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Estrogen-associated migraine headache, including menstrual migraine

Estrogen-associated migraine headache, including menstrual migraine
Literature review current through: Jan 2024.
This topic last updated: May 23, 2023.

INTRODUCTION — Alterations in estrogen levels (increases or decreases) can trigger headaches, including migraines. Changes in estrogen levels can result from biologic processes (eg, menstruation, pregnancy, or menopause) or from use of exogenous hormones (eg, hormone-containing contraceptives, in vitro fertilization). Migraine is the headache type most affected by estrogen.

The diagnosis and management of estrogen-associated headaches will be discussed here. Their definitions, pathophysiology, and a patient-centric approach to treatment will be emphasized. The diagnosis and treatment of other forms of migraine in adults are discussed separately.

(See "Pathophysiology, clinical manifestations, and diagnosis of migraine in adults".)

(See "Acute treatment of migraine in adults".)

(See "Preventive treatment of episodic migraine in adults".)

In this topic, when discussing study results, we will use the terms "woman/en" or "patient(s)" as they are used in the studies presented. We encourage the reader to consider the specific counseling and treatment needs of transgender and gender-expansive individuals.

BACKGROUND

Classification of migraine headache — Beyond presence or absence of aura, migraine can be classified according to the timing of headache in response to fluctuating estrogen levels, typically from the menstrual cycle or use of estrogen-containing contraceptives. The distinction of aura is independent of estrogen-related timing. A discussion of migraine subtypes other than those related to estrogen is available in related content. (See "Pathophysiology, clinical manifestations, and diagnosis of migraine in adults", section on 'Migraine subtypes'.)

Briefly, definitions from the International Headache Society include [1]:

Migraine without aura (MO) – MO is a recurrent headache disorder that typically occurs in attacks lasting 4 to 72 hours. Headache features often include unilateral location, pulsating quality, moderate-to-severe intensity, worsening with physical activity, and association with nausea and/or light and sound sensitivity (table 1). MO is the headache type most often associated with estrogen withdrawal, including menses or the placebo portion of a combined hormonal contraceptive regimen (figure 1) [2]. (See "Pathophysiology, clinical manifestations, and diagnosis of migraine in adults", section on 'Migraine headache'.)

Migraine with aura (MA) – Approximately 25 percent of individuals with migraine experience transient focal neurologic symptoms; these are called aura. Aura are fully reversible and usually precede, or sometimes accompany, the headache. Aura can also occur without any headache. Aura symptoms can include visual, sensory, speech/language, motor, brainstem, or retinal manifestations (table 1). The visual aura rating scale is a useful tool to decide if patients with visual symptoms qualify for the diagnosis of MA [3]. (See "Pathophysiology, clinical manifestations, and diagnosis of migraine in adults", section on 'Migraine aura'.)

Estrogen-associated migraine – Estrogen-associated migraine headaches occur in relation to the menstrual cycle; headache should occur over a minimum of three menstrual cycles to make the diagnosis [1]. Patients with menstrually-timed migraine headaches that occur less frequently are still considered to have menstrual migraine [4]. While the headaches can occur with or without aura, without aura is more common. The fluctuating estrogen levels can be physiologic (menses, pregnancy, postpartum, and perimenopause) (figure 2) or exogenous (combined estrogen-progestin contraceptives, menopause hormone therapy, and assisted reproductive technology, including in vitro fertilization) (figure 1) [5-7].

For the categories below, the definition of menses includes endometrial bleeding from the normal menstrual cycle or from withdrawal of exogenous hormones during the medication-free week for users of combined estrogen-progestin contraceptive oral pills, transdermal patches, or vaginal rings [1]. The first day of menses is counted as day 1 (ie, there is no day 0). It is unclear if menstrual migraine (MM) and menstrually related migraines (MRMs) are distinct entities or variable presentations of the same phenomenon.

Menstrual migraine (MM) – Pure MM attacks occur in close temporal relationship to the onset of menstruation, starting from two days prior to three days after the first day of menses or withdrawal bleeding (ie, -2 days to +3 days) (table 2) [1]. MM does not occur outside of menses. The headaches can occur with or without aura.

Menstrually related migraine (MRM) – MRM has the same onset in relation to menses as MM above, but headaches can also occur at other times in the menstrual cycle (table 2) [1]. MRM typically occurs during menses for at least two of every three menstrual cycles plus other occurrences. The headaches can occur with or without aura. Headache diary data suggest that MRM last longer, require more medication to treat, and are more likely to reoccur compared with migraines that are unrelated to menses for the same patients [8].

