Menstrual Migraine: Pathophysiology, Diagnosis, and Impact

The incidence of migraine varies over the course of the menstrual cycle. In the general population, approximately 60% of women with migraine report an increased frequency of headache during menses. The estrogen withdrawal that occurs just prior to the onset of menses and that leads to loss of serotonergic tone is thought to be the trigger for headaches that arise at this time of the menstrual cycle. The ability of triptans, specific serotonin receptor agonists, to prevent menstrual migraine is consistent with this hypothesis. Moreover, compared with headaches that occur during other times in the cycle, menstrual migraines are more severe in most women and may be of longer duration, as well as more resistant to treatment in a subset of women.     

Perimenstrual headaches: Unmet needs

The risk of migraine is increased among women during a 5-day perimenstrual window that starts 2 days before the onset of menses and continues through the first 3 days of menstruation. For some women with menstrual migraine, headaches that occur at this time are more severe, of longer duration, and more disabling. Although it is recognized that menstrual migraine requires specific management, there remain a number of unmet needs. In particular, comorbidity can result in women with menstrual migraine presenting to obstetrician/gynecologists or psychiatrists rather than primary care physicians or neurologists. Failure to diagnose menstrual migraine will lead to suboptimal management. Accurate diagnosis is insufficient unless it results in effective treatment strategies. Although effective and specific treatments for menstrual migraine have been developed, there is a need to define individual timing and duration of perimenstrual prophylaxis.     

Understanding the Causes and Prevention of Menstrual Migraine: The Role of Estrogen

Menstruation increases the risk of migraine in susceptible women. In a subpopulation of women with menstrual migraine, headaches occurring in association with onset of menses may be more severe and of longer duration than headaches experienced by the same woman at other times of her menstrual cycle. Although menstrual migraines share many clinical characteristics of other types of migraines, their occurrence is predictable provided that the patient has regular menstrual cycles. Therefore, short-term prevention regimens can be considered for women whose headaches are not adequately managed with acute therapies.     

Understanding the causes and prevention of menstrual migraine: the role of estrogen

Menstruation increases the risk of migraine in susceptible women. In a subpopulation of women with menstrual migraine, headaches occurring in association with onset of menses may be more severe and of longer duration than headaches experienced by the same woman at other times of her menstrual cycle. Although menstrual migraines share many clinical characteristics of other types of migraines, their occurrence is predictable provided that the patient has regular menstrual cycles. Therefore, short-term prevention regimens can be considered for women whose headaches are not adequately managed with acute therapies.     

Tailoring Management Strategies for the Patient With Menstrual Migraine: Focus on Prevention and Treatment

Many women report an increased frequency of headaches around the time of menses. For some women, these headaches are more severe, of longer duration, and lead to greater disability than those occurring at other times in the menstrual cycle. A headache diary is critical to properly diagnose menstrual migraine (MM) by prospectively documenting headache days, severity of headache, and the headaches' relationship to menses. In women with diagnosed MM, acute treatment has been proven to be effective in randomized clinical trials. For those women who have predictable periods and may require preventive therapy, short-term prevention is a reasonable approach due to the predictability of MM. Although several agents (eg, naproxen sodium, magnesium, triptans) have been evaluated for prevention of MM, all but triptans have been assessed in small trials of between 20 and 35 women. Naratriptan, frovatriptan, and, most recently, zolmitriptan have been proven effective in preventing MM. Triptans are generally well tolerated, and the long-term safety of these agents is currently being evaluated. The flexibility of using acute and preventive therapy allows physicians to tailor treatment of MM and meet the needs of individual patients.     

