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 common headache types are discussed elsewhere.
●(See "Evaluation of headache in adults".)
●(See "Pathophysiology, clinical manifestations, and diagnosis of migraine in adults".)
●(See "Acute treatment of 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. However, we encourage the reader to consider the specific counseling and treatment needs of transgender and gender-diverse individuals.
BACKGROUND
Types of migraine — When migraines occur, regardless of estrogen level, the headache can be of several major types, as defined by the International Headache Society [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) – MA is primarily characterized by transient focal neurologic symptoms that are fully reversible and usually precede, or sometimes accompany, the 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].
●Estrogen-associated migraine – Estrogen-associated migraines include both MO and MA that are triggered by fluctuations in estrogen levels. Sources of changing 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) [4-6].
Menstrual migraine and menstrually related migraine are common estrogen-associated migraines. For both, the definition of menses includes endometrial bleeding from the normal menstrual cycle or from withdrawal of exogenous hormones, such as combined estrogen-progestin contraceptive oral pills, transdermal patches, or vaginal rings [1]. It is unclear if menstrual migraine and menstrually related migraines 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 two days after the first day of menses or withdrawal bleeding (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 headache attacks can also occur at other times in the menstrual cycle (table 2) [1]. MRM typically occur 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 suggests that MM last longer, require more medication to treat, and are more likely to recur compared with migraines that occur unrelated to menses for the same patients [7].
Pathophysiology of estrogen and migraine — The pathophysiology of migraine 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'.)
Activation of central pain pathways, whether from the cortex or from the brain stem, stimulates the trigeminal vascular system, which innervates cerebral blood vessels, causing associated release of vascular inflammatory substances, such as calcitonin-gene related peptide (CGRP), cytokines, and prostaglandins [8]. Estrogen has been shown to modulate this pathway in multiple complex ways through variable effects at different doses on the above vascular inflammatory substances [9].
Supporting data include the following:
●Hormonally related genetic differences have been found in adult females who suffer from MM [10].
●In female mice, estrogen affects central processing, with declining levels lowering the threshold for inducing cortical spreading depression [11].
●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 and cerebral vessels to serotonin [12,13].
Discussion of the genetic basis of migraines is presented elsewhere. (See "Pathophysiology, clinical manifestations, and diagnosis of migraine in adults", section on 'Genetic basis'.)
Impact of estrogen on migraine incidence — Migraine occurs more frequently in females than males, which makes female physiology one of the most common risk factors. The prevalence of migraine is three times higher in women than men [14]. The age when the prevalence for women markedly starts to climb occurs in early adolescence, reflecting the onset of menses, and markedly decreases following menopause. A study of data from the United States National Health Interview Survey reported three-month migraine incidence of 19.1 percent for females and 9.0 percent for males, but this varied by age [15]. In a different survey study of 120,000 households in the United States, cumulative lifetime migraine incidence was 43 percent for females and 18 percent for males; incidence in females peaked between 20 and 24 years of age [16].
QUESTIONS REGARDING ESTROGEN AND MIGRAINE
Can patients with migraine use estrogen-containing contraceptives? — Patients experiencing migraine without aura (MO) can safely use estrogen-containing contraceptives, including oral pills, transdermal patches, and vaginal rings. Individuals with migraines with aura (MA) are generally not candidates for estrogen-containing contraceptives [17-19]. However, the absolute risk of stroke in women with MA on combined hormonal contraceptives (CHC) is small, and good quality studies specific to low-dose estrogen products are lacking [20]. Therefore, the use of CHCs in women with MA should be individualized. For those with a clear indication for CHCs, such as endometriosis or those who desire this method after a clear discussion of the risks, their use is reasonable.
We and other experts use comprehensive tables of medical conditions and personal characteristics from the World Health Organization (WHO) and the Centers for Disease Control and Prevention (CDC) to guide contraceptive choice. Summary tables can be found through the WHO's Medical Eligibility Criteria for Contraceptive Use 2016 and the CDC's Summary Chart of US Medical Eligibility Criteria for Contraceptive Use [17,18].
Can estrogen-containing contraceptives reduce migraine? — Patients with menstrual migraine (MM) and menstrually related migraines without aura can benefit from use of estrogen-progestin-containing contraceptives to both prevent migraine and provide reliable contraception [21,22]. (See 'Hormonal therapy' below.)
By contrast, patients who experience MA, of any type, should avoid estrogen-containing contraceptives. (See 'Hormonal therapy' below.)
What if migraines develop while using an estrogen-containing contraceptive?