Nonmenstrual migraine (NMM) – NMM attacks also occur in temporal relationship to menstruation but occur exclusively outside of the menstrual window (ie, beyond three days following the onset of menstruation to up to two days from the start of onset of menses) [1]. These headaches can occur with or without aura.

Pathophysiology of estrogen impacting migraine headache — The pathophysiology of migraine is likely multifactorial. It is thought to be related to changes in neural networks involved in pain connectivity. (See "Pathophysiology, clinical manifestations, and diagnosis of migraine in adults", section on 'Pathophysiology'.)

Briefly, activation of central pain pathways, whether from the cortex or from the brain stem, stimulates the trigeminovascular system, which innervates cerebral blood vessels, causing associated release of vascular inflammatory substances, such as calcitonin gene-related peptide (CGRP) [9], cytokines, and prostaglandins [10]. Estrogen has been shown to modulate this pathway in multiple complex ways through variable effects at different doses, altering these vascular inflammatory substances [11]. Interestingly, when sensitivity to pain stimuli in healthy women was assessed during different phases of the menstrual cycle, a reduced pain threshold was seen, particularly in women with premenstrual symptoms [12]. Further, a study of women with episodic migraine show that they have higher CGRP levels in plasma and tear fluid during menstruation than healthy controls [9]. Estrogen-driven changes may be modulated through effects on the endogenous opioid system. Oxytocin (OT) may also play a role in estrogen withdrawal migraine. OT is produced in the hypothalamus and has widespread effects within the central nervous system, including mood regulation and pain suppression [13].  

Supporting data include the following:

Hormonally related genetic differences have been found in adult females who suffer from MM [14].

In female mice, estrogen affects central processing, with declining levels lowering the threshold for inducing cortical-spreading depression [15].

Increases in sensitivity to nociceptive responses to both peripheral and central stimuli appear to be influenced by estrogen. Estrogen affects the sensitivity of serotonin and dopaminergic receptors as well as cerebral vessels to serotonin [16,17].

The pathophysiology of migraine, including the genetic basis of migraine for some patients, is discussed in greater detail separately.

(See "Pathophysiology, clinical manifestations, and diagnosis of migraine in adults".)

(See "Pathophysiology, clinical manifestations, and diagnosis of migraine in adults", section on 'Genetic basis'.)

Prevalence of migraine in females — Female physiology is one of the most common risk factors for migraine development [18-20]. Migraine is up to three times more prevalent in females than males with reported lifetime prevalence of 17.5 and 8.6 percent, respectively [21]. Before puberty, the prevalence of migraine is similar for females and males. Migraine prevalence in females starts to climb in early adolescence (which coincides with the onset of menses), peaks during the 20s and 30s, and decreases following menopause [5,20]. Observational studies of females with migraine have reported approximately 18 to 25 percent note a relationship between menses and migraine onset [22-24].

COMMON CLINICAL QUESTIONS ABOUT ESTROGEN AND MIGRAINE

What is the stroke risk at baseline, with migraine, or with estrogen use? — There is evidence that females with migraine are at increased risk of ischemic stroke [25-27], but the absolute increase in risk of stroke remains low for most in the absence of other stroke risk factors [28]. The complex interactions of migraine with stroke risk, female sex, and impact of estrogen use are reviewed in detail separately.

(See "Migraine-associated stroke: risk factors, diagnosis, and prevention", section on 'Epidemiology'.)

(See "Migraine-associated stroke: risk factors, diagnosis, and prevention", section on 'Female sex'.)

(See "Migraine-associated stroke: risk factors, diagnosis, and prevention", section on 'Estrogen-containing contraception'.)

Can patients with migraine use estrogen-containing medications? — Patients with migraine may be candidates for estrogen-containing medications, such as contraceptives and hormone therapy for menopause. Factors that influence safety include the presence or absence of aura and other medical conditions. Use of estrogen-containing contraception in patients with migraine is discussed in related content.

(See "Migraine-associated stroke: risk factors, diagnosis, and prevention", section on 'Hormonal contraception'.)

(See "Migraine-associated stroke: risk factors, diagnosis, and prevention", section on 'Menopausal hormone therapy'.)

Can estrogen-containing contraceptives reduce migraine headache frequency? — Patients with estrogen-related migraine (including MM and MRM) without aura can benefit from use of estrogen-containing contraceptives to reduce the incidence of estrogen-associated migraine and provide reliable contraception [29,30]. (See 'Hormonal contraceptives for continuous prophylaxis' below.)

