DNG) in women with menstrually-related migraine (MRM)

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Original research article

Effect of a contraceptive pill containing estradiol valerate and dienogest (E2V/DNG) in women with menstrually-related migraine (MRM)☆ Rossella E. Nappi a, b,⁎, Erica Terreno a, b , Grazia Sances b, c , Ellis Martini a , Silvia Tonani a , Valentina Santamaria a , Cristina Tassorelli b, c , Arsenio Spinillo a, b a

Department Obstetric and Gynecology, Research Centre for Reproductive Medicine, IRCCS S. Matteo Foundation, University of Pavia, Italy b University Consortium for Adaptive Disorders and Head Pain (UCADH), University of Pavia, Italy c Headache Science Centre, IRCCS C. Mondino National Institute of Neurology Foundation, 27100 Pavia, Italy Received 28 October 2012; revised 24 January 2013; accepted 2 February 2013

Abstract Background: Combined hormonal contraception might worsen migraine in sensitive women, especially during the free-hormone interval, and raise concerns about the vascular risk. The characteristics of a contraceptive pill containing estradiol valerate/dienogest (E2V/DNG) might be of potential benefit in women with menstrually related migraine (MRM) who choose to use oral contraception for birth control. Study design: This was a prospective diary-based pilot study. Thirty-two women (age N 35 years) [n= 18 who had never used combined oral contraceptives (COCs) and n= 14 who had previously used COCs] diagnosed with MRMs according to the International Headache Society criteria were included. During the observational period, women filled in a diary with the clinical characteristics of migraine attacks. After a three-cycle run-in period, each subject received a COC containing E2V/DNG (Qlaira®/Natazia®; Bayer HealthCare, Berlin, Germany) administered using an estrogen step-down and progestogen step-up approach. Follow-up evaluations were scheduled at the last cycle of run-in and at the third and sixth cycles of treatment. Results: The number of migraine attacks was significantly reduced at the third (pb.001) and sixth cycles (pb.001) in comparison with the run-in period. A similar result was evident for the duration (pb.001 at the third and pb.001 at the sixth cycle) as well as for the severity of head pain (pb.001 at the third and pb.001 at the sixth month). Indeed, a significantly lower number of analgesics were used at the third cycle (pb.001) in comparison with baseline, and a further decrease was evident at the sixth cycle (pb.001) in comparison with the third cycle of E2V/DNG use. Interestingly, duration and severity of head pain were significantly correlated with the number of days of dysmenorrhea at the third cycle (r= .89, p=.000 and r= .67, p=.02; respectively) and at the sixth cycle (r= .76, p=.000 and r= .62, p=.04; respectively) in women without complete remission of menstrual cramps during the study period. Conclusions: The present diary-based pilot study indicates that the use of a pill containing EV2/DNG for six cycles has a positive effect in women with MRM and suggests an association between dysmenorrhea with COCs use as a potential feature of refractory head pain. © 2013 Elsevier Inc. All rights reserved. Keywords: Migraine without aura; Hormonally associated headaches; Estradiol valerate; Dienogest; Bleeding; Dysmenorrhea

1. Introduction

☆ Conflicts of interest: During the past 2 years, Professor R.E. Nappi had a financial relationship (lecturer, member of advisory boards and/or consultant) with Bayer-Schering Pharma, Eli Lilly, Gedeon Richter, Merck Sharpe & Dohme, Novo Nordisk, Pfizer Inc. and Teva/Theramex. ⁎ Corresponding author. Research Centre for Reproductive Medicine, Section of Obstetrics and Gynecology, IRCCS Policlinico San Matteo, Piazzale Golgi 2, 27100 Pavia, Italy. Tel.: +39 0382 501561; fax: +39 0382 423233. E-mail address: [email protected] (R.E. Nappi).