●Migraine with initial use of an estrogen-containing contraceptive – If migraine occurs 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 [23]. 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 [24]. However, if severe headaches or neurologic accompaniments to headache (MA) develop or worsen, estrogen use should be discontinued and alternative contraceptive methods offered. (See "Contraception: Counseling and selection".)
●Migraine 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) [25,26]. Continuous hormonal regimens may reduce migraine frequency and severity [27]. 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 [28].
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".)
Does migraine with and without aura increase stroke risk? — Cumulative data support an increasing risk of stroke in individuals with migraine, particularly MA [29]. Meta-analyses have reported the stroke risk to be 2.0 to 2.5 times greater in females with MA [30,31]. There is some evidence that increased MA frequency is related to greater ischemic stroke risk [32]. Fortunately, the absolute increase in risk of stroke remains low for most patients; patients with migraine in the Women's Health Study experienced four additional ischemic stroke events per 10,000 women per year [33]. However, on a population level, the small increase in absolute risk remains important as the prevalence of females with MA is over 4 percent [34]. Stroke risk of MA is further magnified when combined with other traditional risk factors, such as smoking and hypertension [31].
The complex interaction of migraine and stroke risk is reviewed in detail separately. (See "Headache, migraine, and stroke", section on 'Migraine as a risk factor for stroke'.)
Does estrogen use increase stroke risk in patients with migraine? — Both exogenous estrogen and migraine appear to increase the risk of stroke from baseline. Baseline stroke incidence varies from 3.4 per 100,000 in females 15 to 19 years old to 64.4 per 100,000 in females 45 to 49 years old [35]. These risks can be further increased by presence of other risk factors for stroke, such as cardiovascular disease, cigarette smoking, diabetes, and hypertension.
●Stroke risk – A 2- to 16-fold increased risk of stroke has been estimated for patients with migraine who use estrogen-containing contraceptives [20,36,37]. Studies have not typically evaluated risk by estrogen dose or delivery system. One study that examined the risk of stroke by presence or absence of aura reported aura increased the risk of stroke by approximately 50 percent [38]. A later meta-analysis that evaluated individuals with MA reported a sevenfold increased risk for those using estrogen-containing oral contraceptives [30].
●Presence of additional stroke risk factors – Stroke risk is further exacerbated by presence of underlying stroke risk factors. For example, one case-control study used a commercial claims database of 1884 cases of ischemic stroke among women 15 to 49 years old matched to 7536 controls without ischemic stroke [39]. In this study, the risk of ischemic stroke was increased more than 2.5-fold by cigarette smoking (adjusted odds ratio [aOR] 2.59), hypertension (aOR 2.73), diabetes (aOR 2.78), MA (aOR 2.89), and ischemic heart disease (aOR 5.49). For those with MA who also used an estrogen-containing contraceptive, the aOR for ischemic stroke was 6.08. By contrast, the risk for stroke among those with MA who were not using an estrogen-containing contraceptive was 2.65. Furthermore, among those with MO, the risk of ischemic stroke was only 1.77 with the use of an estrogen-containing contraceptive.
●Impact of estrogen dose – Increasing estrogen doses appears to increase stroke risk. In a large, population-based cohort study in Denmark, the relative risk (RR) of ischemic stroke increased with increasing doses of ethinyl estradiol (20 microgram dose: adjusted RR 0.88-1.53; 30 to 40 microgram doses: adjusted RR 1.40-2.20) [35]. However, given that the cumulative incidence of stroke is only 11 strokes/100,000 females ages 15 to 45, the absolute number of women experiencing stroke is low [39]. Compared with those with neither migraine nor CHC use, the OR of ischemic stroke was highest among those with MA using CHCs (OR 6.1, 95% CI 3.1-12.1).
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 [17,18].
●(See "Intrauterine contraception: Background and device types", section on 'Levonorgestrel IUD'.)
●(See "Etonogestrel contraceptive implant".)
●(See "Depot medroxyprogesterone acetate (DMPA): Efficacy, side effects, metabolic impact, and benefits".)
●(See "Progestin-only pills (POPs) for contraception".)
PATIENT ASSESSMENT FOR ESTROGEN-ASSOCIATED MIGRAINE
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. Evaluation starts with a detailed history to determine if the patient's headaches are consistent with migraine and, if so, whether the migraines 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) and exogenous (eg, hormonal contraceptives, fertility therapy) alterations.
Specific questions that can identify hormonal triggers include the following:
●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 menstrual migraines and menstrually related migraines occur up to two days prior or two days following the first day of menses [40]. (See 'Types of migraine' above.)
