somerville andCarey22 reported that 41% of women in their studyimproved. However, treatment-associated effects ofpolymenorrhoea and breakthrough bleeding limitacceptability.

Oestrogen withdrawal and migraineEvidence is generally in favour of menstrual attacks beingassociated—at least in some women—with fallingconcentrations, or “withdrawal”, of oestrogen. The clinical

evidence suggests that ovulation is not a necessary precursorto menstrual attacks because migraine occurs in otherhormonal situations when oestrogen concentrations fall inthe absence of ovulation—eg, women taking the combinedoral contraceptive pill who experience migraine attacksduring the pill-free week, when amounts of oestrogen fallafter 21 days of high concentrations.23 In women usinghormone-replacement therapy, migraine attacks occurredduring the oestrogen-free week in the regimen of 21 days ontreatment, 7 days off.24 In a placebo-controlled double-blindcrossover study of hysterectomised women with bilateraloophorectomies, increased frequency of headache wasreported after courses of oestrogen.25 Migraine attacks alsooccur directly after giving birth, a time when oestrogenconcentrations plummet.26

Somerville20,27,28 did several studies in a small group ofwomen who had a history of pure menstrual migraine in thepreceding six menstrual cycles. He noted that oestrogen“priming” with several days of exposure to high oestrogenconcentrations is necessary for migraine attacks to resultfrom oestrogen withdrawal, such as that in the late lutealphase of the menstrual cycle. This effect would explain whymigraine attacks are not associated with ovulation. Incontrast to sustained high oestrogen concentrations in theluteal phase, oestrogen concentrations are low in thefollicular phase and do not prime the system sufficiently forthe drop in oestrogen immediately after ovulation to have aneffect.

Several other studies support Somerville’s oestrogenwithdrawal theory. Epstein and co-workers29 noted that theextent of decline from peak to trough oestrogen was greaterin 14 women with migraine compared with 8 women in thecontrol group who did not have migraine. They concludedthat variation in hormonal activity might be a relevant factorin all women with migraine; factors additional to thehormonal environment could account for the developmentof menstrual attacks. Lichten and colleagues30 studied 28postmenopausal women challenged with oestrogen. Theyconfirmed that, in women with a history of premenopausal

Normal cycle

Migraine

Migraine

=progesterone injection

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/mL)

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2

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Figure 3. The role of progesterone in menstrual migraine. Reproducedwith permission from Lippincott, Williams & Wilkins.19

Definitions of menstrual migraine disorders16

Pure menstrual migraine

Attacks of migraine without aura occur exclusively on day 1±2 ofmenstruation (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 1±2 of the menstrual cycle in at leasttwo of three consecutive menstrual cycles.

Additional attacks of migraine with or without aura at other times of thecycle.




menstruation-related migraine, a drop in oestrogenconcentrations in the plasma could precipitate migraineattacks, and that a period of oestrogen priming wasnecessary.

My colleagues and I31 studied 40 women with puremenstrual or menstruation-related migraine age 29–49 years(mean 43 years). Urine was collected daily for assay overthree menstrual cycles and analysed for LH, oestrone-3-glucuronide, pregnanediol-3-glucuronide, and FSH. Datafrom individual women showed migraine associated morewith decreasing concentrations of oestrogen than with risingconcentrations. Furthermore, menstrual attacks lastedlonger than non-menstrual attacks (figure 4). In an analysisof pooled data, the incidence of migraine attacks wasinversely associated with urinary oestrogen concentrationsacross the menstrual cycle: an attack was significantly more

likely to occur in association withfalling oestrogen in the late luteal orearly follicular phase of the menstrualcycle and less likely to occur during thesubsequent part of the follicular phaseduring which oestrogen concentrationsrose (figure 5). No association was seenbetween migraine attacks and urinaryconcentrations of progestogens.

