migraña influencia hormonal

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HORMONAL INFLUENCE ON MIGRAINE

Susan L. Hutchinson, MD

Women suffer from migraine headache at a 3:1 ratio to men. This ratiois not established until puberty. Before puberty, boys and girls experiencemigraine at an equal ratio, and some studies indicate that boys havea higher incidence of migraine than girls before puberty. This established3:1 ratio of women to men for migraine prevalence after puberty remainsfairly constant until menopause [1]. At menopause, two thirds of womenmigraineurs experience a reduction or cessation of their migraines. Giventhis prevalence data, it seems that hormones play an important role inwomen with migraines. This article explores the hormonal influence onmigraine.

According to the American Migraine Study II from 1999, the annualprevalence of migraine sufferers in the United States is 28 millionindividuals over the age of 12 (21 million female and 7 million maleindividuals). Migraine peaks at 25 to 55 years of age. These figures indicatean approximate 18% annual prevalence for women and a 6% prevalence formen [2]. However, this 18% of women is based on all women over the age of12 across all age spans. Further analysis of epidemiologic studies indicatesan annual prevalence as high as 27% among women 30 to 39 years of ageand 26% among women 40 to 49 years of age. By 60+ years of age, theannual incidence declines to 8% (Fig. 1) [2].

A study looking at the prevalence and characteristics of migraine ina population-based cohort reported that migraine has affected up to 40.9%of women by the conclusion of the reproductive years [3]. Migraine iscommon among women and especially among women in their child-bearing years. These are years involving lots of hormonal changes. Howdoes a womans hormonal milieu affect migraine?

A landmark study done by Sommerville [4] in 1972 provided supportfor a specific hormonal influence on migraine. He compared the effect on

From the Headache Center, Womens Medical Group of Irvine, Irvine, California; and theDepartment of Family Practice, University of California Irvine, Orange, California

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migraine by giving late luteal injections of estradiol in women who hadmenstrual-related migraine versus giving late luteal injections of pro-gesterone. Late luteal injections of estradiol delayed migraine occurrencebut not bleeding. Late luteal injections of progesterone delayed the onsetof bleeding but not migraine. Sommerville postulated that the drop inestrogen that occurs at menses was an important migraine trigger(Fig. 2).

Translating Sommervilles findings to clinical practice, migraine man-agement in women now includes hormonal strategies. Such strategies arediscussed later in this article. Falls in estrogen occur perimenstrually, withthe postpartum state, during surgical menopause, and when hormone orcontraception is cycled. This is often why many women migraineurs ex-perience their migraines on the placebo week of their pill pack.

The relationship of changes in estrogen to migraine is only partiallyunderstood. Estrogen is a neuromodulator and can affect receptor densityinvolving the serotonergic, noradrenergic, and opiatergic systems [5].When estrogen levels decrease, monoamine oxidase levels increase in thebrain, causing a drop in serotonin level. This serotonin drop causes thecerebral blood vessels to be more susceptible to biochemical markers,such as calcitonin gene-related peptide, substance P, prolactin, endoge-nous endorphins, norepinephrine, and serotonin. These biochemicalmarkers have been implicated in the migraine process [68]. Falling

FIGURE 1.

Rates of migraine prevalence by age. Although the annual prevalence rate of

migraine is 18% for all women over 12 years of age, this graph shows thatmigraines affect women the most during their child-bearing years. ( FromLipton RB, Stewart WF, Diamond S, et al. Prevalence and burden of migraine inthe United States: data from the American Migraine Study II. Headache2001;41:64657; with permission.)

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estrogen levels decrease the postsynaptic neuronal junctions for serotoninand endogenous endorphins, priming the brain and causing it to be moresensitive to pain. Nonmigraine pain is also experienced as more intenseperimenstrually, probably as a result of this decrease in endogenous opioidactivity [9].