●If the patient has used a combined estrogen-progestin contraceptive (oral pills, transdermal patches, vaginal rings), how did these products affect the migraines? Migraines 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'.)
●Which other types of contraceptives has the patient used, and have they impacted migraine frequency? Migraine improvement or resolution with use of non-estrogen based methods is suggestive of estrogen-associated migraine. Patients whose migraine patterns do not change with use of non-estrogen-containing contraceptives likely have routine migraines. (See "Pathophysiology, clinical manifestations, and diagnosis of migraine in adults", section on 'Migraine headache'.)
●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.
●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.)
●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 OF MENSTRUAL MIGRAINE
Approach to treatment — Patients with menstrual migraines (MM) and menstrually related migraines (MRM) have reported their headaches are more painful, last longer, and require more doses of medication compared with patients with other migraine types [42,43]. Fortunately, patients with MM and MRM have multiple treatment options, including targeted therapy for acute symptoms, preventive therapy (short- or long-term), or a combination [44].
This discussion will review treatment approaches specific to MM and MRM. Clinical factors that impact treatment choice include presence of aura, desire or plan for pregnancy, or active pregnancy. Treatment typically progresses, as listed below, in the following order: (1) nonpharmacologic lifestyle changes, (2) symptomatic treatment (first over-the-counter and then prescription), (3) short-term prophylactic therapy for MM not responsive to symptomatic therapy, and (4) daily preventive therapy if the headaches occur frequently, severely, or are refractory to symptomatic therapy. In addition, there are several devices that are approved for migraine prevention [45]. Other medical comorbidities also factor into treatment selection. The approach to treatment of all types of migraine is presented in related content.
●(See "Acute treatment of migraine in adults", section on 'Approach to treatment'.)
●(See "Preventive treatment of episodic migraine in adults".)
●(See "Chronic migraine".)
Without aura — Patients with MM or MRM but no aura have all migraine treatment options available to them. Treatment generally proceeds from lower to higher resource interventions, as listed in the order below under "with aura." Detailed discussion of treatment of acute migraine is presented in related content. (See "Acute treatment of migraine in adults".)
Lifestyle interventions — Lifestyle changes are those that decrease known migraine triggers and are the mainstay of nonpharmacologic therapy for MM and MRM as well as other 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.
Symptomatic therapy — Symptomatic therapies are those used to reduce or resolve the acute headache and related symptoms as they happen. This approach does not try to prevent the headaches from occurring. First-line therapies are the over-the-counter analgesics. For patients who are unable to tolerate these medications or whose symptoms do not adequately respond to allow the patient to perform usual activities, we add prescription therapy in the order presented below. The medication is started at the onset of headache and stopped when the headache resolves.
Over-the-counter analgesics — Patients whose symptoms persist despite lifestyle changes are next offered a trial of over-the-counter analgesics. These include nonsteroidal anti-inflammatory drugs (NSAIDs), acetaminophen, and combination products (eg, acetaminophen, aspirin, and caffeine, commercial name Excedrin) [46,47]. As the optimal regimen is not known, we start with:
●Oral acetaminophen 650 mg every 6 hours or 1000 mg every 8 hours. Choice depends on dose availability.
and
●Either ibuprofen 600 mg every 6 hours or naproxen 500 mg every 12 hours.
Other doses, frequencies, and NSAIDs may be used. While several NSAIDs have reported efficacy in treating migraine, studies directly comparing the available NSAIDs for treatment of migraine are limited. Specific agents and supporting data are reviewed elsewhere. (See "Acute treatment of migraine in adults", section on 'Simple analgesics'.)
Triptans, gepants, and ditans — Common treatments for acute migraine symptoms without aura (MO) that are refractory to over-the-counter analgesics include triptans, ditans and gepants.
●Triptans – Triptans are typical first-line prescription medications because of demonstrated efficacy; patients with menstrual migraine are treated similarly to patients with other migraines. Choice of triptan is individualized based on medication properties, migraine characteristics, delivery route, patient response, and insurance coverage. The migraine characteristics that are of greatest importance in choosing a triptan include time to maximum intensity of the headache, duration of a typical migraine, and the frequency and timing of associated nausea and vomiting. In the author's practice, a commonly used initial regimen is:
•With onset of headache, sumatriptan 100 mg orally.
•The dose can be repeated in two hours if the headache has not adequately improved.
•Maximum dose of 200 mg/day.