Supplementation of oestrogenIf the oestrogen withdrawal theory iscorrect, the maintaining of high, stableconcentrations of oestrogen shouldprevent migraine attacks. Somerville20

showed that migraine attacks could bepostponed by intramuscular injectionof long-acting oestradiol valerate inoil; migraine attacks later occurredwhen the concentration of oestradiolin the plasma fell (figure 6). Thisfinding also supports Somerville’sprevious research showing a lack ofeffect of progesterone on migraine—if

progesterone was an important factor, the timing ofmenstrual attacks would have been unaffected by the use ofoestrogen supplements. Somerville further attempted tocontrol oestrogen fluctuations with oral oestrogens andoestrogen implants. Both of these routes of delivery failedto provide stable concentrations of oestradiol and so, notsurprisingly, were of no benefit.28 The fact that short-actingoestrogen did not produce the same results as the long-acting supplements confirms the hypothesis that long-termoestrogen exposure is necessary for withdrawal to triggermigraine attacks.

More recent trials with more stable routes of deliveryhave shown efficacy. de Lignières and co-workers32 studied18 women with strictly defined menstrual migraine whocompleted a double-blind, placebo-controlled crossover trialwith 1·5 mg oestradiol gel or placebo daily for 7 days duringthree consecutive cycles.32 Treatment was started 48 h beforethe expected attack of migraine. Only eight menstrualattacks occurred during the 26 oestrogen-treated cycles(30·8%) compared with 26 attacks during the 27 placebocycles (96·3%). Attacks during oestrogen treatment weremilder and shorter than during placebo. 18 women alsocompleted a similar trial by Dennerstein and colleagues33 inwhich 1·5 mg oestradiol gel or placebo was used daily for7 days, beginning at least 2 days before the expectedmigraine attack, for four cycles.33 The difference betweenoestradiol gel and placebo was highly significant—favouringthe use of oestradiol gel—and less of the treatment was usedduring active treatment. However, the results were not asimpressive as the study by de Lignières and co-workers.32

Dennerstein and colleagues comment that this might bebecause women in their study had menstruation-relatedmigraine rather than pure menstrual migraine. Thereforemigraine in their participants was only partly hormonedependent.

Follicular phase Luteal phase

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Figure 5. Graphical representation of incidence of migraine versus plasmaconcentrations of oestrogen and progesterone in a group of women withmigraine.30

Figure 4. Incidence of migraine versus urinary oestrogen and progesterone metabolites (E1G andPdG) in a single cycle in one woman. Note the longer duration of migraine associated withmenstruation versus non-menstrual attacks.Reproduced with permission from Lippincott, Williams &Wilkins.31




We31 used 1·5 mg oestradiol gel in a double-blind,placebo-controlled study to prevent perimenstrual migraineattacks in 27 women with regular menstrual cycles andmenstrual migraine or menstrually-related migraine.31 Eachwoman was treated for up to six menstrual cycles (threecycles percutaneous oestradiol and three placebo). Womenused the Clearplan® Easy Fertility monitor to identifyovulation, doing a test each day as required by the monitor,using a sample of early morning urine. Oestradiol gel orplacebo was first used on the tenth day after the first day thatthe monitor signified ovulation and continued daily until,and including, the second day of menstruation. Use ofpercutaneous oestradiol was associated with a significantreduction in the the number of days with migraine andattack severity. No clinically relevant adverse events werereported during the study. However, as Somerville hadfound, there was a significant increase in migraine attacksimmediately after cessation of active gel compared withplacebo. Possible reasons for this post-gel oestrogen-withdrawal migraine are that the dose of oestradiol wasinadequate, the duration of treatment was too short, orperhaps that exogenous oestrogen delays the normal rise ofendogenous oestrogen. This migraine shift associated withdelayed oestrogen withdrawal in the absence of progesteronefurther refutes the importance of progesterone in thedevelopment of menstruation-related migraine.

Oestrogen patches have not been as successful asoestrogen gel in the prevention of migraine attacks.Pfaffenrath34 studied 41 patients completing a trial of 50 µgoestradiol patches versus placebo used daily from 2 daysbefore and up to the expected onset of an attack, duringtreatment phase of 4 months. No significant differences wereseen, although oestradiol was slightly better than placebo inall parameters. Smits and colleagues35 also studied 50 µgpatches versus placebo over three cycles in 20 women andfound no difference between oestradiol and placebo.Pradalier and co-workers36 studied two groups of 12 womenusing either 25 µg or 100 µg patches on day 4 and day 1 (twopatches per cycle) over two cycles, and compared the results

with a pretreatment cycle.36 They found that the 100 µg dosegave a better clinical result than the 25 µg patches, raising thequestion of a critical concentration.