PRESENTATION OF MIGRAINE WITH HORMONALINFLUENCE

The majority of women with menstrual migraine have migraines atother times of the month. These are referred to as menstrual-relatedmigraines. Approximately 60% of female migraineurs have this perimen-strual exacerbation of their migraine headaches. A much smaller percent-age of women migraineurs (about 7%14%) have migraines that occurexclusively in association with menses, occurring from 2 days beforemenses through the first 3 days of the menstrual period. This is referred toas true menstrual migraine [10].

Menstrual migraine often presents as migraine without aura; however,many women report their menstrual-related migraine as more severe, moreprolonged, and less responsive to treatment than their other migraines.

FIGURE 2.

Graph from Sommervilles landmark 1972 study demonstrating the connection

between hormone levels and migraine attacks. (From

Sommerville BW. Therole of estrogen withdrawal in the etiology of menstrual migraine. Neurology1972;22:35565; with permission.)

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Studies indicate that menstrually associated migraines respond as well asnonmenstrually associated migraines to triptan therapy [11,12]. In clinicalpractice, many women disagree with this based on their own experience.

Even with a good response to triptan therapy, frustration with treatmentmay be a result of headache recurrence due to the more prolonged natureof menstrual migraine. A higher rate of recurrence after sumatriptan hasbeen observed in menstrual migraine [13]. The continued drop in estrogencould explain the more prolonged duration of menstrual associatedmigraine (ie, the triptan may relieve the acute headache, but because thetrigger [low estradiol] is still present, the headache may return). Trying tomaintain an even estradiol level may help in reducing the prolongedduration of menstrually associated migraine. Calhoun [14] reported im-proved migraine management when using various strategies to maintain

even estradiol levels.

DIAGNOSIS

The diagnosis of menstrual migraine is made by keeping andreviewing a headache calendar. Tracking the frequency and severity ofthe migraine in association with menses or other hormonal conditions isthe key to making the diagnosis. If the female migraine patient hasheadaches only at the time of menses (ie, the true menstrual migraine),

then concentrated mini-prophylaxis can be a good approach. In mostcases, a woman experiences migraine from other triggers as well asmenses; such triggers can include stress, lack of sleep, weather change,preservatives such as MSG and sulfites, bright light, and certain odors. Inthis more common presentation, attention to the identification andprevention of triggers other than hormonal is important in the overallmanagement of the female migraine sufferer.

There is no blood test or special imaging study to diagnose migraine. Ifa woman presents with a disabling headache every month with her menses,most likely it is menstrual migraine, whether she calls her headachemigraine, tension, sinus, or just a headache. If her headache pattern hasbeen stable for over 6 months and there are no signs of a secondaryheadache, then imaging studies are probably not necessary. The historyand review of the headache diary is the key to diagnosis.

SPECIFIC HORMONAL-RELATED MIGRAINES

Menstrual Migraine

Menstrual migraine is defined as a migraine headache that begins from2 days before a womans menses up to 3 days into the menses. Becausethere is a predictable pattern to the headache, targeted mini-prophylaxis isa good option. Acute and preventive approaches can be taken in themanagement of menstrual migraine.

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Acute strategies can include:

Over-the-counter (OTC) analgesics or nonsteroidal anti-inflamma-tory drugs (NSAIDs)dIf the patient is using these medications,

recommend setting a limit, such as !12 tabs per week during theweek of menstruation to avoid rebound headache. IfO12 tabs areneeded, consider preventive therapy.

Prescription NSAIDS such as naproxen; ibuprofen; ketorolacdKetorolac comes in oral and injectable formulations; the 60 mg IMdose can be useful in the ER setting or if the headache is associatedwith significant nausea or vomiting.