Tailoring management strategies for the patient with menstrual migraine: focus on prevention and treatment

Many women report an increased frequency of headaches around the time of menses. For some women, these headaches are more severe, of longer duration, and lead to greater disability than those occurring at other times in the menstrual cycle. A headache diary is critical to properly diagnose menstrual migraine (MM) by prospectively documenting headache days, severity of headache, and the headaches' relationship to menses. In women with diagnosed MM, acute treatment has been proven to be effective in randomized clinical trials. For those women who have predictable periods and may require preventive therapy, short-term prevention is a reasonable approach due to the predictability of MM. Although several agents (eg, naproxen sodium, magnesium, triptans) have been evaluated for prevention of MM, all but triptans have been assessed in small trials of between 20 and 35 women. Naratriptan, frovatriptan, and, most recently, zolmitriptan have been proven effective in preventing MM. Triptans are generally well tolerated, and the long-term safety of these agents is currently being evaluated. The flexibility of using acute and preventive therapy allows physicians to tailor treatment of MM and meet the needs of individual patients.     

Perimenstrual headache: Treatment options

At least half of women migraineurs experience menstrual migraine (MM), suggesting a hormonal explanation for the incidence of these headaches. Basic science efforts suggest a relationship between estrogen and the neurotransmitters and neuronal structures critical in the pathophysiology of migraine. The notion that MM is more severe, longer in duration, and more resistant to treatment than headaches occurring at other times during the menstrual cycle may apply more to women seeking treatment for their headaches than to migraineurs in the general population. Triptans have been shown to be effective as both an abortive and short-term preventive treatment, and estradiol has been shown to be an effective short-term preventive treatment. Ergotamines, combinations of drugs such as sumatriptan-naproxen sodium, and rizatriptan with dexamethasone show promise in the treatment of of MM.     

Management of Menstrual Migraine: A Review of Current Abortive and Prophylactic Therapies

After menarche, women have an increased prevalence of migraine compared to men. There is significant variability in the frequency and severity of migraine throughout the menstrual cycle. Women report migraines occur more frequently during menses, and that those are more severe than other migraines. This creates a unique challenge of effectively treating menstrually related and pure menstrual migraines. As with treatment of other migraines, both abortive and prophylactic treatment regimens are used. Triptans demonstrate efficacy in the abortive management of menstrually related and pure menstrual migraines. For migraines that occur primarily during menses or that are particularly resistant to other therapies, intermittent prophylactic therapies can be used. Naproxen and estrogens have been studied for this use. More recently, triptans have been examined and have shown efficacy for intermittent prophylaxis of menstrual migraine.     

Perimenstrual Eletripan Prevents Menstrual Migraine: An Open‐Label Study

Objective.— To prospectively evaluate the efficacy of perimenstrual prophylaxis with eletriptan to reduce headaches in women identified with menstrual migraine (MM). Methods.— Female migraineurs self‐reporting a substantial relationship between migraine and menses were evaluated with 3 consecutive months of daily headache recording diaries. A relationship between menses and migraine was evaluated using International Classification of Headache Disorders (ICHD‐II) criteria and a probability model called Probability MM. Women prospectively diagnosed with ICHD‐II MM were treated for 3 consecutive months with perimenstrual eletriptan 20 mg 3 times daily starting 2 days prior to the expected onset of menstruation and continued for a total of 6 days. Headache activity was compared during the 3 months of recording prior to eletriptan therapy and 3 months with eletriptan perimenstrual prevention therapy. Results.— Three months of pretreatment prospective diaries were completed by 126 women. ICHD‐II menstrually related migraine was diagnosed in 74%, with pure MM in 7%. Among those women diagnosed with ICHD‐II MM, 61 completed at least 1 treatment month. Overall change in headache activity was a 46% decrease. The mean percentage of treated menses without migraine occurring during the 6 days of treatment was 71%. The percentage of subjects with 1, 2, and 3 migraine‐free menstrual periods (no migraines occurring 2 days before menses through the first 3 days of menstruation) with eletriptan, respectively, were 14%, 19%, and 53%. Among those subjects who remained headache‐free during the 6 days of eletriptan treatment, migraine occurred during the 3 days immediately after discontinuing eletriptan for 9%. Perimenstrual eletriptan was generally tolerated and no abnormalities were identified on the 6^th day of treatment using either blood pressure recording or electrocardiogram. Conclusions.— Among patients with prospectively identified MM, eletriptan 20 mg 3 times daily effectively reduced MM. A significant reduction in headache activity occurred for 53% of patients. (Headache 2010;50:551‐562)     