0010-7824/$ – see front matter © 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.contraception.2013.02.001

Hormonal fluctuations in women are highly relevant to the clinical expression of menstrually related migraine (MRM) during the entire reproductive life span [1]. The International Headache Society (IHS) criteria define MRM as attacks of head pain with migraine characteristics occurring on day 1 of menstruation ± 2 days in at least two out of three menstrual cycles associated with attacks occurring at other times during the cycle [2]. The recognition of a 5-day menstrual migraine window [3] is based on clinical data [4,5] and on the early observations that a period of several days of

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exposure to high estrogen levels is necessary before estrogen withdrawal can result in migraine at the time of menstruation [6]. Many clinicians are under the impression that migraine attacks related to menses are more severe, longlasting and refractory to both acute and prophylactic treatments [4,7,8]. Indeed, migraine attacks may cover the entire perimenstrual period, from day − 2 to day + 7, because head pain lasts longer and is less responsive to acute treatment [8]. Migraine at menstruation is different in terms of severity from nonmenstrual attacks, even within individuals, and the highest severity is evident on days 1 to 3 when menstrual bleeding starts [3]. Prescribers of combined hormonal contraceptives (CHCs) should be aware that hormonal compounds may trigger the occurrence of migraine and/or tension-type headache (TTH) or exacerbate preexisting attacks, especially around the time of menstruation [9,10]; this is a condition that is also codified in the IHS classification as hormonally associated headaches (exogenous hormone-induced headache and estrogen-withdrawal headache) [2]. Recognizing that the headaches are triggered by estrogen withdrawal, transdermal estradiol supplementation has been proposed for the management of MRM and other hormonally associated headaches [11–13]. For CHCs users reporting estrogen-withdrawal headache during the 7-day free-hormone interval, a different approach has been to shorten the interval from 7 to 4 days or to administer low-dose combined oral contraceptives (COCs) in extended/flexible regimens [14,15]. However, in spite of the considerable advances in terms of safety and tolerability of CHCs in migraine sufferers [16], their use is still questioned especially in women with additional risk factors for stroke, including smoking, hypertension, diabetes, hyperlipidemia and thrombophilia, aged over 35 years [17]. For example, the US Medical Eligibility Criteria rate initiating of estrogen-containing contraceptives as a category 4 for any migraineur over the age of 35 years. The recent availability of COCs containing natural estrogens, either estradiol valerate (E2V) or 17β-estradiol (E2), may offer new perspectives in women with migraine without aura in light of the evidence of a neutral metabolic and hemostatic impact which may be relevant in those cases at higher risk for the potential negative effects of ethinyl estradiol [18]. On the other hand, data on the vascular safety of progestins in migraine sufferers are inconsistent and deserve further research [16]. However, taking into account the estrogen-withdrawal theory in the occurrence of severe MRM, the peculiar dynamic dosing regimen of the combination of E2V with dienogest (DNG), a hybrid progestogen with strong progestational activity in vivo and antiandrogenic properties without estrogenic, glucocorticoid and androgenic activities [19], may influence the course of head pain during its use and at the time of scheduled bleeding. Indeed, E2V/DNG is administered with a very short free-hormone interval (only 2 days) in an estrogen stepdown, progestogen step-up manner, which results in stable E2 levels during the period of intake and also at the time of

withdrawal bleeding [20]. In addition, the evidence that when assuming E2V/DNG-containing pill women report lighter bleeding [21,22] and less symptoms related to estrogen withdrawal [23] may be an additional potential benefit to minimize menstrual-related pain conditions [24]. In this study, we prospectively investigated the effect of a COC containing E2V/DNG on the characteristics (frequency, duration and intensity) of headache with migraine characteristics in women with MRM at baseline who choose to use oral contraception for birth control. In addition, this diary-based study explored the relationship between bleeding profile and dysmenorrhea and the course of head pain during six cycles of E2V/DNG use.