TriptansdIt is okay to dose BID up to 5 days in a row if necessary;sumatriptan injection 6 mg is especially good for severe menstrualmigraines (those that are rapidly escalating or accompanied bynausea and vomiting). Sumatriptan 20 mg and zolmitriptan 5 mgnasal spray formulations are nonoral alternatives to sumatriptaninjection but are not as efficacious and take longer to take effect.The injection begins taking effect in 10 minutes; the nasal sprays 15minutes. The sumatriptan injection can be repeated in 1 hour toa maximum of two injections in 24 hours. Both nasal sprays may berepeated in 2 hours to a maximum of two sprays in 24 hours. For lesssevere migraines, the oral formulations of the seven differenttriptans can be used. Sumatriptan, zolmitriptan, and rizatriptan are

as effective in treating menstrual migraine as they are in treatingnonmenstrual migraine [12]. In addition to treating the headachepain, the triptan class can also control the nausea and vomitingassociated with migraines, including menstrual migraines.

Triptan/NSAID combinationdAdding an NSAID such as naproxen500 mg to the triptan treatment can help achieve greater pain-freeresults for some women. In addition, the NSAID can help withassociated menstrual cramps.

DihydroergotaminedDihydroergotamine is an ergot alkaloid and isnot available in an oral formulation. It is available as a nasal spray

and as other nonparental routes of administration, such as IV or IM.In some women, it may work better than the triptans. Both classesof drugs are considered migraine specific.

For all acute treatments, the desired clinical end-point is for thepatient to be headache and symptom free in 2 hours. Other desirableattributes of acute headache medication include little to no side effects anda low chance of headache recurrence.

Preventive Treatment

Continuous contraception. Continuous contraception, ideally withcontraceptive formulations containing 35 mg or less of estradiol, can beeffective preventive treatment. Any formulation with 35 mg or less ofestrogen is considered low dose. Continuous contraception can be in theform of the oral birth control pill, the transdermal patch (Ortho Evra), and



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the vaginal contraceptive ring (Nuvaring). The woman should have theestrogen/progesterone contraceptive dose delivered every day into herblood system, thereby maintaining a more even estradiol level, which,

theoretically, can help with menstrual migraine control [1518]. It is widelyaccepted in the OB-GYN community that women do not have to cycle offand have a withdrawal bleed every 4 weeks. This continuous contraceptivetechnique has been in wide use for the treatment of endometriosis. Inaddition, the FDA has approved Seasonale, a 35-mg estradiol-containingoral contraceptive, as an extended contraceptive. For Seasonale, the pillpack has 12 weeks of active contraceptive hormone and then a placebo for7 days on week 13. Women taking Seasonale have a period every 13 weeks.This same concept can be applied to other available contraceptive pills andto the new nonoral formulations. To be able to convert from cyclical to

continuous contraception, it is advisable to use a monophasic contracep-tive in which the estrogen and progesterone amounts are the same for thefirst 3 weeks of pill pack. This same continuous contraceptive approach tominimizing menstrual migraine can be applied to the transdermal patchand the vaginal ring. The traditional cyclical method for the contraceptivepatch is for the woman to wear and change the patch every week and thenon week 4 to not wear a patch and experience a withdrawal bleed. Toconvert to continuous method, the woman is instructed to continue to usethe patch every week until she and her health care provider decide to cycle.Most typically, this is every 3 months; however, some OB-GYN MDs do not

feel it is necessary to cycle off that often in the absence of breakthroughbleeding. For the vaginal contraceptive ring, the ring is left in place for 4weeks instead of 3 weeks; the ring is replaced after week 4. These nonoralcontraceptive formulations may provide more steady-state levels ofestradiol and could be an advantage over the oral contraceptives for somefemale menstrual migraine sufferers. In addition, they are especially suitedfor women who often forget to take their oral pill and thereby run the riskof breakthrough bleeding and migraine headache due to the drop inhormone levels. More research needs to be done in this area exploring therelationship of continuous contraception and menstrual migraine control.However, clinical experience indicates that it is a good approach to takingin preventing menstrual migraine.

Estradiol. Estradiol can be effective as migraine prevention if it istaken the week of the placebo if the patient is on contraception or the weekof menses if the patient is not on contraception. Transdermal estradiol0.1 mg is the recommended dose. The concept behind the supplementalestradiol is to prevent the drop in estradiol that occurs at the time ofmenses.