Menstrual migraine: A review of prophylactic therapies

Menstrual migraine is commonly encountered in women who are experiencing attacks of migraine without aura. It remains controversial whether attacks of menstrually associated migraine are more severe and have a longer duration than non-menstrually associated attacks. The pathogenesis of menstrual migraine is not understood completely, but it may be related to estrogen withdrawal or prostaglandin release. Preventative therapies may be considered in those who have failed abortive medications or have attacks lasting longer than 2 days. They can be administered short-term during the perimenstrual time period or continuously throughout the menstrual cycle. Short-term prophylactics should be tried first because menstrual migraines generally last for 1 to 4 days only. Continuous prophylactics may be considered in those with attacks refractory to short-term therapies.     

Naratriptan as short-term prophylaxis of menstrually associated migraine: a randomized, double-blind, placebo-controlled study

OBJECTIVE: To determine the efficacy of naratriptan 1-mg and 2.5-mg tablets twice daily compared with placebo as short-term prophylaxis of menstrually associated migraine. BACKGROUND: Approximately 60% of women with migraine report headaches associated with their menstrual cycles. Results from an open-label study suggest that short-term administration of sumatriptan is useful in the prophylaxis of menstrually associated migraine. METHODS: A randomized, double-blind, three-arm, parallel-group, placebo-controlled study was conducted in women aged 18 years or older with a history of migraine with or without aura, as defined by the International Headache Society, of at least 6 months. Two dose strengths of naratriptan (1 mg, 2.5 mg) or identical-appearing placebo tablets (1:1:1) were administered twice daily for 5 days starting 2 days prior to the expected onset of menses across four perimenstrual periods. End points included the number of menstrually associated migraines, total migraine days, peak headache severity, lost work/activity time, migraine-related quality of life, and incidence of adverse events. RESULTS: Overall, the intent-to-treat population comprised 206 women (naratriptan 1 mg, n = 70; naratriptan 2.5 mg, n = 70, and placebo, n = 66); 171 women treated four perimenstrual periods. Significantly more perimenstrual periods per subject treated with naratriptan, 1 mg, were headache-free compared with placebo (50% versus 25%, P =.003). Naratriptan, 1 mg, significantly reduced the number of menstrually associated migraines (2.0 versus 4.0, P <.05) and menstrually associated migraine days (4.2 versus 7.0, P <.01) compared with placebo. More patients treated with naratriptan, 1 mg, were headache-free across all treated perimenstrual periods compared with placebo (23% versus 8%). No difference in headache severity was observed in breakthrough headaches. The incidence and severity of adverse events was similar across treatment groups. Naratriptan, 2.5 mg, was not statistically superior to placebo for any measure. CONCLUSIONS: Naratriptan, 1 mg, with tolerability similar to placebo, is an effective, short-term, prophylactic treatment for menstrually associated migraine.     

A Prospective Comparison Between ICHD‐II and Probability Menstrual Migraine Diagnostic Criteria

Objective.— To prospectively evaluate the diagnosis of menstrual migraine (MM) by comparing 2 diagnostic systems. Methods.— Female migraineurs self‐reporting a substantial relationship between migraine and menses were evaluated with 3 consecutive months of daily headache recording diaries. A relationship between menses and migraine was evaluated using International Classification of Headache Disorders (ICHD‐II) criteria and a probability model called Probability MM. Results.— Three months of pretreatment prospective diaries were completed by 126 women. ICHD‐II menstrually related migraine was diagnosed in 73.8% with pure MM in 7.1%. ICHD‐II and Probability diagnoses agreed for all cases of ICHD‐II non‐MM and pure MM, with disagreement among women diagnosed with ICHD‐II menstrually related migraine, only half of whom were identified as having a relationship with menses greater than chance alone using the Probability model. Interestingly, 20% of those women self‐reporting a substantial relationship between migraine and menses were not prospectively diagnosed with MM using either diagnostic system. Differences in menstrual vs nonmenstrual headaches were greater when using the Probability model. Conclusions.— Prospective headache diaries are needed to diagnose MM. A probability‐based method, which considers the chance occurrence of headaches during the menstrual cycle, identifies fewer women as having menstrually related migraine compared with the diary‐based methods recommended by the current ICHD‐II candidate criteria. (Headache 2010;50:539‐550)     

