Estrogen and Migraine: Correlations and Prevention. E. Anne MacGregor, MFSRH

Transcription

1 2008 the Author Journal compilation 2008 American Headache Society ISSN doi: /j x Published by Wiley Periodicals, Inc. Original Article Estrogen and Migraine: Correlations and Prevention E. Anne MacGregor, MFSRH Migraine is a neurovascular condition that is influenced by the hormonal milieu. The risk of a migraine attack is increased among women migraineurs during a 5-day perimenstrual window that starts 2 days before the onset of menses and continues through the first 3 days of menstruation. Evidence suggests that the increased risk results from estrogen withdrawal in the concurrent late luteal/early follicular phase. For some women with menstrual migraine, headaches that occur at this time are more severe, are of longer duration, and are more disabling. If patients have regular menses, short-term prevention strategies may provide relief for women whose headaches are not responsive to acute treatment. Clinical trials designed to assess short-term prevention with estrogen supplements and with triptans have demonstrated efficacy in this setting and have provided new insights into the mechanisms underlying menstrual migraine. This review will summarize the implications of these data for the treatment of women with menstrual migraine. Key words: estradiol, progesterone, menses, headache, triptan Abbreviations: RR relative risk, CI confidence interval, GnRH gonadotropin-releasing hormone, LH luteinizing hormone, FSH follicle-stimulating hormone, E 1G estrone-3-glucuronide, MM menstrual migraine, NS not significant, PdG pregnanediol-3-glucuronide (Headache 2008;48:S99-S107) INTRODUCTION The role of estrogen in modulating susceptibility to migraine attacks has been the focus of much research in recent years, prompted in part by the associations between hormonal status and headache in women. During the reproductive years, the prevalence of migraine is approximately 3 times greater in women than in men. 1 An estimated 51% of women migraineurs in the general population believe that menstruation is a trigger for their headaches. 2 Moreover, women report changes in the frequency of migraine during pregnancy, postpartum, and after reaching menopause. 3,4 However, the direction of these changes differs among women, suggesting that From The City of London Migraine Clinic, 22 Charterhouse Square, London, EC1M 6DX, UK. Address all correspondence to E. Anne MacGregor, Director of Clinical Research, The City of London Migraine Clinic, 22 Charterhouse Square, London, EC1M 6DX, UK. the relationship between headache and hormonal milieu in women is complex. One consistent observation has been that, within the population of women migraineurs, the incidence of migraine increases during a 5-day period starting 2 days before the start of menses and extending through the first 3 days of menstruation. 5,6 The period of highest risk for migraine in susceptible women corresponds to estrogen withdrawal in the late luteal and early follicular phases of the menstrual cycle. Menstrual attacks are typically migraine without aura 5 and, in some women, are more severe, of longer duration, 6,7 and more disabling 7-9 than are migraines starting outside the perimenstrual window. The predictable nature of menstrual migraines in women who have regular menses allows for the use of short-term prevention strategies if acute therapies are inadequate. Estrogen supplementation has been used to prevent menstrual migraine by eliminating estrogen withdrawal in the perimenstrual window. Although S99