Continuous transdermal estradiol patch in the symptomaticperimenopausal women. This patch is a form of estrogen replacementtherapy (ERT). It contains no progesterone and does not providecontraception protection. It can be useful in female migraine patientswho have vasomotor symptoms, such as hot flashes and night sweats, andin patients who often experience an exacerbation of headaches and mooddisorders due to the hormonal fluctuation characteristic of perimenopause.

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ERT does not stop ovulation; therefore, the woman experiences hormonalfluctuation from her ovaries.

NSAIDs. Beginning an OTC or prescription NSAID such as naproxen

or ibuprofen several days before the menses and the expected menstrualmigraine and continuing the NSAID several days into menses can be a cost-effective method of menstrual migraine prevention. However, for manywomen, NSAIDs do not provide sufficient protection, and these patientsmay still experience menstrual migraine.

Long-acting tripans. Long-acting tripans, such as naratriptan (1 mgor 2.5 mg) or frovatriptan (2.5 mg), dosed daily for 3 to 5 days in a rowduring the vulnerable menstrual migraine time frame can be effective asmigraine prevention. Frovatriptan has a longer half-life than naratriptanand can be dosed as 2.5 mg once daily or 2.5 mg twice daily. In a study

looking at frovatriptan for menstrual migraine prophylaxis, patients wererandomized to frovatriptan 2.5 mg QD, frovatriptan 2.5 mg BID, or placebofor 6 days perimenstrually. Frovatriptan 2.5 mg once daily and frovatriptan2.5 mg twice daily were superior to placebo in reducing the frequency,severity, and impairment of the menstrually associated migraine [18]. Fornaratriptan, the recommended dosage is 2.5 mg taken as one half tablettwice a day for 3 to 5 days. Studies on naratriptan showed goodeffectiveness with the 1 mg and with 2.5 mg [19]; therefore, it is econom-ical to have the female migraineur break the 2.5 mg tablet in half whentaking naratriptan for menstrual migraine prevention.

Shorter-acting oral triptans. Shorter-acting oral triptans, such assumatriptan 50 to 100 mg, rizatriptan 5 to 10 mg, zomitriptan 2.5 to 5 mg,almotriptan 6.25 to 12.5 mg, or eletriptan 20 to 40 mg, can be effective astreatment for menstrual migraine prevention. For most women, the higheroral dose of tripan is more likely to render them headache free. If themedication is taken early, there is little difference in side effects.Therefore, to start with the highest available dose of the oral triptan ispreferable in the treatment of menstrual migraine for most women. All oraltriptans can be redosed in 2 hours to a maximum of 200 mg daily forsumatriptan, 30 mg daily for rizatriptan, 10 mg daily for zolmitriptan, 25 mgdaily for almotriptan, and 80 mg daily for eletriptan.

Progesterone-only oral contraceptives. Progesterone-only oralcontraceptive can be effective in women who are sensitive to estrogen andfor whom the previously described methods are ineffective for menstrualmigraine. It is best to avoid Depo-Provera in women migraineurs because itmay cause headache as a side-effect that could last 3 months due to the3-month duration of action of Depo-Provera.

GnRH agonist. A GnRH agonist (Depo-Lupron) given IM should beused for refractory cases only. It suppresses ovarian hormone production.This treatment causes medication-induced menopause; therefore, thequestion of increasing risk of osteoporosis and giving add-back estrogenneeds to be addressed.

In most cases, a combination of acute and preventive treatment isideal. If the female migraine patient has no or few headaches other thanwith her menses, then targeted mini-prophylaxis is an option. In some



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cases, a patient may be on a prophylactic headache medication but stillexperiencing breakthrough migraine at the time of her menses. Increasingthe dose of the prophylactic treatment around the time of menses may be

helpful. Medications such as a tricyclic antidepressant or a selectiveserotonin reuptake inhibitor (SSRI) can be increased around the time ofmenses to achieve better headache control.