Is there a critical threshold?The suggestion from these studies is that the 25 µg and 50 µgpatches are not effective in the prevention of menstrualattacks of migraine as they result in suboptimal doses,achieving serum oestradiol concentrations of 25 pg/mL and40 pg/mL respectively. A study of migraine in the pill-freeinterval of combined oral contraceptives with an oestrogenpatch on the last day of the pill cycle, replaced on the fourthday of the pill-free interval, also suggested that 50 µg patchesare a suboptimal dose to prevent oestrogen-withdrawalattacks.37 Lichten and co-workers30 noted the mean oestradiolconcentration on the day of oestrogen-withdrawal migrainewas 46·4 pg/mL (SD 5·6).30 de Lignières and Bousser38

reported that at least 60 pg/mL is needed to preventoestrogen-withdrawal migraine attacks, as well as 1·5 mgpercutaneous oestrogen gel daily.38 Similarly, the 100 µg patchleads 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 withovulation, despite high concentrations of oestrogen followedby an immediate drop at this time of the cycle. Somervillesuggested that a period of sustained oestrogen exposure isnecessary for oestrogen withdrawal to provoke migraineattacks. When Somerville studied two women with ovulatoryfailure, they experienced migraine attacks 9 days and 10 daysafter 5 mg depot delivery of oestradiol valerate.20 In bothpatients, oestrogen concentrations had decreased for 7 daysafter treatment.

Lichten and co-workers30 gave postmenopausal women5 mg depot oestradiol and noted that migraine attacksoccurred between 14 days and 21 days after treatment andwere associated with a decline in oestradiol concentrations.30

Mean oestradiol concentrations were above baseline at day 7but had declined to below baseline by day 14.

Suppression of endogenous oestrogen cycleSuppression of cyclical ovarian activity is generally effectivefor the management of menstrual migraine. Notably,women who have amenorrhoea report improvement inmigraine. However, even when ovulation is suppressed,breakthrough bleeding can occur and is commonlyassociated with migraine attacks. Somerville hypothesisedthat because fluctuations in oestrogen concentrations canoccur even when ovulation is suppressed, oestrogenwithdrawal will still be a migraine trigger.22

Continuous hormonal treatments are particularly usefulif cycles are irregular or when the above strategies proveineffective despite a convincing hormonal link. Magos andcolleagues39 showed that implant doses large enough tosuppress ovulation and produce constant oestrogenconcentrations in the plasma achieved a 96% response ratein 24 patients.39

Analogues of gonadotropin-releasing hormone seemeffective,40,41 although adverse effects of oestrogen deficiency

Figure 6. The role of oestradiol withdrawal in “menstrual” migraine.Reproduced with permission from Lippincott, Williams & Wilkins.31

Normal cycle

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(eg, hot flushes) restrict their use. The hormones are alsoassociated with a reduction in bone density and should nottypically be used for more than 6 months without regularmonitoring and bone densitometry. “Add-back” continuouscombined oestrogen and progestogen can be given tocounter these difficulties.41,42

Clinical and research data support an associationbetween attacks of migraine without aura and withdrawal ofeither endogenous or exogenous oestrogen, after oestrogenpriming. This can be prevented by the maintenance ofconstant concentrations of oestrogen, with or withoutsuppression of the natural menstrual cycle.

Oestrogen and migraine with auraIn contrast to oestrogen withdrawal associated with attacksof migraine without aura, high plasma concentrations ofoestrogen seem to be associated with attacks of migrainewith aura.

High concentrations of oestrogen have been reported inwomen with migraine with aura during the normalmenstrual cycle: mean oestradiol concentrations in womenwith migraine with aura during the normal menstrual cycle(94·4 pg/mL [SD 28·3]) were double those of the controlgroup (50·6 pg/mL [SD 8·9]) and women with migrainewithout aura (41·6 pg/mL [SD 7·1]).43 Whether womendiagnosed with migraine with aura also had attacks withoutaura was not clear.