By contrast, patients who experience aura should generally avoid estrogen-containing contraceptives [31,32]. (See "Migraine-associated stroke: risk factors, diagnosis, and prevention", section on 'Estrogen-containing contraception'.)

What if migraine headache develops while using an estrogen-containing contraceptive?

Migraine headaches with initial use of a cyclic estrogen-containing contraceptive – If migraine headaches occur in the initial treatment cycle of an estrogen-containing contraceptive, there is only a one-third chance that it will occur in the next cycle [33]. Patients should be encouraged to continue the method, unless there are other reasons to discontinue or change, and track their headache symptoms. There is no clear evidence that switching to a lower dose of estrogen will improve headaches [34]. However, if severe headaches or neurologic accompaniments to headache (ie, aura, MA) develop or worsen, estrogen use should be discontinued and alternative contraceptive methods offered. (See "Contraception: Counseling and selection".)

Migraine headache persists with continued use of an estrogen-containing contraceptive – Patients may be susceptible to the changing estrogen levels rather than the absolute level. Patients with MO triggered by the falling estrogen levels experienced during placebo week may find their headaches improve with use of extended- or continuous-dose regimens (ie, no placebo week for pills or rings) [35,36]. Continuous hormonal regimens may reduce migraine frequency and severity [37]. In a study evaluating the effects of hormonal contraception in patients with MM, 39 percent of patients with contraception-induced amenorrhea reported no MO days during the preceding month [38].

Discussions specific to each type of estrogen-progestin contraceptive are presented separately:

(See "Combined estrogen-progestin oral contraceptives: Patient selection, counseling, and use".)

(See "Contraception: Transdermal contraceptive patches".)

(See "Contraception: Hormonal contraceptive vaginal rings".)

Can progestin-only contraceptives be used by patients with migraine? — Progestin-only oral contraceptives do not appear to confer a risk of ischemic stroke and can be used by patients with migraine, although there is no universal consensus on this approach [31,39].

(See "Intrauterine contraception: Background and device types", section on 'Levonorgestrel IUD'.)

(See "Contraception: Etonogestrel implant".)

(See "Depot medroxyprogesterone acetate (DMPA): Efficacy, side effects, metabolic impact, and benefits".)

(See "Contraception: Progestin-only pills (POPs)".)

PATIENT ASSESSMENT FOR ESTROGEN-ASSOCIATED MIGRAINE HEADACHE

Diagnosis of migraine — The diagnosis of migraine is a clinical one that is based on history and physical examination that meet diagnostic criteria for migraine (table 1). Evaluation starts with a detailed history to determine if the patient's headaches are consistent with migraine and if so, whether the migraine headaches are with or without aura. Secondary headache or migraine mimics need to be excluded. Additional questions include the frequency, intensity, duration, prior therapies (medical and nonmedical), and other associated neurologic symptoms. Use of a headache calendar or diary to track symptoms and medication may be helpful (form 1). (See "Pathophysiology, clinical manifestations, and diagnosis of migraine in adults", section on 'Diagnosis'.)

Diagnosis of estrogen-associated migraine — Once the diagnosis of migraine is established, additional questions determine if the migraines are temporally related to changes in estrogen levels. Migraine frequency and severity are assessed across the patient's hormonal epoch, including both endogenous (eg, menses, pregnancy, postpartum, menopausal transition) and exogenous (eg, hormonal contraceptives, fertility therapy) alterations.

Specific questions that can identify hormonal triggers include the following:

Impact of menstrual cycle – Are the migraines associated with ovulation or menses? If yes to either, then questions are asked about the specific timing of each in relation to migraine. Pure MM headaches and menstrually related migraine headaches occur up to two days prior or two days following the first day of menses [40]. (See 'Classification of migraine headache' above.)

Impact of hormonal contraceptives – If the patient has used a combined estrogen-progestin contraceptive (oral pills, transdermal patches, vaginal rings), how did these products affect the migraines? Migraine headaches that cluster during the placebo part of the cycle are driven by estrogen withdrawal and may respond to continuous-dose regimens. (See "Combined estrogen-progestin oral contraceptives: Patient selection, counseling, and use", section on 'Continuous or extended use'.)

Impact of other contraceptives – Which other types of contraceptives has the patient used, and have they impacted migraine frequency? Migraine improvement or resolution with use of nonestrogen-based methods is suggestive of estrogen-associated migraine. Patients whose migraine patterns do not change with use of nonestrogen-containing contraceptives likely have routine migraines. (See "Pathophysiology, clinical manifestations, and diagnosis of migraine in adults", section on 'Migraine headache'.)