Detailed information on triptans, selection, and dosing is presented in related content. (See "Acute treatment of migraine in adults", section on 'Triptans'.)
There are data supporting the use of almost all the triptans for the treatment of MM and MRM, including almotriptan, frovatriptan, naratriptan, rizatriptan, sumatriptan, and zolmitriptan; the percent free from headache at two to four hours after treatment ranges from approximately 50 to 70 percent [48-54]. The therapy chosen should consider the headache characteristics, including time to maximal intensity and the degree and timing of associated nausea and vomiting. Other considerations include the patient's other medical conditions, prior medication intolerances and failures, drug availability, and cost. Stroke, uncontrolled hypertension, coronary artery disease, and hemiplegic migraine are contraindications to the use of triptans. Preparations, choice of triptan, and dosing are discussed separately. (See "Acute treatment of migraine in adults", section on 'Triptans'.)
●Ditans and gepants – Two newer classes of acute migraine therapies, the ditans and gepants (also known as CGRP antagonists), do not cause vasoconstriction and thus can be used in patients with stroke, hypertension, or coronary artery disease [55,56]. For patients with MM who are unable to take triptans or have an inadequate response to triptans and other less commonly used migraine medications such as antiemetics, treatment with oral ditans or gepants is a potential next step. These medications are generally not first-line therapy because of significant cost and trials specific to patients with MM and MRM are limited. (See "Acute treatment of migraine in adults", section on 'CGRP antagonists'.)
•Ditans – Although the high affinity selective serotonin 1F receptor agonist lasmiditan has demonstrated success in treating acute migraine [55,57,58], its use has been limited due to CNS sedation and prescriber information warning not to drive or operate machinery for eight hours after use [59]. A study evaluating lasmiditan or placebo in 303 patients with perimenstrual migraine reported pain relief two hours after treatment occurred in more patients following lasmiditan 200 mg compared with placebo (33.6 versus 7.6 percent, odds ratio 6.04, 95% CI 2.39-15.25) [60]. More information on lasmiditan is available in related content. (See "Acute treatment of migraine in adults", section on 'Lasmiditan'.)
•Gepants – If selected, a typical prescription would be ubrogepant 50 mg orally with repeat dosing in two hours if needed, up to a maximum dose of 200 mg/day. Discussions of the drug class mechanism and supporting data are presented in related content. (See "Acute treatment of migraine in adults" and "Acute treatment of migraine in adults", section on 'CGRP antagonists'.)
Medications less commonly used — Ergots and antiemetics are much less commonly used given the higher efficacy and improved tolerability of triptans. Caffeine use can trigger rebound headaches, so it is often avoided. However, some patients find these medications useful in reducing headache.
●Ergots – (See "Acute treatment of migraine in adults", section on 'Ergots'.)
●Antiemetics – These may be used alone or in conjunction with other symptomatic therapies to shorten the duration of a migraine attack. (See "Acute treatment of migraine in adults", section on 'Antiemetics'.)
●Caffeine – The author generally avoids use of caffeine for treatment of migraine because use of caffeine may result in rebound headache. One exception is pregnant individuals who may use caffeine-containing products; caffeine in combination with butalbital and aspirin or acetaminophen can be effective. The use of all symptomatic medications needs to be limited to prevent medication overuse headache; use is typically restricted to two days a week to avoid headache exacerbation.
•(See "Benefits and risks of caffeine and caffeinated beverages", section on 'Headache'.)
•(See "Chronic migraine", section on 'Epidemiology'.)
Neurostimulator treatment — There are several neurostimulator devices approved for acute migraine treatment: the CEFALY device, gammaCore (vagal nerve stimulator), and Nerivio (a remote electrical modulation) [61-63]. Prescribing a neurostimulator device is a useful option when there is a concern for polypharmacy; these are not typically first-line therapies. While these devices should theoretically be safe in pregnancy, they have not been tested in this population. (See "Chronic migraine", section on 'Neurostimulation'.)
Preventive therapy
Miniprophylaxis — In patients for whom acute therapy does not control their migraines adequately, short-term prophylactic treatment with cyclic use of medication timed to the usual onset of headache can be employed. This is most useful for individuals with regular menstrual cycles in whom medication is started several days prior to menses and continued through the time frame during which they are at risk for migraine. Treatment progresses in the order below until symptoms are adequately controlled.
●NSAIDs – NSAIDs have been successfully used in short-term prevention of MM; NSAIDS are readily available, low cost, and low risk. 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, headache intensity, and duration [64]. 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) [65]. While the optimal NSAID, dose, and duration for miniprophylaxis 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).