2 S100 July/August 2008 this approach has been successful in preventing migraine during treatment, in a substantial percentage of treated women, headache onset is actually delayed rather than prevented. 14 Triptans, selective serotonin 5-HT 1B/1D receptor agonists with well-established efficacy in acute treatment of migraine, 15 have also been evaluated in the setting of short-term prevention of menstrual migraine Mimicking serotonin action at 5-HT 1B/1D receptors is thought to induce cranial vasoconstriction, inhibit peripheral neurons, and inhibit transmissions through second-order neurons of the trigeminocervical complex. 15 Any one of these mechanisms could explain their therapeutic activity in patients with migraine. This article will present the epidemiologic evidence indicating that perimenstrual estrogen withdrawal triggers migraine in susceptible women. The clinical implications of results from short-term prevention trials for management of patients with menstrual migraine will also be discussed. CLINICAL CHARACTERISTICS OF MENSTRUAL MIGRAINE The incidence and severity of headaches along with timing of menses were analyzed in a diary study of 81 menstruating women migraineurs selected from the general population. 5 Headaches were classified as migraine with aura, migraine without aura, and tension-type headaches. In this population of migraineurs, migraine without aura was more frequent on the 2 days before and the 2 days after the start of menstruation, whereas tension-type headaches were more frequent on the first 2 days of menstruation. Migraine with aura did not show a similar pattern of increasing frequency. Compared with headaches at other times, migraines that occurred on days 1 and 2 of the menstrual cycle were reported to be more painful, although the difference in pain intensity was small (difference of 0.39 on a scale of 1-10). However, for migraine without aura, symptoms, duration, and disability were not different. 5 These findings in women selected from the general population suggest that menstrual migraines are similar to migraines at other times. However, the results are not substantiated by other investigators. Other studies have found that, at least for some women, menstrual migraines are more severe and associated with greater disability than are attacks outside the perimenstrual window. Another diary study monitored the frequency and clinical characteristics of headaches in 155 women migraineurs who were treated at a headache clinic. 6 Participants kept records of their migraines over the course of a total of 693 menstrual cycles. The pooled risk of migraine was 1.7 times greater on the 2 days before menstruation and 2.5 times greater on days 1-3 of the menstrual cycle than on other days in the menstrual cycle (Fig. 1). Migraines were 3.4 times more likely to be severe and 4.7 times more likely to be associated with vomiting on the first 3 days of menstruation. 6 In a study of 64 women referred to a headache clinic for care, diary cards were used to record attributes of headaches occurring over the course of 2 months. 7 Nonmenstrual migraines were defined as those that started on any day other than day -2 to day +7 of the menstrual cycle. Characteristics of menstrual migraines were broken down for premenstrual attacks (day -2 to day-1), menstrual attacks (day +1 to day +2), and late menstrual attacks (day +3 to day +7). In this population, premenstrual attacks and menstrual attacks lasted longer, were more likely to be severe, were less responsive to initial treatment, and were more likely to relapse than were nonmenstrual attacks. Loss of work hours due to migraine also was greater during premenstrual attacks than nonmenstrual attacks. 7 Fig 1. Relative risk of migraine during the perimenstrual phase vs all other days. *P <.001, P < RR, relative risk; CI, confidence interval. 6

3 S101 These results are similar to those of 2 large studies that used questionnaires rather than diaries to gather data. 8,9 In a Dutch population of women with menstrual migraine, headache-related limitations were reported by 84% for social activities, 81% for housework, 58% for other family activities, and 45% for work. 8 In a general practice setting, women reported that they were less productive for a longer time when migraines were associated with menstruation. 9 The weight of the evidence suggests that, at least for some affected women, menstrual migraine attacks are more difficult to manage than are attacks that occur outside the perimenstrual window. DIAGNOSING MENSTRUAL MIGRAINE Once the diagnosis of migraine has been made, diary cards are essential to determine the relationship between migraine attacks and menstruation. The International Headache Society defines menstrual migraine as migraine without aura that occurs between day -2 and day +3 of the menstrual cycle (where day 1 is the first day of bleeding and there is no day 0) in at least 2 of 3 menstrual periods. 20 Menstrual migraine is further categorized as being pure menstrual migraine, attacks occurring exclusively at menses, and menstrually related migraines, which occur in women who experience attacks at other times of their menstrual cycles as well as in association with the onset of menses. For the purposes of this review, the 2 subcategories of menstrual migraine are considered to have a similar pathophysiology and require similar treatment. To avoid recall bias, patients should be asked to record when menstrual bleeding starts and when headaches occur for 3 cycles. 20 Review of the record at a follow-up visit will allow identification of patients who have headaches on day -2 today+3 of the cycle in at least 2 of the 3 cycles and thus may benefit from preventive therapies. Response to acute treatments can also be monitored during this 3-month period. This information can then be used to individualize treatment. TREATING MENSTRUAL MIGRAINE Acute treatment of menstrual migraine is essentially the same as for any other migraine. Standard abortive therapies using a combination of agents to treat pain, nausea, and vomiting with migrainespecific agents such as ergots and triptans may be effective for many women. Similarly, standard prophylactic therapies may be effective in reducing the incidence of menstrual migraine, although further studies are necessary to provide support for their use in prevention of menstrual migraine. Women who have irregular menses or who need contraception may benefit from continuous hormonal therapy, but many do not. These women may need to consider miniprophylaxis in combination with hormonally controlled cycles to enable miniprophylaxis to be effectively used. Perimenstrual prophylaxis reduces the risk of migraine rather than treating symptoms once they occur and should be considered for women with disabling menstrual migraine who have regular menses and predictable migraine attacks. 21 IMPACT OF HORMONES ON TREATMENT Increasing understanding of the complex relationship between reproductive function and the brain has led to several theories to explain menstrual migraine (Fig. 2). Although the estrogen withdrawal theory of menstrual migraine is widely held at this point, evidence suggests at least an ancillary role for prostaglan- Fig 2. Overview of relationships of ovarian hormones and the central nervous system. GnRH, gonadotropin-releasing hormone; LH, luteinizing hormone; FSH, follicle-stimulating hormone.