Change in contraception – Has there been a recent change in contraceptive method or formulation (eg, change from one type of oral contraceptive pill to another)? Changes in estrogen levels, either increases or decreases, may trigger migraines in some patients.

Impact of pregnancy – For patients who have been pregnant:

How did pregnancy affect migraines? Estrogen-related migraines are generally worse in the first trimester and improve in the second trimester. (See 'Pregnancy' below.)

How did the migraines change in the postpartum period? The precipitous fall in estrogen levels experienced by postpartum individuals may trigger migraines in susceptible patients. However, individuals who breastfeed exclusively for a long enough duration to suppress estrogen levels often experience a reduction in migraine frequency. (See 'Pregnancy' below and 'Lactating patients' below.)

Impact of fertility therapy – Has the patient undergone fertility therapy? If so, which kind? Patients whose migraines are triggered by changes in estrogen states may have more headaches in association with in vitro fertilization. In one study, headache occurred most frequently following gonadotropin-releasing hormone analog-induced hypothalamic-pituitary-ovarian axis downregulation, which is associated with low estrogen levels [41]. (See "In vitro fertilization: Overview of clinical issues and questions".)

TREATMENT PROGRESSION — Patients with any type of estrogen-associated migraine have multiple treatment options, including targeted treatment for acute symptoms, preventative therapy as needed, or continuous prophylaxis [42].

Typical treatment progression includes:

(1) Nonpharmacologic lifestyle changes for migraine prevention

(2) Acute treatment of symptoms (first over the counter and then migraine-specific drugs)

(3) Preventative treatment

Mini prophylaxis with cyclic use of preventative therapy timed to the usual onset of headache

Continuous (ie, daily) prophylaxis for headaches that occur frequently, are severe, or are refractory to acute therapy or mini prophylaxis. Patients with estrogen-associated migraine headache have the options of established migraine-specific drugs or treatment with hormonal contraception.

The approach to treatment of all types of migraine is presented in related content.

(See "Acute treatment of migraine in adults".)

(See "Preventive treatment of episodic migraine in adults".)

(See "Chronic migraine".)

Lifestyle interventions — Lifestyle changes are those that decrease known migraine triggers and are the mainstay of nonpharmacologic therapy for all migraine types. All patients receive counseling on maintenance of regular routines for eating, sleeping, and exercise. Patients may find symptom diaries helpful to track migraine onset and identify potential triggers. Magnesium (up to 360 mg/day) and riboflavin (400 mg/day) supplements may help reduce migraine headache frequency as well [43,44]. (See "Pathophysiology, clinical manifestations, and diagnosis of migraine in adults", section on 'Precipitating and exacerbating factors'.)

Acute treatment — Acute treatment of estrogen-associated migraine headache is the same as for other migraine headaches; the purpose is to reduce or resolve the acute headache and related symptoms as they happen. This approach does not try to prevent the headaches from occurring. Therapy typically starts with the over-the-counter analgesics and progresses through migraine-specific drugs as needed (eg, triptans, calcitonin gene-related peptide [CGRP] antagonists, lasmiditan). Patients are reassessed for treatment efficacy after two to three months.

Detailed discussion of the approach to treatment, drug selection, and use is provided in separate content. (See "Acute treatment of migraine in adults".)

Preventive therapy — Patients with frequent or disabling estrogen-associated migraine (MM, MRM, and NMM), or those who do not experience adequate relief with acute treatment, are candidates for medication prophylaxis. Options include mini (ie, cyclic) and continuous prophylaxis. Continuous preventive therapy for all other types of migraine headache is discussed separately. (See "Preventive treatment of episodic migraine in adults", section on 'Indications'.)

Mini prophylaxis — In general, mini, or short-term, prophylaxis involves cyclic use of medication starting just prior to the usual onset of headache. For patients with estrogen-associated migraine, this approach is most useful for individuals with regular menstrual cycles and relatively predictable resultant migraines. Patients start medication several days prior to menses and continue through the time frame during which they are at risk for migraine. Treatment progresses in the order below until symptoms are adequately controlled. Patients are reassessed for treatment efficacy after two to three months.