2. Materials and methods This prospective, diary-based study was carried out at the University Consortium for Adaptive Disorders and Head Pain and at the Research Center for Reproductive Medicine, Department of Obstetrics and Gynecology, IRCCS S. Matteo Foundation, University of Pavia, Italy. The study protocol was approved by the local university Ethical Committees. Thirty-two women suffering from MRM diagnosed according to the IHS criteria [3] entered the present study after they had signed informed consent. To be eligible to participate in the study, women had to be aged 35 years or older and had a body mass index (BMI) between 19 and 29 kg/m 2. Smokers were excluded, as well as women diagnosed with any kind of other risk factors for stroke (hypertension, diabetes), including migraine with aura. The study sample included one group of women (n= 18) who had never used COCs and asked for the possibility to initiate hormonal contraception to prevent unwanted pregnancy and/or to treat medical and/or gynecological conditions and another group of women (n= 14) who had stopped COCs at least 3 months before because of exacerbation of MRM and were willing to restart hormonal contraception for personal and/or clinical reasons. Women were using their habitual analgesics, mainly nonsteroidal anti-inflammatory drugs (NSAIDs) such as naproxen sodium (550 mg, oral route), ibuprofen (400 or 800 mg, oral route) or indomethacin (50 or 100 mg, rectal or oral route) or triptans (sumatriptan 25, 50 or 100 mg; rectal or oral route) almotriptan (12.5 mg, oral route), eletriptan (80 mg, oral route), or rizatriptan (10 mg, oral route), to extinguish migraine attacks and were not using any migraine drug prophylaxis prior entering the study. At the first visit, women underwent a general and neurological examination, laboratory testing, a gynecological general history and a structured interview to diagnose primary headaches. Each woman reported at least one MRM attack per cycle during each of the last three menstrual cycles. In 62.5% of the cases, TTH was also diagnosed. The observational period lasted nine menstrual cycles during which time women filled in a validated headache diary which had been used in previous studies [13,25]. The

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Table 1 Clinical characteristics of women with MRM at baseline in previous COCs users and never COCs users

Migraine attacks (n) [mean ± SD] Duration (h) [mean±SD] Severity (h score=3) [mean±SD] Analgesics (n) [mean±SD] Associated phenomena [n (%)] Nausea [n (%)] Vomiting [n (%)] Phonophobia [n (%)] Photophobia [n (%)] TTH [n (%)] Dysmenorrhea [n (%)] Bleeding (days) [mean±SD] Cycle length (days) [mean±SD]

Previous COCs users (n=14)

Never COCs users (n= 18)

Full study group (n= 32)

2.6 ±0.9 46.6±14.4 21.2±8.6 4.4±1.3 14 (100) 14 (100) 13 (92.9) 14 (100) 14 (100) 8 (57.2) 13 (92.9) 5.2±1.1 25.3±1.8

2.8 ± 1.0 43.2±13.1 22.4±6.5 5±1.0 18 (100) 18 (100) 15 (83.3) 18 (100) 18 (100) 12 (66.7) 15 (83.3) 5.6±1.1 25.4±1.6

2.7±0.9 44.7±13.5 21.9±7.4 4.7±1.1 32 (100) 32 (100) 28 (87.5) 32 (100) 32 (100) 20 (62.5) 28 (87.5) 5.4 ± 1.1 25.3±1.7