Characteristics of Menstrual vs Nonmenstrual Migraine: A Post Hoc,Within‐Woman Analysis of the Usual‐Care Phase of a Nonrandomized Menstrual Migraine Clinical Trial

Objective.— To compare, using a within‐woman analysis, the severity, duration, and relapse of menstrual vs nonmenstrual episodes of migraine during treatment with usual migraine therapy. Background.— Studies comparing the clinical characteristics of menstrual and nonmenstrual migraine attacks have yielded conflicting results, contributing to disagreement regarding whether menstrual migraine attacks are clinically more problematic than nonmenstrual migraine attacks. Methods.— Post hoc within‐woman analysis of the usual‐care phase (month 1) of a 2‐month, multicenter, prospective, open‐label study at 21 US medical practices (predominantly primary care). Participants were women ≥18 years of age with regular predictable menstrual cycles (28 ± 4 days) who self‐reported a ≥1‐year history of migraine attacks occurring between days ?2 and +3 (menses onset = day +1) and ≥8 such attacks within the previous 12 cycles. Migraine treatment episodes were categorized as menstrual (occurring on days ?2 to +3 of menses) or nonmenstrual (occurring on days +4 to ?3 of menses). Pain severity, functional impairment, duration, relapse in 24 hours, and use of rescue medication were compared. Sources of variability (within‐ or between‐patient) were determined using mathematical modeling. The http://www.clinicaltrial.gov code for trial is NCT00904098. Results.— Women (n = 153; intent to treat) reported 212 menstrual (59.2%) and 146 nonmenstrual (40.8%) migraine treatment episodes. Compared with nonmenstrual treatment episodes, menstrual episodes were more likely to cause impairment (unadjusted odds ratio, 1.65, 95% CI, 1.05‐2.60; P = .03), were longer (unadjusted hazard ratio 1.68; 95% CI, 1.31‐2.16; P < .001), and were more likely to relapse within 24 hours (unadjusted odds ratio, 2.66; 95% CI, 1.25‐5.68; P = .01). Within‐patient effects accounted for only 18‐33% of the total variance in these outcomes. Conclusions.— Post hoc, within‐woman analysis of migraine treatment episodes categorized based on International Headache Society criteria showed that menstrual treatment episodes were more impairing, longer lasting, and more likely to relapse than nonmenstrual treatment episodes in this selected population of women with frequent menstrual migraine. The current analysis indicates that most of the variability in these outcomes is due to differences between headache types and not within‐patient differences for a given type of headache, suggesting that menstrual episodes are potentially treatable. These findings underscore the differences between menstrual and nonmenstrual episodes of migraine and the need to offer effective migraine treatment to women. (Headache 2010;50:528‐538)     

Menstrual Migraine and Intermittent Ergonovine Therapy

The treatment of patients suffering with menstrual migraine is sometimes a difficult and frustrating problem for the physician. As many menstrual migraine headaches are refractory to abortive therapy, prophylactic therapy is often needed. Ergonovine maleate, an ergot derivative with vasoconstrictive properties, has been used with some success in migraine headache patients. Forty patients who were treated with intermittent prophylactic ergonovine were studied over six months. The patients ranged in age from 22 to 40 years, and all suffered with menstrual migraine headaches which were refractory to abortive therapy. Each patient took ergonovine maleate 0.2 mg three to four times daily during menses and recorded headache occurrence and severity. After three months, 24 patients (60%) reported significantly less severe attacks, six patients (15%) reported less frequent headaches and 14 patients (35%) reported no improvement. After six months there was a decrease in effectiveness with 20 patients (50%) reporting significantly less severe headaches and two patients (5%) reporting less frequent headaches. This limited study suggests that ergonovine maleate may be of value in the treatment of difficult menstrual migraine patients.     