●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) [66]. 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 [67]. 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 preventive therapy — Use of continuous preventive therapy is reasonable for patients who have contraindications to acute migraine therapy, experience frequent or long-lasting migraines, are at risk for developing headaches from medication overuse, and in those whose migraines significantly reduce their quality of life or function despite avoiding triggers and acute therapy [68,69]. All preventive medications for migraine can be considered for individuals with MM and MRM without aura (table 3). However, patients who are planning to become pregnant or are already pregnant should avoid valproic acid and topiramate. Discussions of the approach to medication selection and use for preventive therapy of migraines are found elsewhere.
●(See "Preventive treatment of episodic migraine in adults".)
●(See "Headache during pregnancy and postpartum", section on 'Preventive therapies'.)
Hormonal therapy — Individuals with debilitating MM or MRM who do not have aura can be offered hormonal therapy with estrogen-progestin contraceptives to suppress their physiologic cycling of estrogen and progesterone (figure 2). Patients with MM or MRM who also desire effective contraception may particularly benefit from this approach. The choice of product depends on patient preferences around oral versus vaginal medication, daily use versus interval insertion, availability, and cost, among other variables. (See "Combined estrogen-progestin oral contraceptives: Patient selection, counseling, and use", section on 'Our approach to COC selection'.)
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 [70]. Options for treatment include [71]:
●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 "Contraception: Hormonal contraceptive vaginal rings", section on 'Insertion and use'.)
•(See "Contraception: Transdermal contraceptive patches", section on 'Extended cycle use'.)
●Use of estrogen-progestin oral pills with ultralow (10 to 15 micrograms) or low doses (20 to 30 micrograms) (table 4).
●Use of extended-cycle preparations that reduce the number of withdrawal bleeds to four per year (table 4).
Neuromodulation — Several neural stimulatory devices are also available, which have efficacy in both acute and preventive therapy. Data specific to patients with MM and MRM are limited. (See "Acute treatment of migraine in adults", section on 'Neuromodulation'.)
With aura — In general, patients experiencing MM and MRM 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. (See 'Can patients with migraine use estrogen-containing contraceptives?' above.)
For acute treatment, hormonal therapies containing pharmacologic doses of estrogen and triptans are contraindicated in patients with stroke, cardiovascular disease, uncontrolled hypertension, and complicated migraine with aura, such as hemiplegic migraine. Fortunately, the overall risk for ischemic complications is low [72]. All other nonpharmacologic interventions, over-the-counter analgesics, antiemetics, ditans, and gepants (also called CGRP antagonists) can be offered.
●(See "Acute treatment of migraine in adults".)
●(See "Preventive treatment of episodic migraine in adults".)
UNIQUE POPULATIONS
Pregnancy — During pregnancy, migraines are generally worse during the first trimester, with improvement ranging from 77 to 83 percent by the second trimester [73-75]. 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 [76]. Nonpharmacologic interventions that may decrease migraine frequency are encouraged. (See 'Lifestyle interventions' above.)
Treatment of pregnant patients with migraine is mainly symptomatic rather than preventive. With the potential exception of magnesium oxide, preventive medications are usually avoided. The rationale is that most patient's migraines 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 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. The approach to treatment of migraine in pregnancy is presented separately. (See "Headache during pregnancy and postpartum", section on 'Acute migraine treatment'.)
The treatment of acute and chronic migraine in pregnancy is reviewed in detail separately. (See "Headache during pregnancy and postpartum", section on 'Migraine'.)
Postpartum — Individuals with menstrually related migraines or pure menstrual migraine often have a postpartum exacerbation of headaches. Headache intensity, duration, and need for analgesic therapies have all been reported to increase [75]. Once other potential causes of postpartum headache have been excluded, the treatment is then guided by lactation status.
●Nonbreastfeeding postpartum patients are treated similarly to nonpregnant individuals. (See "Acute treatment of migraine in adults", section on 'Approach to treatment'.)
●Postpartum patients who are breastfeeding 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 appears to have a protective effect and has been attributed to more stable estrogen levels [74]. Breastfeeding patients 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. Both NSAIDs and triptans are safe in this population. (See "Headache during pregnancy and postpartum", section on 'Acute migraine treatment'.)
Peri- and postmenopause — Many patients' migraines decrease after the menopausal transition, especially if they have a hormonal trigger [77]. 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 [78]. However, symptoms may initially worsen during perimenopause or early menopause [77].