Our approach to mini prophylaxis for patients with estrogen-associated migraine is:

NSAIDs – Nonsteroidal anti-inflammatory drugs (NSAIDs) have been successfully used in short-term prevention of MM; NSAIDs are readily available, low cost, and low risk. While the optimal NSAID, dose, and duration for mini prophylaxis are not known, the author suggests use of naproxen sodium 500 mg twice daily, to begin one to two days before typical onset of MM, and to continue for the duration during which the patient is at risk for hormonal migraine (usually for a total of five to seven days).

In a trial comparing naproxen sodium 500 mg twice daily with placebo in 40 individuals with MM, naproxen was more effective in reducing headache days, intensity, and duration [45]. In a small trial, mefenamic acid 500 mg three times a day was compared with placebo in 24 patients with MM, and more patients receiving mefenamic acid reported pain relief (79 versus 17 percent, respectively) [46].

Triptans – For patients who do not respond to cyclic NSAID therapy, the next option is cyclic use of triptan medication to prevent or reduce migraine frequency. As with NSAIDs, the optimal drug, dose, and duration of treatment are not known. The author suggests either zolmitriptan 2.5 mg twice daily or frovatriptan 2.5 mg daily (choice determined by patient response, availability, and cost) to start two days prior to typical headache onset and to continue for a total of five days.

Supporting data for this approach include:

A meta-analysis of six trials reported a reduction in MM days with short-term use of frovatriptan (2.5 mg daily or twice daily), naratriptan (1 mg twice daily), and zolmitriptan (2.5 mg two or three times daily) [47]. Frovatriptan and zolmitriptan were also associated with decreased headache severity and less need for rescue medication. As a result, the authors concluded that frovatriptan 2.5 mg twice daily and zolmitriptan 2.5 mg two or three times a day were the preferred treatments.

A nonrandomized study of 38 individuals with MM compared treatment with frovatriptan (2.5 mg daily), transdermal estrogen (25 micrograms), or naproxen sodium (500 mg daily) for the short-term prevention of MM [48]. Treatment was started two days before the expected onset of menstrual headache for a total of six days. Patients receiving frovatriptan reported reduced incidence of daily migraine and severity compared with the other therapies. The average prevalence of MM was 60 percent with frovatriptan, 79 percent with estrogens, and 78 percent with naproxen. However, if the number of triptan doses needed to treat MRM is such that patients have inadequate medication to treat other migraines, continuous preventive therapy is warranted.

Continuous prophylaxis — Patients with estrogen-associated migraine may require continuous prophylaxis rather than acute episodic treatment or mini prophylaxis because these individuals have reported their headaches are more painful, last longer, and require more doses of medication compared with patients with other migraine types [4,49,50]. Treatment options include nonhormonal migraine-specific drugs and hormonal contraceptives.

Nonhormonal continuous options — Nonhormonal continuous prophylaxis is the daily use of medication aimed at preventing migraine. Patients who may benefit include those with contraindications to acute migraine therapy, who experience frequent or long-lasting migraines, are at risk for developing headaches from medication overuse, have unpredictable menstrual cycles (eg, polycystic ovary syndrome [PCOS]), and whose migraines significantly reduce their quality of life or function despite avoiding triggers and using acute therapy [51,52]. All preventive medications for migraine can be considered for individuals with estrogen-associated migraine (table 3). However, patients who are planning to become pregnant or are already pregnant should avoid valproic acid and topiramate. These medications have a larger body of supporting evidence compared with hormonal contraceptives for prophylaxis and can be used by patients who cannot use or do not want hormonal contraception. Patients are reassessed for treatment efficacy after two to three months.

Detailed discussions of nonhormonal medications, selection, and data supporting their use for preventing migraine headache are available separately.

(See "Preventive treatment of episodic migraine in adults".)

Hormonal contraceptives for continuous prophylaxis — Hormonal contraceptives are an option for headache suppression unique to patients with estrogen-associated migraine headache.

Treatment rationale — Hormonal contraceptives can be given to suppress fluctuating hormone levels and thereby reduce estrogen-associated migraine. This therapy would not be expected to alter the frequency of nonhormonally-mediated migraine. Patients who desire hormonal contraception or who gain other medical benefit from hormonal contraception (eg, treatment of dysmenorrhea, heavy menstrual bleeding, endometriosis) may prefer this approach rather than nonhormonal continuous prophylaxis as they can address two health issues with one medication.