following data were collected by patients: menstrual diary, the numbers of headache attacks, the number of hours of headache pain, the number of hours of severe headache pain, associated phenomena and analgesic use. Pain intensity was graded hourly on a 3-point scale, where 1=mild, does not impair daily activities; 2=moderate, may inhibit, but does not prohibit, daily activities; and 3=severe, prohibits daily activities. Associated phenomena included photophobia, phonophobia, nausea and vomiting (expressed as number of episodes), while analgesic use was the number of habitual analgesics/MRM attack. “Spotting" was defined as any vaginal bleeding that did not require the use of sanitary protection such as tampons or pads. "Bleeding" was defined as vaginal bleeding that required the use of sanitary protection. Menstrual cramps were also recorded daily on a 4-point scale, where 0=absent dysmenorrhea, 1=mild dysmenorrhea, 2=moderate dysmenorrhea and 3=severe dysmenorrhea. The duration of dysmenorrhea was expressed as the number of days with menstrual cramps, while the severity was calculated as the sum of daily scores/number days with dysmenorrhea. Women recorded every headache attack, both migraine without aura and other types of head pain during the study period. After a three-cycle run-in period, each subject received an E2V/DNG-containing oral contraception (Qlaira®/Natazia®; Bayer HealthCare, Berlin, Germany): E2V/DNG was administered using an estrogen step-down and progestogen step-up approach (E2V 3 mg on days 1–2, E2V 2 mg/DNG 2 mg on days 3–7, E2V 2 mg/DNG 3 mg on days 8–24, E2V 1 mg on days 25–26 and placebo on days 27–28). Study medication was initiated on the first day of bleeding, and there were no tablet-free days between treatment cycles. Follow-up evaluations were planned at the end of the third and of the sixth cycles of treatment. 2.1. Statistical analysis The clinical characteristics of headache attacks were calculated from the diaries at the last cycle of run-in and at

the third and sixth cycles of COC use. Details on bleeding profile, as well as data on dysmenorrhea (number of days of menstrual cramps and severity score), were also collected at the same time points. The data presented in Tables 1 and 2 are expressed as mean±standard deviation (SD) or percentage, as appropriate. Within- and between-subjects analysis was performed by using Student's t test or χ 2 when appropriate, and the data reported in Fig. 1 were expressed as mean±SD and standard error (SE).

3. Results The mean (± SD) age of the study sample was 40.6±3.5 years and the mean (± SD) BMI was 24.4±1.9 kg/m 2, without significant differences between previous COCs users (age 40.1±4.1 years, BMI 24.5±1.8 kg/m 2) and never COC users (age 41.0±3.0 years, BMI 24.3±2.1 kg/m 2). The clinical characteristics of headache attacks collected by diaries and by a structured interview according to the IHS criteria at baseline are reported in Table 1, as well as the Table 2 Course of MRM in women with and without persistence of dysmenorrhea at the third cycle (n=17 and n= 12, respectively) and the sixth cycle (n= 17 and n=11, respectively) of E2V/DNG use

Migraine attacks (n) Duration (h) of head pain Severity (h with pain intensity score=3) Analgesics (n) used to treat MRM

Persistent dysmenorrhea

3rd cycle (n= 29)

6th cycle (n= 28)

Without With Without With Without With Without With

2.0±0.8 2.4±0.5 24.6±10.0 24.8±10.7 13.5±4.1 18.2±4.6⁎ 3.1±0.7 3.6±0.7

1.9±0.7 2.0 ± 0.8⁎⁎ 24.9±8.9 22.7±10.0 13.3±3.9 17.4±5.7⁎⁎ 2.9±0.7 3.0±0.5

Mean values±SD of migraine characteristics in the two groups of women using E2V/DNG. ⁎ pb.03; with vs. without. ⁎⁎ pb.008; with vs. without.

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N°

hours

cycle

hours

cycle

N°

cycle

cycle

Fig. 1. Course of MRM throughout the study period in women assuming a contraceptive pill containing E2V/DNG (please note: 32 women at baseline; 29 women at the third cycle; 28 women at the sixth cycle). *pb.001 vs baseline; **pb.001 vs the third cycle.

duration and length of the menstrual cycle and the presence of dysmenorrhea. At baseline, only three women (9.4%) reported mild spotting (1 day in two subjects and 2 days in one subject). 3.1. Effect of E2V/DNG-containing pill on the course of migraine in women with MRM Four women dropped out, stopping COC use (two subjects because of a significant increase in the frequency and intensity of migraine after two and four cycles, respectively; one subject because of prolonged bleeding after one cycle; and one subject because of amenorrhea for the first two cycles and exacerbation of head pain at the time of expected bleeding). Therefore, the effects of EV/DNG use on headache with migraine characteristics were calculated in 29 women at cycle 3 and in 28 women at cycle 6. In every parameter studied, significant reductions were seen from baseline at the third and sixth cycles (Fig. 1). The number of migraine attacks declined from 2.7±0.9 days at baseline to 2.2±0.7 (pb.001) at cycle 3 and 2.0±0.7 (pb.001) at cycle 6. Similarly, the duration of headaches dropped from baseline of 44.7±13.5 h to 24.7±10.1 h (pb.001) at cycle 3 and remained reduced 24.1±9.2 h (p b .001) at cycle 6. The numbers of hours of severe pain decreased from baseline of