4 S102 July/August 2008 dins. Prostaglandin levels in the endometrium increase 3-fold from the follicular phase to the luteal phase, with maximal release at menstrual bleeding. 21,22 Estrogen and progesterone withdrawal trigger the breakdown of the endometrium, which in turn increases circulating levels of prostaglandins. Their release into the bloodstream is associated with menstrual cramps, throbbing headache, nausea and vomiting, backache, and diarrhea. If prostaglandins are injected into individuals of either sex, headache ensues. 23 Prostaglandin inhibitors such as naproxen sodium provide relief. 21 Further research is needed to understand how these molecules may affect susceptibility to menstrual migraine. Estrogen and Migraine. The relationship between occurrence of migraine and levels of estrogen and progesterone has been characterized in 38 women with confirmed menstrual migraine and regular menses between 21 and 35 days. 24 Early-morning urine samples were collected on each day of the study to determine the time of ovulation and to analyze levels of urinary estrone-3-glucuronide and pregnanediol, metabolites of estrogen and progesterone, respectively. Over the course of 9 menstrual cycles per participant, frequency of migraine was analyzed across 4 phases of the menstrual cycle: follicular-phase rising estrogen, postovulatory-phase falling estrogen, luteal-phase rising estrogen, and late-luteal/earlyfollicular phase falling estrogen (Fig. 3). As expected, estrogen decline in the late luteal/early follicular phase was associated with the greatest frequency Fig 3. Estrogen and menstrual migraine in 120 cycles from 38 women. E 1G, estrone-3-glucuronide; PdG, pregnanediol- 3-glucuronide. Adapted with permission from MacGregor EA et al (2006). 24 Table. Relative risk (RR) of migraine in 35 women treated with perimenstrual estradiol or placebo 14 RR (95% CI) During gel.78 ( ).04 Days 1-5 post gel 1.40 ( ).03 Days 6-10 post gel 1.04 ( ) NS of migraine. Headache was less frequent in both phases of estrogen rising than in the late luteal and postovulatory phases of falling estrogen. No criticalthreshold estrogen level was associated with onset of migraine. 24 Estrogen for Prophylaxis of Menstrual Migraine. Short-Term Prevention. In the next stage of this study, short-term prevention with estrogen supplementation was assessed in a double-blind, crossover trial. 14 Women were treated with 1.5 mg of transdermal estradiol gel or placebo gel starting 6 days before the first full day of bleeding and continuing until the second full day of menstruation. Each woman treated 3 cycles with estradiol and 3 cycles with placebo. The start of treatment was scheduled to allow 3 days for circulating levels of estrogen to reach steady state. Use of the 1.5-mg estradiol gel, which is equivalent to a blood level of about 75 pcg/ ml, 25 resulted in a 22% reduction in the number of migraine days per woman. However, this benefit was outweighed by a 40% increase in the occurrence of posttreatment headache (Table). 14 Fifteen of the 22 women who had fewer migraines while on treatment developed migraines within the first 5 days after stopping estradiol administration. 14 This is particularly interesting in that estrogen withdrawal resulted in migraine even in the absence of progesterone, lending more support for the independence of this association from other hormonal influences. Ending treatment on day +2 was intended to allow estrogen levels to drop with sufficient time for the follicular-stage estrogen levels to rise. 14 On average, with estradiol treatment, estrone- 3-glucuronide levels remained significantly higher than with placebo for the first 3 days after treatment was stopped (P <.0001). The timing of the estrone- P