In rare cases, estrogen can aggravate migraines in a female patient. Inthese cases, it may be necessary to stop any estrogen and consider, forexample, the progesterone-only pill. Anytime hormones are prescribed orthe hormonal regimen or dose is changed, close attention to any change inheadache is warranted. The best way to track any change in headachepattern is by having the patient keep a headache diary and report to youany worsening of her headache after hormone treatment is instituted.

Occasionally, a woman may develop new-onset aura or worsening of herheadache on contraception. In these cases, stop the hormone and watchfor improvement in the headache pattern. In some cases, imaging and otherevaluations to rule out a secondary headache may be necessary.

The safety of prescribing hormones and contraception is often a topicof concern for practicing clinicians. Migraine patients younger than 45years of age have a slightly higher risk of stroke than the generalpopulation. There is no increased risk of stroke in female migraine patientsover 45 years of age compared with the general population over 45 yearsof age [20]. For the majority of female migraineurs, hormones and

contraception are not contraindicated. If the female patient has migrainewithout aura, her risk of stroke is less than if she has migraine with aura.Her risk increases with the use of contraception. The greatest risk of strokeis if the patient, in addition to having migraines, smokes and has othercardiac risk factors (Table 1).

There is ongoing debate and lack of consensus among headacheexperts on whether it is safe for a female patient who has migraine withaura to go on contraception. Most female migraine patients have migrainewithout aura, which carries a smaller risk of stroke (Table 1) [20]. Manyheadache clinicians allow a female patient who has migraine with aura togo on contraception if the aura is predictable and uncomplicated. A moredense aura, any worsening of aura, or new-onset aura while the patient ison contraception necessitate a cessation of contraception. These at-riskpatients should, in most cases, be placed on aspirin. Some headacheexperts also suggest using vitamin B2 (riboflavin) daily.

PREGNANCY AND MIGRAINES

According to epidemiologic data, most female migraine patientsreport improvement in their migraines, especially by the second and thirdtrimesters [20]. Such improvement is considered to be secondary to thesustained high levels of estradiol that occur during the second and thirdtrimester. However, some women experience their first migraine duringpregnancy [21]. Also, many women experience migraine headaches the

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first trimester; often, some may not even know they are pregnant early inthe first trimester. Therefore, the choice of acute and prophylacticmedication is important in the child-bearing years for female migrainesufferers.

Most OB-GYN providers prefer no medication treatment duringpregnancy and often recommend nonpharmacologic measures. Thesenonpharmacologic measures may include biofeedback; acupuncture;

physical therapy; hot/cold packs; massage; relaxation exercises; regularsleep; avoidance of caffeine, alcohol, and nicotine; and regular meals.Nonpharmacologic treatment may not be enough for most pregnant

migraine patients. When medication is needed, most OB-GYNs recommendTylenol (category B), Tylenol with codeine (category C), Vicodin (categoryC), metoclopramide (category B), and NSAIDs. Most OB-GYNs do notrecommend NSAIDs during the first trimester due to organogenesis (mostOB-GYNs prefer no NSAIDS at any time during pregnancy). No NSAIDsshould be taken after week 32 to prevent premature closure of the patentductus arteriosus.

Metoclopramide (Reglan) is an anti-dopaminergic agent and can exertanti-migraine action in addition to relief of the nausea and vomiting thatmay be associated with migraine. It may be useful to try 5 to 10 mgmetoclopramide slow IVP in a pregnant woman with a severe migraine.This can be done in an emergency room setting or in the doctors office.

The class of triptans is category C for pregnancy. Category C indicatesthat the risk of the medication has to be weighed against the benefit for thefemale pregnant patient. All the triptan manufacturers have a PregnancyRegistry. The combined Sumatriptan and Naratriptan Pregnancy Registry isthe largest to date. A review of the International Interim Report covering the

period of January 1, 1996 through April 30, 2004 reveals the following [22]:

A total of 449 pregnancy exposures to sumatriptan or naratriptan The proportion of pregnancies with birth defects after earliest

exposure in the first trimester is 4.3%; the proportion with birthdefects with any trimester of exposure is 4.5%.