No aura — Individuals with debilitating estrogen-associated migraine who do not have aura can be offered hormonal therapy with estrogen-containing contraceptives to suppress their physiologic cycling of estrogen and progesterone (figure 2) [29,30]. Use of progestin-only methods is also reasonable, although supporting data are mainly with desogestrel [35]. Use of hormonal contraceptives to reduce migraine frequency may particularly benefit patients with estrogen-associated migraine who also desire effective contraception and/or have other indications for hormonal contraceptives (eg, heavy menstrual bleeding, dysmenorrhea, endometriosis-related pain). Patients are reassessed for treatment efficacy after two to three months.

Mechanism of action – Estrogen-progestin contraceptives prevent the midcycle rise in estrogen that triggers ovulation. Continuous or extended dosing of these products avoids estrogen withdrawal. In sensitive individuals, a decrease in estrogen level greater than 10 micrograms of ethinyl estradiol may trigger an estrogen withdrawal migraine [53].

Choice of treatment – The choice of product depends on patient preferences around oral versus vaginal medication, daily use versus interval insertion, impact on bleeding patterns, availability, and cost, among other variables. (See "Combined estrogen-progestin oral contraceptives: Patient selection, counseling, and use", section on 'Our approach to COC selection'.)

Options for treatment include [54]:

Continuous dosing – Continuous dosing (ie, without placebo week) of estrogen-progestin oral pills or vaginal rings (transdermal contraceptive patches are not advised for continuous dosing regimens).

-(See "Combined estrogen-progestin oral contraceptives: Patient selection, counseling, and use", section on 'Continuous or extended use'.)

-(See "Contraception: Hormonal contraceptive vaginal rings", section on 'Insertion and use'.)

-(See "Contraception: Transdermal contraceptive patches", section on 'Extended cycle use'.)

Low estrogen doses – Use of estrogen-progestin oral pills with ultralow (10 to 15 micrograms) or low doses (20 to 30 micrograms) (table 4).

Extended-cycle products – Use of extended-cycle preparations that reduce the number of withdrawal bleeds to four per year (table 4).

Efficacy – Small observational studies have reported that use of hormonal contraception is associated with reductions in migraine frequency, but data are limited. [35]. Regimens evaluated included estrogen-progestin oral pills, progestin-only (desogestrel) pills, combined hormonal contraceptive patch, and combined hormonal contraceptive vaginal ring [55-60].

Examples of representative studies in patients with estrogen-associated migraine include:

In a study including 32 patients with menstrually related migraine, use of extended-cycle combined contraceptive pills (ethinyl estradiol 30 mcg and levonorgestrel 150 mcg) was associated with reduced daily headache scores compared with no treatment, but the difference was of unclear clinical impact (pretreatment daily headache count 1.29 ± 0.10 versus extended treatment daily count 1.10 ± 0.14) [61].

In an observational study of 28 patients with estrogen-associated migraine who were using cyclic estrogen-progestin contraception, the number of days with migraine was roughly double during the hormone-free week compared with the treatment weeks (hormone free week 2.18 ± 1.59; week 2, 0.7 ± 0.98; week 3, 0.55 ± 0.96; week 4, 0.68 ± 1.19) [62].

With aura — In general, patients experiencing estrogen-associated migraine with aura should avoid pharmacologic levels of estrogen-containing products for preventive therapy. However, some patients may find the absolute risk of stroke is acceptably low, experience benefits from estrogen use that outweigh the risks (eg, treatment of endometriosis and related pain with combined hormonal contraceptives), or place higher value on the choice of contraceptive method. Treatment with progestin-only hormonal contraceptives are another option [55,56]. (See 'Can patients with migraine use estrogen-containing medications?' above.)

Neuromodulation — Several neural stimulatory devices are also available for both acute treatment and prophylactic therapy. Data specific to patients with MM and MRM are limited. Discussion of neuromodulation treatments is presented separately. (See "Acute treatment of migraine in adults", section on 'Neuromodulation'.)

UNIQUE POPULATIONS

Pregnancy — During pregnancy, migraine headaches are generally worse during the first trimester but approximately 80 percent of patients improve by the second trimester [63-65]. Though pregnancy ultimately reduces migraine both with and without aura, the reduction appears to be greater for individuals without aura. In a case-control study of 300 patients with migraine, pregnancy resulted in reduction or resolution of migraine for 77 percent of patients without aura compared with 44 percent of patients with aura [66]. Nonpharmacologic interventions that may decrease migraine frequency are encouraged. (See 'Lifestyle interventions' above.)