Hormonal management of migraine associated with menses and the menopause: a clinical review

OBJECTIVE: This article reviews hormonal strategies used to treat headaches attributed to the menstrual cycle or to peri- or postmenopausal estrogen fluctuations. These may occur as a result of natural ovarian cycles, or in response to the withdrawal of exogenously administered estrogen. BACKGROUND: A wide variety of evidence indicates that cyclic ovarian sex steroid production affects the clinical expression of migraine. This has led to interest in the use of hormonal treatments for migraine. METHODS: A PubMed search of the literature was conducted using the terms "migraine,"treatment,"estrogen,"hormones,"menopause," and "menstrual migraine." Articles were selected on the basis of relevance. RESULTS: The overarching goal of hormonal treatment regimens for migraine is minimization of estrogen fluctuations. For migraine associated with the menstrual cycle, supplemental estrogen may be administered in the late luteal phase of the natural menstrual cycle or during the pill-free week of traditional combination oral contraceptives. Modified contraceptive regimens may be used that extend the duration of active hormone use, minimize the duration or extent of hormone withdrawal, or both. In menopause, hormonally associated migraine is most likely to be due to estrogen-replacement regimens, and treatment generally involves manipulating these regimens. Evidence regarding the safety and efficacy of these regimens is limited. CONCLUSIONS: Hormonal treatment of migraine is not a first-line treatment strategy for most women with migraine. Evidence is lacking regarding its long term harms and migraine is a contraindication to the use of exogenous estrogen in all women with aura and those aged 35 or older. The harm to benefit balances of several traditional nonhormonal therapies are better established.     

Menstrual Migraine With Features of Cluster Headache. A Report of 10 Cases

Ten patients with menstrually related migraine headaches and significant features of cluster headache are described. The mean age of onset of the headache was 29 years. The duration of the pain was more typical for migraine, with an average of 3 days. The pain was sharp with associated tear formation and nasal congestion. Eight of the women described significant nausea. Only one reported any type of cluster headache outside of the menstrual time. Four patients experienced tension headaches, and four also had migraines not related to menses (without cluster features).
Preventive medications were generally not helpful. The abortive medications that did help included sumatriptan, Cafergot PB® suppositories, and corticosteroids. Oxygen was useful in two patients. While analgesics did help three patients, lidocaine nasal spray was ineffective in four of the women.     

Hormonal Changes Throughout Life in Women

The changes in hormonal milieu associated with menarche, pregnancy, lactation, and menopause are frequently accompanied by changes in the patterns and frequency of migraine. Migraine headache is more common in females and, for many women, the onset of this condition occurs at menarche. As many as 60% of women migraineurs report an association between migraine and menstruation, and evidence suggests that estrogen withdrawal may be a trigger for menstrual migraine in susceptible women. Moreover, in the majority of women, migraine frequency increases during the pill-free interval with oral contraceptive use and during the postpartum period, which are other times of decreasing estrogen levels. Migraine frequency tends to decrease during periods of increasing or stable estrogen levels. For these reasons, the numerous neuroendocrine effects elicited by estrogen have been evaluated to explain its role in migraine. Overall, estrogen appears to be a key factor in menstrual migraine, but it is likely to be only one of several factors that act in concert to trigger migraine in susceptible women. Understanding the relationship of the different hormonal milieus through the natural course of women's lives can guide diagnosis and treatment.     