TABLE 1.

Comparison of Odds Ratios and Risk Factors for Stroke

Risk Factor Odds Ratio

Migraine 3Migraine with aura 6Migraine plus OCs 517Migraine and OCs

and smoking34

Note: Look for risk factors such as smoking, hypertension, and migraine with dense aura todetermine if OCPs are appropriate.

Abbreviations: OC, oral contraceptive; OCP, oral contraceptive pill.



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Registry findings do not suggest a greater proportion of birth defectsamong these prospectively reported pregnancies when comparedwith that expected in the general population of pregnant women.

There is no consistent pattern of defects among the birth defectsreported to the Registry.

In conclusion, there is no evidence suggesting teratogenicityassociated with sumatriptan or naratriptan use; however, sample size isinsufficient to lead to definitive conclusions regarding such risk [22].

The pregnancy registries for the other triptan manufacturers show noincreased risk; the numbers in the other registries are smaller than theSumatriptan/Naratriptan Pregnancy Registry. It is important to reportpregnancy exposures to the respective registries. The phone numbers areas follows:

GlaxoSmithKline (sumatriptan/naratriptan) 800-336-2176 Merck (rizatriptan) 800-986-8999 Astra-Zeneca (zomitriptan) 302-886-8494 OrthoMcNeil (almotriptan) 800-682-6532 Pfizer (eletriptan) 800-438-1985 Endo (frovatriptan) 800-462-3636

Migraine Prophylaxis in Pregnancy

As with acute pharmacologic treatment, it is preferable for the femalepregnant patient not to take medication unless absolutely necessary. If thefemale pregnant patient is experiencing frequent or severe migraines, thenmedication may be necessary. The following categories may be used:

Beta blockers, such as propanolol and timolol (category C) SSRIs, such as fluoxetine, sertraline, and paroxetine (category C) Bupropion (category B) Gabapentin or topiramate (category C)

Many pregnant women have relief of their migraines by the secondtrimester; therefore, it is recommended that a trial taper-off of a preventiveheadache medication be done during the second trimester.

Lactation and Migraines

For many pregnant women, there is marked improvement in theirmigraine headaches during the second and third trimesters, in part due tothe sustained high levels of estradiol. For many migraine sufferers, theirmigraines return soon after delivery due to the precipitous drop inestrogen. For postpartum migraineurs who want to breastfeed, the issue ofsafety arises. Which medications are safest for the breastfeeding womanwho needs acute migraine medication? Prescription and OTC NSAIDs areconsidered safe; however, they may not provide sufficient relief. Triptans

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are classified by the American Academy of Pediatrics (AAP) as use withcaution. For many postpartum women, a triptan was the drug of firstchoice before pregnancy and lactation. The commonly accepted practice

has been to allow the female migraine patient to take her normal triptanbut to then discard her breast milk for the next 6 to 8 hours. The AAPrecently concluded that sumatriptan is compatible with breastfeeding;therefore, it seems that it is no longer necessary to pump and discard thebreast milk if sumatriptan is used [23].

Some women suffer postpartum depression and migraines. Supple-mental transdermal estrogen may be helpful in the treatment of bothconditions during the postpartum period. Providing supplemental estrogencan help treat the precipitous drop in estrogen that occurs after delivery;a more even level of estradiol may help both conditions. The transdermal

route may be preferable to the oral route because it provides a more steadylevel of estradiol. For women who require a preventive agent during thepostpartum period because of the severity or frequency of her migraineattacks, beta-blockers and SSRIs are often used. Most migraine patientswho want to breastfeed are able to do so with appropriate and effectivetreatment. Therefore, migraine treatment and breastfeeding are compat-ible for the majority of female migraineurs.