Treatment of pregnant patients with migraine is mainly acute rather than preventive, with the potential exception of magnesium oxide, coenzyme Q, and acetaminophen. The rationale is that most patients' migraine headaches improve by the second trimester, four to six weeks of preventive therapy are needed to determine efficacy, and none of the preventive migraine therapies have extensive safety data in pregnancy. The approach to treating migraine in pregnancy is presented separately. (See "Headache during pregnancy and postpartum", section on 'Acute migraine treatment'.)

Postpartum — Individuals with menstrually related migraine (MRM) headache or pure MM headaches often have a postpartum exacerbation of headaches. Headache intensity, duration, and need for analgesic therapies have all been reported to increase [65]. Once other potential causes of postpartum headache have been excluded, the treatment is then guided by lactation status.

Nonlactating postpartum patients are treated similarly to nonpregnant individuals. (See "Acute treatment of migraine in adults", section on 'Approach to treatment'.)

Postpartum patients who are lactating are advised to avoid ergots and codeine because of potential impact on the infant. The safety of medication use in breastfeeding mothers can be checked by searching the drug name in the Lexicomp drug interactions program included with UpToDate or by searching the drug name in other resources, such as LactMed. Nonsteroidal anti-inflammatory drugs (NSAIDs) and triptans are the author's preferred symptomatic medications in the postpartum period. (See "Headache during pregnancy and postpartum", section on 'Acute migraine treatment'.)

More information on the evaluation and management of migraine in the postpartum period can be found in related topics.

(See "Headache during pregnancy and postpartum", section on 'Evaluation of postpartum patients'.)

(See "Headache during pregnancy and postpartum", section on 'Postpartum patients'.)

Lactating patients — Breastfeeding (or pumping) appears to have a protective effect and has been attributed to more stable estrogen levels [64]. Lactating patients are advised to avoid codeine because of potential impact on the infant. The safety of medication use in breastfeeding patients can be checked by searching the drug name in the Lexicomp drug interactions program included with UpToDate or by searching the drug name in other resources, such as LactMed. Both NSAIDs and triptans are safe in this population. (See "Headache during pregnancy and postpartum", section on 'Acute migraine treatment'.)

Peri- and postmenopause — Fluctuating estrogen levels during peri- and early menopause may initially worsen migraine symptoms [67]. Many patients' migraines decrease after the menopausal transition is completed, especially if they have a hormonal trigger [67]. In one population-based study, headache was reported by 34 percent of premenopausal participants versus 24 percent of postmenopausal participants at the end of the study period [68].

Patients whose migraine headaches worsen in the perimenopausal transition can reasonably use estrogen-containing contraceptives or physiologic hormone therapy, assuming no other contraindications. Hormone-based treatment presumes that declining estrogen is the cause of worsening, which is not clear. Patients who desire treatment can target their migraine headaches only, as discussed above, or treat both their migraine headaches plus menopausal symptoms. Treatment selection is influenced by patient preferences, presence of other symptoms, comorbid medical conditions, availability, and cost.

Estrogen-containing therapy – Patients who are candidates for estrogen therapy and who desire one treatment for both migraine and menopause symptoms can reasonably consider a trial of hormone therapy [69]. There is evidence that the physiologic doses of estrogen in hormone therapy, particularly when delivered by transdermal estrogen patch, do not confer the same risk of stroke in patients with MA as that related to estrogen-containing contraceptives (ie, supraphysiologic estrogen doses) [70].

Nonestrogen therapy – Selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, and gabapentin have been shown to be effective in both menopause-related migraine worsening and other vasomotor symptoms [71,72].

The clinical manifestations and treatment options of symptoms related to menopause are discussed in detail elsewhere.

(See "Clinical manifestations and diagnosis of menopause".)

(See "Treatment of menopausal symptoms with hormone therapy".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Migraine and other primary headache disorders" and "Society guideline links: Contraception".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

Beyond the Basics topics (see "Patient education: Headache causes and diagnosis in adults (Beyond the Basics)" and "Patient education: Headache treatment in adults (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

Migraine types and prevalence – Beyond presence or absence of aura, migraine can be classified according to the timing of headache in response to fluctuating estrogen levels, typically from the menstrual cycle or use of estrogen-containing contraceptives. Estrogen-associated migraine include menstrual migraine (MM, the most common), menstrually related migraine (MRM), and nonmenstrual migraine (NMM). As migraine can be triggered by changes in estrogen levels, migraine is up to three times more prevalent in females compared with males. (See 'Background' above.)