Both estrogen-containing contraceptives and physiologic hormone therapy for patients with migraines that worsen in the perimenopausal transition are reasonable. Hormone-based treatment presumes that declining estrogen is the cause of worsening, which is not clear. Patients who desire treatment can target their migraines only, as discussed above, or their migraines plus menopausal symptoms. 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 [79,80]. For patients who desire a trial of hormone therapy for menopause management, there is evidence that the physiologic doses of hormone therapy, particularly transdermal estrogen patches, do not confer the same risk of stroke in patients with migraines with aura as that related to estrogen-containing contraceptives [81]. Treatment selection is influenced by patient preferences, presence of other symptoms, comorbid medical conditions, availability, and cost.
The clinical manifestations and treatment options 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 description – Migraine is a recurrent headache disorder that typically occurs in attacks lasting 4 to 72 hours. Migraines can occur with or without aura, and can be triggered by fluctuations in estrogen levels (estrogen-associated migraine). The most common estrogen-associated migraine is menstrual migraine (MM). As migraine can be triggered by changes in estrogen levels, migraine is two to three times more prevalent in biologic females compared with males. (See 'Types of migraine' above.)
●Clinical challenges of migraine and estrogen use – 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 (with the exception of physiologic doses of estrogen, such as for menopause therapy).
•(See 'Questions regarding estrogen and migraine' above.)
•(See "Treatment of menopausal symptoms with hormone therapy", section on 'Women with migraines'.)
●Evaluation and diagnosis – Evaluation starts with a detailed history to determine if the patient's headaches are consistent with migraine and, if so, whether the migraines are with or without aura. Secondary headache or migraine mimics need to be excluded. The diagnosis of migraine is a clinical one that is based on history and physical examination that meet diagnostic criteria for migraine. Once the diagnosis is established, additional questions determine if the migraines are temporally related to changes in estrogen levels. (See 'Patient assessment for estrogen-associated migraine' above.)
●Impact of menstrual and menstrually-related migraine – Patients with menstrual migraine (MM) and menstrually-related migraines (MRM) have reported that their headaches are more painful, last longer, and require more doses of medication compared with patients with other migraine types. Treatment options include lifestyle changes, targeted therapy for acute symptoms, preventive therapy (short or long term), or a combination thereof. (See 'Treatment of menstrual migraine' above.)
●Treatment options – Clinical factors that impact treatment choice include presence of aura, desire or plan for pregnancy, or active pregnancy. (See 'Approach to treatment' above.)
•No aura present – Patients with MM or MRM without aura generally have all migraine treatment options available to them. For patients who have not had adequate response to lifestyle changes, over-the-counter analgesics, and/or symptomatic therapy, preventive therapy or hormonal treatments may be options. (See 'Without aura' above.)
-For individuals who desire preventive therapy, we suggest an initial trial of cyclic rather than continuous treatment (Grade 2C). Use of miniprophylaxis rather than continuous prophylaxis reduces the total amount of medication used by the patient. However, use of continuous preventive therapy is reasonable for patients who have contraindications to acute migraine therapy, experience frequent or long-lasting migraines, are at risk for developing headaches from medication overuse, and in those whose migraines significantly reduce their quality of life or function despite avoiding triggers and acute therapy. (See 'Miniprophylaxis' above and 'Preventive therapy' above.)
-For patients who desire a trial of miniprophylaxis, we suggest an initial trial of NSAIDs rather than triptans, although triptans represent a reasonable alternative (Grade 2C). NSAIDs are readily available, low cost, and low risk. The author uses 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). (See 'Miniprophylaxis' above.)
•With aura – For patients experiencing MM and MRM with aura, we suggest avoiding pharmacologic levels of estrogen-containing products for preventive therapy (Grade 2C). However, some patients may find the absolute risk of stroke is acceptably low, experience benefits from pharmacologic 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. By contrast, physiologic treatment with estrogen, such as for menopause hormone therapy, is not contraindicated. (See 'With aura' above.)
-Triptans are contraindicated in patients with stroke, cardiovascular disease, uncontrolled hypertension, and complicated migraine with aura, such as hemiplegic migraine. (See 'With aura' above.)
-All other symptomatic nonpharmacologic interventions, over-the-counter analgesics, antiemetics, ditans, and calcitonin-gene related peptide antagonists can be offered. (See 'With aura' above.)
•Unique populations – Pregnant, postpartum, lactating, and peri- or postmenopausal patients all have changes in estrogen levels that can impact the frequency of estrogen-associated migraines. Treatment for these groups 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.