Perimenopause and Migraine

Perimenopause is characterized as a time of change in whichhormones, including estradiol and progesterone, fluctuate widely. The ageof onset of perimenopause varies but typically begins around the 47 yearsof age and lasts for approximately 4 years until menopause, at which timethe ovaries no longer function. For many women, this time of hormonalfluctuation is characterized by troublesome vasomotor symptoms, such ashot flashes and night sweats, exacerbation of her migraine headaches, andoften the onset or exacerbation of mood disorders such as depression oranxiety. Hormone blood test results are difficult to interpret because thelevels fluctuate widely, even in a given day. Menses are often unpredict-able, further complicating migraine treatment, including mini-prophylaxisregimens. Successful mini-prophylaxis of menstrual migraines requiresa predictable menstrual pattern that is often absent in the perimenopausalwoman.

Clinically, some women in this change before the change (whichperimenopause is often referred to) may benefit from low-dose supple-mental estrogen. Estrogen can be given in an oral form, as a transdermalpatch, or as a topical gel or cream. If the woman does not needcontraception, then the estrogen would be a form of hormone replacementtherapy (HRT) and, as such, would not suppress ovarian function. In thiscase, the womans ovaries would still create hormonal fluctuation;however, the low-dose supplemental estradiol can often help thevasomotor symptoms, including disrupted sleep, which may be exacerbat-ing migraine control. In addition, the supplemental estrogen may help with



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migraine control and with mood disorders. The patient should be instructedto keep a headache diary and to watch for any change in headache patternas the HRT is instituted. A non-oral route, such as the transdermal patch,

may provide a more steady level of estradiol than the oral route.Transdermal estradiol is available in a patch as low as 0.014 mg/d ofestradiol. In most cases, the initial dose should be low; then the medicationshould be titrated to the therapeutic dose as the headache pattern iswatched. If the woman is still having menses, then progesterone is usuallynot needed, but that decision should be made by the treating gynecologist. Ifthe perimenopausal female migraine patient needs contraception, thena low-dose monophasic form of birth control can be instituted if she isa nonsmoker and is felt to be a good candidate for contraception.

Because of the exacerbation of migraine attacks that many perime-

nopausal women experience, preventive medication may be needed. Ifappropriate intervention is not taken to prevent the frequent headachepattern that many women in perimenopause experience, then trans-formation from episodic migraine to chronic daily headache may be theresult. In this age group, there can be an increase in depression, in part dueto the hormonal fluctuations. Attention to the frequent comorbidity ofdepression and migraine in this population can help in overall managementof this population of female migraineurs. Understanding that hormonalfluctuation can aggravate migraine control can help in treating thispopulation of women.

Menopause and Migraine

Menopause is often defined as no menses for 1 year or by a folliclestimulating hormone (FSH) level O30. Normal ranges for blood tests canvary among laboratories, but, in general, an elevated FSH with a lowestradiol characterizes the menopausal state. For many menopausalwomen, migraine headaches improve or go away. For others, there canbe a change in their migraines, such as experiencing migraine equivalents(the aura without the headache). In menopause, the ovaries no longerproduce estrogen or progesterone; this can dramatically help a womanwho had migraines aggravated by hormonal fluctuation before menopause.

Many menopausal migraine patients want to go on HRT to helpalleviate moderate to severe vasomotor symptoms, such as hot flashes,night sweats, and insomnia. Patients may be concerned that the HRT willaggravate their migraines. In these patients, it is recommended to start ona low dose of HRT and titrate up carefully to achieve relief of menopausalsymptoms while watching any change in headache pattern. Often, HRTdoes not aggravate migraine headaches. The transdermal estradiol patchand topical estrogen may be less likely to aggravate headaches [24,25]. Inwomen who need estrogen and progesterone, use both drugs daily.Otherwise, when the estrogen is stopped, migraine may occur. The patientshould be instructed to watch any change in headache pattern as HRT isinstituted.