21.9±7.4 h to 15.4±4.9 h (pb.001) at cycle 3 and continued at the lower levels of 15.0±5.0 h (pb.001) at cycle 6. A significant reduction in the number of analgesics was observed from baseline of 4.7±1.1 to 3.3±0.7 (pb0.001) at cycle 3, which dropped even lower to 2.9±0.6 by cycle 6 (pb.001 cycle 3 vs. cycle 6). A similar trend of beneficial effect of E2V/DNG use was observed in previous COCs users and never COC users throughout the study period (data not shown). Finally, we did not find any significant difference in the occurrence of other types of headache or in phenomena associated with migraine, with only a nonsignificant trend for reduction of vomiting by the end of the study. 3.2. Effect of E2V/DNG-containing pill on bleeding and dysmenorrhea in women with MRM E2V/DNG combination was well tolerated by each woman, and the bleeding pattern changed significantly throughout the study. Indeed, the number of bleeding days was significantly reduced at cycle 3 (3.7±0.9, pb.001) and cycle 6 (3.5±0.8, pb.001) in comparison with baseline (5.4± 1.1). Spotting was reported by 31% of women (9/29) at cycle 3 and by 21.4% of women (6/28) at cycle 6, and the mean number of spotting days was 2.6±1.2 and 2.5±0.8,

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respectively. No significant correlation was evident between the course of headache with migraine characteristics and the bleeding profile (both withdrawal and spotting days) throughout the study. Dysmenorrhea was significantly reduced in women using E2V/DNG, with 58.6% (17/29) at cycle 3 and 60.7% (17/28) at cycle 6 reporting complete remission of menstrual cramps. Interestingly enough, at baseline, the number of migraine attacks was significantly lower in those four women not reporting dysmenorrhea in comparison with those suffering from menstrual cramps (1.7±1.0 vs. 2.8±1.2, pb.03). In addition, the number of days with bleeding was significantly lower in those women not reporting dysmenorrhea at baseline (4±0.0 vs. 5.6±1.1 in those women with dysmenorrhea, pb.006). Moreover, a positive significant correlation was evident at baseline between the number of days with bleeding and both the number of days with dysmenorrhea (r= .84, p=.000) and the severity score for menstrual cramps (r= .42, p=.02). In women who continued to experience dysmenorrhea while on E2V/DNG, both the number of days and the severity score of menstrual pain showed a nonsignificant trend toward reduction at cycle 3 in comparison with baseline, an effect that was maintained at cycle 6 of observation (data not shown). Table 2 reports the course of migraine according to the presence of dysmenorrhea at the third and sixth cycles of E2V/DNG use. Severity of head pain was significantly lower in women whose dysmenorrhea resolved with E2V/DNG compared with the head pain scores of those women still suffering from menstrual cramps both at the third and at sixth cycles. A positive significant correlation was evident between duration of headache with migraine characteristics and the number of days with dysmenorrhea at the third cycle (r= .89, p=.000) and at the sixth cycle (r= .76, p=.000) of EV/DNG use, but not at baseline. A similar result was found for severity of head pain and the number of days with dysmenorrhea at the third and sixth cycles (r= .67, p=.02 and r= .62, p=.04; respectively). As expected, there was a correlation between the mean number of analgesics used for headache with migraine characteristics and severity of menstrual cramps at the third and at sixth cycles (r= .77, p=.003 and r= .44, p=.02; respectively).