Migraine without aura commonly improves with use ofcombined oral contraceptives. By contrast, migraine withaura worsens or attacks with aura develop for the first time.44

Granella and colleagues45 studied 100 women with migrainewith typical aura, with no history of attacks of migrainewithout aura. Women were age-matched to controls withmigraine without aura and no history of attacks with aura.They found worsening of migraine was more likely to occurwith use of combined oral contraceptives in the women withpre-existing migraine with aura. These women were alsomore likely to continue to have attacks during pregnancy.

Women with pre-existing migraine without aura maydevelop aura for the first time during pregnancy.46,47 Also, if awoman has her first ever migraine attack when pregnant, it islikely to be with aura.48

In four case studies of women developing aura associatedwith starting hormone-replacement therapy,49 two womenhad no previous history of attacks with aura, and two had apast history of migraine with and without aura but had hadno migraine attacks with aura for several years beforestarting hormone-replacement therapy. In all cases, alowering of oestrogen dose or change to the route of deliverywas associated with loss of aura.

Kaiser and Meienberg50 reported on 10 women seen in anophthalmology clinic who were using transdermal oestrogenpatches 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 withaura also had attacks without aura is unknown. All sixwomen developed increased headache severity andaccompanying visual scintillations. One woman with noprevious history of migraine developed visual scintillationswith no accompanying headache. Withdrawal of oestrogensand additional prophylactic antimigrainous therapy led toimprovement in all women, with complete loss of migrainein four patients.

There may be a critical concentration of oestrogen abovewhich aura may be triggered. Oestrogen concentrationsfluctuate throughout the menstrual cycle, with largeinterindividual and intraindividual variations in serumconcentration, exposing susceptible women to thisadditional migraine trigger. With respect to oestrogenreplacement therapy, peak plasma concentrations ofoestradiol vary with dose and route of delivery.51 This couldaccount for the development of aura with some routes andnot with others. There are also large interindividual andintraindividual variations in plasma concentrations after theuse of natural oestrogens irrespective of route ofadministration.51 Furthermore, some women continue toproduce significant amounts of oestrone and oestradiol inextraovarian sites such as adipose tissue after menopause.52

Therefore not all women are deficient in oestrogen after themenopause and, for some, standard doses of oestrogenreplacement might be more than they require.

Migraine with aura and ischaemic strokeWhy should we be concerned with the development of aura inwomen using oestrogens? It depends on whether or not aurais truly associated with an increased risk of stroke. Results ofseveral studies suggest that, in young women, migraine withaura is associated with a greater risk of ischaemic stroke thanmigraine without aura (table 1).53–55 Stroke risk is substantiallyincreased by smoking and use of combined oralcontraceptives (table 2).53,55 To date, no study has been able toassess the separate risks associated with migraine with auraand migraine without aura in women taking combined oralcontraceptives, because the low absolute risk of ischaemicstroke in this population results in numbers too small forsubgroup analysis. Migraine may only be a risk factor forischaemic stroke in women whose migraine is a symptom ofan unidentified disorder that predisposes to stroke. For

Table 1. Odds ratios (OR) for ischaemic-stroke risk inwomen with migraine with and without aura

Study Migraine without aura Migraine with auraOR (95% CI) OR (95% CI)

Tzourio et al53 3·0 (1·2–5·8) 6·2 (2·1–18·0)

Carolei et al54 1·0 (0·5–2·0) 8·6 (1–75)

Chang et al55 2·97 (0·66–13·5) 3·8 (1·27–11·5)

Table 2. Additional risk factors and odds ratios (OR) forrisk of ischaemic stroke in patients with migraine

Additional risk factor Tzourio et al53 Chang et al55

OR (95% CI) OR (95% CI)

None 3·5 (1·8–6·4) 3·54 (1·3–9·6)

Combined oral contraceptives 13·9 (5·5–35·1) 6·59 (0·8–54·8)

Smoking 10·2 (3·5–29·9) 37·39 (2·1–25·5)

Smoking and combined oral Not analysed 34·4 (3·27–361)contraceptives




example, many of the cases in the study by Tzourio andcolleagues53 had underlying pathology and controls did notundergo the same investigations. However, the results aresufficient evidence for some authorities to caution against, orto contraindicate, use of combined oral contraceptives bywomen with migraine with aura.56–58

Because ischaemic stroke is rare in women ofreproductive age, the odds ratios should be interpreted inthe context of absolute risk. In Europe annual incidencerates range from one to three strokes per 100 000 for allwomen younger than 35 years, rising to ten per 100 000 in allwomen over 35 years.59 Hence, age is significant in theassessment of risk.