Estrogen replacement therapy: current recommendations

Estrogen replacement therapy is effective for the prevention and treatment of postmenopausal osteoporosis and should be offered to all women at high risk for osteoporosis. Such therapy is particularly beneficial for prevention of spinal compression fractures; in addition, it alleviates menopausal symptoms (hot flushes, genitourinary symptoms, and changes in mood). In each patient, these benefits must be weighted against the potential risks of endometrial hyperplasia and carcinoma, breast tenderness, hypertension, vascular headaches, and the inconvenience of menstrual bleeding if the uterus is intact. The risk of endometrial cancer associated with estrogen replacement therapy can be considerably reduced by the addition of a progestin, and other side effects can be diminished or eliminated by use of the new transdermal estrogen preparations. Thus, estrogen replacement therapy should be considered in all women who have experienced natural or surgically induced menopause, and it is advisable in women who have osteoporosis or an increased risk for this disorder and no contra-indications to its use. Estrogen replacement therapy should be instituted as soon after menopause as possible and seems to be well tolerated until at least 75 years of age.     

Epidemiology and Treatment of Menstrual Migraine and Migraine During Pregnancy and Lactation: A Narrative Review

The peak prevalence of migraine occurs in women of reproductive age, and women experience a higher burden of migraine symptoms and disability compared to men. This increased burden of migraine in women is related to both developmental and temporally variable activational effects of female sex hormones. Changing levels of female sex hormones affect the expression of migraine during pregnancy, and, to a lesser degree, lactation, and are the mechanism underlying menstrual migraine. This review describes the evidence for sex differences in the expression of migraine across the reproductive epoch; reviews the epidemiology of migraine during pregnancy, lactation, and menses; and summarizes the available evidence for safety and efficacy of acute treatments during pregnancy and lactation and for menstrual migraine. Areas of controversy in treatment of migraine during pregnancy, including the use of magnesium, triptans vs butalbital combination medications, and onabotulinum toxin, are also explored.     

Women's issues of migraine in tertiary care

OBJECTIVES: To document the frequency and types of symptoms of migraine in a large group of female migraineurs in tertiary care. Background.-Hormonal changes remain a significant accompaniment in the life cycle of the female migraineur. Little is documented on the relationship of women's issues to other features of migraine or to the lives of patients with migraine. Successful management of migraine mandates attention to women's issues from menarche to beyond menopause. The more information available to this end, the more confidently the clinician can prognosticate, guide, and treat the female patient. METHODS: Women's issues were evaluated in 504 women with migraine diagnosed according to the criteria of the International Headache Society (codes 1.1 and 1.2). The variables graded on a scale of 0 to 3 at the initial visit included premenstrual syndrome, menopausal symptoms, use of birth control pills, use of hormone replacement therapy, hormonal triggering of headaches, worsening of headaches with birth control pills or hormone replacement therapy, headaches with menses only, headaches with menses and at other times, headaches in pregnancy, headaches unchanged in pregnancy, headaches worse in pregnancy, and headaches better in pregnancy. These variables were stratified by age and headache diagnosis. RESULTS: Premenstrual syndrome was reported in 68.7% of patients, menopausal symptoms in 29.0%, and headaches attributed to birth control pills or hormone replacement therapy in 24.4% of patients. Sixty-four point nine percent of women had headaches with menses as well as at other times, while 3.4% of women had headaches exclusively with menses. A pregnancy was reported in 61.3% of the women; 20.4% did not experience headache in pregnancy. Of the 79.6% who did experience headache, 17.8% reported that headaches improved in pregnancy, 27.8% reported headaches to be unchanged, and 34% reported a worsening of headaches. Hormone replacement therapy or birth control pills triggered headaches in 64% of the study group. Patients with 100% aura were significantly different from patients with 0% aura, being less likely to have headaches worsening with birth control pills or hormone replacement therapy (P <.01) and more likely to have headaches occurring during pregnancy (P <.05). When patients with 100% aura were matched for age, headache frequency, use of birth control pills or hormone replacement therapy, and use of prophylactic medications with patients having 0% aura, the former were significantly less likely to have menopausal symptoms (P <.05), less likely to have headaches worsening with birth control pills or hormone replacement therapy (P <.01), and more likely to have headaches occurring only during pregnancy (P <.05). CONCLUSIONS: This study provides a documentation of women's issues in a large cohort of patients. Stratification by headache type, presence of aura, and age refine the study.