5 S103 3-glucuronide nadir was highly variable, even in the same woman. Therefore, in some women, estrogen treatment was stopped before follicular-phase estrogen levels had started to rise. Had active treatment been continued until follicular-phase estrogen levels were rising, it is possible that posttreatment headaches could have been avoided. In this study, estradiol treatment extended the average length of the follicular phase by 1 day. 14 Thus, further studies are needed to investigate the effects of longer estradiol treatment on the duration of the follicular phase. Safety and Tolerability of Estrogen Supplements. In general, natural estrogen supplements are safe and well tolerated, but their safety can be concerning to women. It is important to emphasize to patients that there is no evidence that supplements increase the risks of cancer or thrombosis in women who are producing endogenous estrogen. However, their use is contraindicated in women who have a history of estrogen-dependent tumors or venous thromboembolism. 21 If supplements are used for more than 6 months, confirming ovulation by measuring day 21 blood progesterone levels is recommended. Continuous Prevention. For women whose menstrual migraines are not adequately controlled with acute treatment and who have irregular menses, continuous hormonal treatments may be considered. 21 Although no studies have been conducted specifically in menstrual migraine, results from a recent study comparing headache frequency with extended-cycle combination contraceptives and standard 21-day hormone/7-day placebo contraceptives are promising. 26 Daily headache scores decreased significantly with the extended-cycle formulation (P <.0001). It is interesting to note that the benefit was not limited to women who had a greater incidence of headaches during the placebo week of the standard contraceptive cycle. Randomized controlled studies are needed to confirm the efficacy of extended-dosage contraceptives for prevention of menstrual migraine. In addition, estrogen-containing oral contraceptives are associated with a small absolute risk of stroke in young female migraineurs with aura. 27 Hence, combined hormonal contraceptives are contraindicated for use in women with migraine with aura. Alternatives to Estrogen. Suppression of ovulation with gonadotropin-releasing hormone (GnRH) analogs may be considered for women whose menstrual migraines are not controlled with any other therapeutic strategy. However, prolonged use of GnRH analogs is associated with accelerated bone resorption that limits their use, although this can be tempered with add-back hormone replacement therapy. 21 ESTROGEN, SEROTONIN, AND MIGRAINE Estrogen freely crosses the blood-brain barrier, and concentrations in the brain mirror levels in the blood. 28 Estrogen receptors are widely distributed through the brain, and estrogen exerts profound effects on a number of neurotransmitter systems, including the serotonergic system. In general, estrogen increases serotonergic tone. Estrogen is associated with increased production of serotonin, reduced serotonin reuptake, and decreased serotonin degradation. 28 Thus, as has been discussed in more detail in a paper by Drs. Scharfman and MacLusky elsewhere in this supplement, the female brain must have mechanisms in place to compensate for the rapid, cyclic changes in levels of this potent neurohormone during each menstrual cycle. It has been hypothesized that inadequate compensation results in decreased tone in inhibitory serotonergic systems, lowering the threshold for migraine. 28 How triptans, serotonin 5-HT 1B/1D receptor agonists, 15 act to interfere with hormonal effects on migraine is not fully understood. However, triptans have been shown to be effective in preventing menstrual migraine when taken perimenstrually, suggesting that they do indeed inhibit the effects of estrogen withdrawal. Naratriptan, frovatriptan, and zolmitriptan have been evaluated for short-term prevention in randomized, placebo-controlled trials, and those trials will be the focus of this discussion. It is important, however, when reviewing the results, to note that the trial designs differed in important features, such as the timing of treatment and the primary efficacy end points. Naratriptan is the best studied of the triptans, having been evaluated in 3 randomized, placebocontrolled trials. 17,18 In the first study, 206 women were

6 S104 July/August 2008 randomized to receive twice-daily treatment with naratriptan 1 mg, naratriptan 2.5 mg, or placebo. Treatment was started 2 days before the expected onset of menstrual migraine and continued for 5 days. The primary end point was the number of menstrual migraines that occurred over 4 consecutive cycles. Patients treated with naratriptan 1 mg had significantly fewer menstrual migraines than did those treated with placebo (P <.01). In addition, a significantly greater percentage of women in the naratriptan 1-mg group were headache free than in the placebo group (50% vs 25%, P =.003). Treatment with naratriptan 2.5 mg did not result in significant benefit compared with placebo. The reason for this surprising result is not known. The most frequently reported adverse events were dizziness and dyspeptic symptoms. The incidence of treatment-related adverse events was similar across all 3 treatment groups. 17 Naratriptan 1 mg has been evaluated further in 2 randomized, placebo-controlled trials of identical design. 18 In these trials, the treatment regimens were slightly longer than were those in the first trial. Treatment with naratriptan 1 mg or placebo taken twice daily was initiated 3 days before the onset of menstrual migraine and continued for 6 days. The primary efficacy end point was the mean percentage of treated cycles without menstrual migraine attacks per patient. In study 1 (N = 290), the primary efficacy end point was significantly greater in the naratriptan 1-mg group than in the placebo group among women who took study drug in at least one cycle (38% vs 29%, P <.05). Results were similar in the women who were treated for all 4 cycles. In study 2 (N = 365), the percentage of cycles without menstrual migraine per patient was 34% in the naratriptan group and 24% in the placebo group (P <.05) among women treated for at least one cycle. Results in the group treated for all 4 cycles were similar. 18 A Kaplan-Meier analysis was used to evaluate the time to first-reported migraine with naratriptan or placebo (Fig. 4). 18 The percentage of patients who reported headaches in the first few days after stopping study medication was higher in patients who had taken naratriptan. This increase in posttreatment headaches was seen consistently over the 4 months of % of Patients Without Attack % of Patients Without Attack Study Treatment Day (6 = Last Day of Treatment) Naratriptan Study 2 Placebo Treatment Day (6 = Last Day of Treatment) Naratriptan Placebo Fig 4. Kaplan-Meier analysis of time to onset of first migraine in women treated with naratriptan 1 mg or placebo twice daily for short-term prevention of menstrual migraine. Reprinted from Mannix et al (2007) with permission from Blackwell Publishing. 18 each trial. No serious adverse events attributed to study medication were reported in either study, and no individual drug-related adverse event was reported in more than 2% of patients in a treatment group in either study. The mechanism by which headaches are delayed but not prevented with naratriptan may ultimately provide a new lens with which to view these complex interactions that have not yet been explained. The finding that naratriptan treatment was associated with posttreatment headaches was surprising because no increase was observed in an earlier study of short-term prevention with frovatriptan. 16 Frovatriptan was evaluated in a randomized, doubleblind, crossover study involving 506 women with menstrual migraine. Patients were treated for 3 cycles with a randomized sequence of 3 treatment regimens: frovatriptan 2.5 mg once daily, frovatriptan 2.5 mg twice daily, or placebo. A double dose of study medi-