Interplay between migraine and estrogen – The complex interplay of estrogen, headache, and stroke risk prompts many clinical challenges, including the use of estrogen-containing contraceptives in patients with migraine, use of hormonal products to reduce migraine, impact of migraine on stroke risk, and additional stroke risk conferred by estrogen use in patients with migraine. While patients with migraine without aura can safely use estrogen-containing products, those with aura should generally avoid them (exceptions include physiologic doses of estrogen, such as for menopause therapy).

(See 'Common clinical questions about estrogen and migraine' above.)

(See "Treatment of menopausal symptoms with hormone therapy", section on 'Women with migraines'.)

Evaluation and diagnosis of estrogen-associated migraine – Evaluation starts with a detailed history to determine if the patient's headaches are consistent with migraine and, if so, whether the migraine headaches are with or without aura. Secondary headache or migraine mimics need to be excluded. Once the diagnosis is established, additional questions determine if the migraine headaches are temporally related to changes in estrogen levels. (See 'Patient assessment for estrogen-associated migraine headache' above.)

Lifestyle interventions – We counsel all patients on maintenance of regular routines for eating, sleeping, and exercise as preventive measures. Patients may find symptom diaries helpful to track migraine onset and identify potential triggers to avoid. Magnesium and riboflavin supplements may reduce headache frequency. (See 'Lifestyle interventions' above.)

Acute treatment Acute treatments are used to reduce or resolve the headache and related symptoms as they happen; this approach does not try to prevent the headaches from occurring. Treatment options are the same for migraine with or without estrogen association and include simple analgesics followed by migraine-specific agents. Detailed discussions of treatment options, selection, and use are presented in related content. (See "Acute treatment of migraine in adults".)

Preventive therapy – Patients with frequent or disabling estrogen-related migraine, or those who do not experience adequate relief with acute treatment, are candidates for medication prophylaxis. Medication prophylaxis can be taken only around the time of predictable headaches (ie, mini prophylaxis) or daily (ie, continuous). Patient response is assessed after two to three months. (See "Preventive treatment of episodic migraine in adults".)

Mini prophylaxis for patients with predictable headache – For individuals with frequent or disabling estrogen-related migraine headaches that are predictable, we suggest an initial trial of mini prophylaxis (ie, cyclic) rather than episodic acute treatment or continuous prophylaxis (Grade 2C). Mini, or short-term, prophylaxis involves cyclic use of medication timed to the usual onset of the hormonally-related headache and thereby reduces the total amount of medication needed. (See 'Mini prophylaxis' above.)

This approach is most useful for individuals with regular menstrual cycles and relatively predictable resultant migraine headaches. Alternately, use of continuous preventive therapy is reasonable. (See "Preventive treatment of episodic migraine in adults".)

For patients who elect a trial of mini prophylaxis, we suggest an initial trial of nonsteroidal anti-inflammatory drugs (NSAIDs) rather than triptans (Grade 2C). While triptans are a reasonable alternative, we prefer an initial trial of NSAIDs because they are readily available, low cost, and low risk. The author uses naproxen sodium 500 mg twice daily beginning one to two days before typical migraine onset and continuing through the typical migraine duration. (See 'Mini prophylaxis' above.)

Continuous headache prophylaxis for patients with unpredictable headache - For patients with severe/disabling estrogen-associated migraine whose headaches or menstrual cycles are not predictable, we suggest continuous headache prophylaxis rather than acute episodic treatment or mini prophylaxis (Grade 2C). This approach is also reasonable for patients who do not have an adequate response to mini prophylaxis. Continuous prophylaxis is the daily use of medication aimed at preventing migraine. Specific recommendations for choice of nonhormonal drugs and their supporting evidence are provided separately. (See "Preventive treatment of episodic migraine in adults".)

In patients with both estrogen-associated migraine without aura and with other indications for hormonal contraception, hormonal contraception is a reasonable option for continuous prophylaxis. This approach provides effective contraception, potentially treats other issues (eg, dysmenorrhea, heavy menstrual bleeding, endometriosis-related pain), and utilizes one drug for multiple indications. Patients without other indications for hormonal contraception or with frequent nonhormonal migraine are likely better treated with established migraine headache treatment options. Patients with aura should avoid estrogen-containing products for preventive therapy. (See "Preventive treatment of episodic migraine in adults".)

Unique populations – Pregnant, postpartum, lactating, and peri- or postmenopausal patients all have changes in estrogen levels that can impact the frequency of estrogen-associated migraine headaches. Treatment for these patients is individualized. (See 'Unique populations' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Anne Calhoun, MD, FAHS, who contributed to an earlier version of this topic review.

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Topic 5441 Version 48.0

References

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