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If a woman requiring estrogen replacement therapy develops anincrease in her headaches, there are several empirical strategies that maybe used, including reducing the dose of estrogen or changing from

a conjugated estrogen to pure estradiol, to synthetic ethinyl estradiol, or toa pure estrone [26]. Migraineurs have sensitive nervous systems andbenefit from the most pure medications, especially with hormonal therapy.Avoidance of drugs like conjugated estrogen, which is likely to triggermigraine, seems prudent.

If a menopausal migraine patient has a uterus, then progesterone isnecessary in addition to estrogen to prevent uterine cancer. Some non-oralforms of HRT, such as the transdermal patch, have progesterone withestradiol in the same patch. Some menopausal women cannot toleratesupplemental estrogen; in these women, even low doses may exacerbate

migraine, and non-estrogen products may be needed to treat vasomotorsymptoms.

Acute migraine treatment in the menopausal woman can include thetriptan class in most cases. Attention to cardiac risk factors becomesespecially important in this population of migraine sufferers to ensure thatthe triptan class of medication is safe. An alternative could be a NSAIDsuch as naproxen if triptans are contraindicated.

Migraine prevention in the menopausal woman should take intoaccount coexisting conditions such as hypertension, fibromyalgia, de-pression, and insomnia. Choosing a preventive medication that can treat

more than one condition is desirable because this population of agingwomen is often on multiple medications.

RED FLAGS IN THE FEMALE MIGRAINEUR

New-onset aura in a patient who previously only experiencedmigraine without aura

A change or worsening in the pattern of the headache Complex or dense aura New-onset migraine O50 years of age (it is rare to have migraines

develop as a new condition over the age of 50)

In addition to the red flags listed above, look for temporal arteritis inthe female menopausal patient presenting with headache. Be on alert forsecondary headache, even in established migraine patients. Keep in mindthat migraine patients can also develop a secondary headache. If there issuspicion of a secondary headache, consider imaging studies or referral toa headache specialist.

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

exacerbation of migraine headaches perimenstrually. For many of thesewomen, exacerbation of migraines can occur at other times of hormonalchange, such as pregnancy, postpartum, and perimenopause. Attention to



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a womans hormonal status can help in the management of the femalemigraine patient.

More research is needed to provide evidence-based medicine for

much of what we do clinically for our female migraine patients. In themeantime, trying to maintain an even estradiol level can help in manywomen with hormonally related migraine headaches. Understanding thathormones influence migraine headaches can help the health-care providerand patient achieve optimal headache management.

Key Points

Identifying times of hormonal change in the female migraine patient isimportant.

Correlating hormonal changes with a womans migraine headache patterncan help in determining if there is a hormonal connection for that particularfemale patient. The best way to do this is for the female migraine patient tokeep a headache diary.

Consider strategies to minimize hormonal fluctuation, especially estrogen;this may help prevent hormonally related migraines.

Targeted mini-prophylaxis is a good treatment option for menstrualmigraine.

For most female migraineurs, contraception and HRT are not contra-indicated.

References

[1] Stewart WF, Lipton RB, Celanto DD, et al. Prevalence of migraine headache in theUnited States, relation to age, income, race, and other sociodemographic factors.JAMA 1992;267:649.

[2] Lipton RB, Stewart WF, Diamond S, et al. Prevalence and burden of migraine in the

United States: data from the American Migraine Study II. Headache 2001;41:64657.[3] Launer IJ, Terwindt GM, Ferrari MD. The prevalence and characteristics of migraine ina population-based cohort. Neurology 1990;53:53742.

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[5] Marcus DA. Interrelationships of neurochemicals, estrogen and recurring headache.Pain 1995;62:12939.

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Address reprint requests to

Susan L. Hutchinson, MDHeadache Center, Womens Medical Group of Irvine

16300 Sand Canyon Avenue, Ste 311Irvine, CA 92618

e-mail: [email protected]

mailto:[email protected]:[email protected]

migraña influencia hormonal

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