In older women transient ischaemic attacks arecommonly misdiagnosed as aura.60 There is also concernabout the potential influence of hormone-replacementtherapy on the risk of stroke in women with migraine.Unfortunately, to date no studies have assessed the relationof migraine, hormone-replacement therapy, and stroke. Itwould be very interesting if future studies looked at migraineas a possible marker for ischaemic stroke. The true effect ofhormone-replacement therapy on ischaemic stroke isunclear. Past observational studies that suggested a beneficialeffect of hormone-replacement therapy have been hamperedby healthy-user bias. Data from randomised, placebo-controlled studies suggest that 1 mg oral 17�-oestradiol dailyhas no significant effect on ischaemic stroke inpostmenopausal women with previous cerebrovasculardisease (relative risk 1·1 [95% CI 0·8–1·4]).61 0·625 mg oralequine oestrogen combined with 2·5 mg medroxypro-gesterone acetate daily did not increase ischaemic risk inpostmenopausal women with previous cardiovasculardisease (relative hazard 1·09 [0·88–1·35]).62,63 By contrast,studies of healthy postmenopausal women taking 0·625 mgoral equine oestrogen combined with 2·5 mgmedroxyprogesterone acetate daily show increased risk ofischaemic stroke compared with those taking placebo

(hazard ratio 1·44 [1·09–1·90].64 An equivalent outcome hasbeen reported in healthy postmenopausal women taking0·625 mg oral equine oestrogen daily.65

Oestrogen has favourable long-term effects oncardiovascular markers—it raises plasma concentrations ofhigh-density-lipoprotein cholesterol while loweringconcentrations of low-density-lipoprotein cholesterol andimproving endothelial vascular function.66 However,oestrogen also has adverse physiological effects, particularlyon thrombotic markers and can induce a hypercoagulablestate in susceptible individuals.67 This differential effect hasnot been seen with oral hormone-replacement therapy usedin the above studies but whether or not similar results applyto more physiological non-oral routes of delivery or withlower oestrogen doses is unknown.

Clinical data support an association between attacks ofmigraine with aura and increased risk of ischaemic stroke inyoung women. This risk is increased by use of combined oralcontraceptives. Although there are no data to suggest thatmigraine with aura is associated with an increased risk ofstroke in older women using hormone-replacement therapy,no studies to date have included migraine as a parameter forstroke risk.

Future researchClinical trial evidence supports an association betweenoestrogen withdrawal and attacks of migraine without auraafter a period of sustained oestrogen exposure of no morethan 7 days. However, the minimum necessary duration ofexposure to oestrogen is unknown. Studies suggest theexistence of a critical oestrogen threshold, although futureresearch is needed to confirm this.

Clinical evidence implies an association between highconcentrations of oestrogen and attacks of migraine withaura. However, further research is needed to establish theexact relation. The potential association between migrainewith aura and increased risk of stroke also needsconfirmation, with clarification of the role of oestrogen.Perhaps a more fundamental question is why does oestrogenaffect migraine in some women and not others?

Conflict of interestI have no relevant conflicts of interest to declare.

Role of the funding sourceNo funding source had a role in the preparation of this review or thedecision to submit it for publication.

Search strategy and selection criteriaData for this review were identified by a search of MEDLINEwith the terms “(o)estrogen”, “ethinyl(o)estradiol”,“(o)estradiol”, “(o)estrogen replacement therapy”, “migraine”.184 articles were identified by this means but many had limitedrelevance. The search strategy identified 17 clinical trials ofwhich eight were relevant to this review. In addition, referencesfrom the author’s own files and peer-reviewed presentations atInternational Congresses were considered.

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1962; 51 (suppl 136): 1–151.2 Scher A, Stewart W, Lipton R. Migraine and

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Oestrogen Lancet 2004