7 S105 cation was taken on the first day (2 days before the expected onset of menstrual migraine) of the 6-day treatment each cycle. The primary efficacy end point in this trial was the incidence of menstrual migraine during treatment. In the population of women who were treated for at least one cycle, the incidence of menstrual migraine was 67% with placebo, 52% with frovatriptan 2.5 mg once daily (P <.0001 vs placebo), and 41% with frovatriptan 2.5 mg twice daily (P <.0001 vs placebo). Kaplan-Meier analysis of time to first headache showed no evidence of an increased incidence of migraine after stopping treatment with either dosage of frovatriptan (Fig. 5). Frovatriptan was well tolerated in both regimens. Although nausea and dizziness were reported more frequently with frovatriptan treatment, headache and dysmenorrhea were more common with placebo. 16 These results are consistent with a recent analysis of the safety and tolerability of frovatriptan in women with difficult-to-treat menstrual migraine. 29 Pooled data from 2 studies involving a total of 962 patients were analyzed. A similar percentage of adverse events was reported for placebo and frovatriptan 2.5 mg taken once or twice daily for 6 days beginning 2 days before migraine. % of Patients without MM Treatment Day (last treatment day is day 6) Fig 5. Kaplan-Meier analysis of time to onset of first migraine in women treated with frovatriptan 2.5 mg once daily, frovatriptan 2.5 mg twice daily, or placebo for short-term prevention of menstrual migraine (MM). Reprinted with permission from Silberstein et al (2004). 16 Zolmitriptan has also been shown to be effective in the prevention of menstrual migraine in a randomized, placebo-controlled trial, but no analysis of posttreatment headache was reported. 19 A total of 244 women who had menstrual migraine in at least 75% of cycles were randomized to zolmitriptan 2.5 mg 3 times daily, zolmitriptan 2.5 mg 2 times daily, or placebo 3 times daily. Treatment was started 2 days before the expected onset of menstrual bleeding and continued for 7 days. The primary efficacy end point was the percentage of patients who achieved at least a 50% reduction in the frequency of menstrual migraines over 3 consecutive cycles. A significantly greater percentage of women achieved the primary efficacy end point with zolmitriptan 2.5 mg thrice daily (59%) and with zolmitriptan 2.5 mg twice daily (55%) compared with placebo (38%; P =.0007 vs thrice daily and P =.002 vs twice daily). Good tolerability was seen in patients taking zolmitriptan 2 or 3 times daily for 7 days. 19 The data from these clinical trials demonstrate that perimenstrual treatment with triptans can successfully prevent migraine during therapy. Treatment with naratriptan, frovatriptan, or zolmitriptan on multiple days was not associated with an increase in serious adverse events and was generally well tolerated. However, only frovatriptan has been shown to prevent rather than delay headache onset until treatment has stopped. CONCLUSIONS Menstrual migraines are disabling, and prophylaxis should be considered if acute therapy is not adequate. If diary cards confirm a diagnosis of menstrual migraine and the patient has predictable menstruation, perimenstrual prophylaxis may be a useful approach. Continuous hormonal contraceptives can be considered if menstruation is irregular or if contraception is required. In choosing the appropriate prophylactic therapy, consideration should be given to the possibility of posttreatment headaches. REFERENCES 1. Lipton RB, Stewart WF, Diamond S, Diamond ML, Reed M. Prevalence and burden of migraine in the

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