4. Discussion This prospective diary-based pilot study showed that, in women with MRM, the use of COC containing EV2/DNG for six cycles significantly reduced the number of attacks, duration and severity of head pain, and analgesics intake. Interestingly, duration and severity of headache with migraine characteristics were significantly correlated with the number of days of dysmenorrhea in those women who experienced persistent (but reduced) menstrual cramps. Our results suggest that a pill containing EV2/DNG may be used in women with migraine without aura related to the

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menstrual cycle without exacerbating the condition. Because ischemic stroke is such a rare (but catastrophic) event, no claims of safety can be made based on the numbers of women in this trial [16]. Further long-term studies are needed to establish safety because the surrogate markers of limited hemostatic and metabolic impact of E2-containing pills [26,27] cannot be used to predict cardiovascular risks in women until validated by clinical trials [28]. Once safety in lower risk migraines is established, more extended studies in women with more risk factors can determine if E2V/DNG pills are a suitable option in head pain sufferers over 35 years of age who need CHC for bleeding control and other menstrual-associated symptoms. The estrogen step-down/progestogen step-up 28-day E2V/DNG OC provides relatively stable plasma E2 levels [20,29], which are important because it is the abrupt estrogen decline which has been implicated as a trigger factor for headache around the time of menstrual bleeding [6,9,12,13]. However, other strategies to prevent E2 drop during perimenstrual period have been tried with variable results because the dose of estrogen seems critical to obtain a clear benefit in preventing MRM; in one study, a 40% increase in migraines was seen in the E2 supplement group within the 5 days after stopping E2 supplementation compared to a placebo group [13]. Moreover, it is not completely understood whether individual women have a peculiar neuroendocrine threshold of vulnerability to the drop or to the change of E2 plasma levels depending on a multitude of other mechanisms, including neuromodulators, proinflammatory mediators and vascular factors [30]. That being so, we believe that the lack of estrogen withdrawal is not the sole factor to explain the positive effect of E2V/DNG on the course of migraine reported in the present study. Indeed, the effectiveness of E2V/DNG in reducing the amount of bleeding and associated symptoms [22,23] also has to be taken into account because headache with migraine characteristics improves to a greater extent in those women reporting complete remission of menstrual cramps during the study period. In addition, a significant correlation between days with bleeding and dysmenorrhea has been found during E2V/DNG use. Although the pathogenesis of menstrual-related pain conditions is not fully understood, menstrual-related overproduction of prostaglandins (PGs) is implicated in the pathophysiology of both head pain and dysmenorrhea [24]. Indeed, saliva levels of several PGs increase during attacks of menstrual migraine associated with dysmenorrhea, and the treatment with a single-tablet combination of sumatriptan, the progenitor of all triptans, and an NSAID, such as naproxen sodium, prevents elevation of some PGs [31]. It is likely that such effect mediates the long-lasting relief in menstrual migraineurs with dysmenorrhea of this combined tablet in comparison with placebo [32]. Apart from being considered the first-line therapeutic option for managing dysmenorrhea [33], NSAIDs may be also effective in achieving a reduction in menstrual blood loss in women with

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heavy menstrual bleeding (HMB) [34]. Collectively, these findings suggest a link between pelvic pain and head pain which is likely to be mediated by mechanisms involved in endometrial function. DNG is a specific progesterone receptor agonist with potent oral endometrial activity [19,35] which significantly reduces the release of molecules highly implicated in the occurrence of menstrual-related pain conditions. Among several antiproliferative and anti-inflammatory effects, DNG has been shown to inhibit aromatase and COX-2 expression as well as PG E(2) production in human endometriotic stromal cells [36]. When administered alone, DNG at a dose of 2 mg/day has a specific indication in the treatment of endometriosis [35], while it reduces HMB when combined with E2V [37]. Interestingly, several lines of evidence indicate a high degree of comorbidity between endometriosis and migraine headache, and the increased sensitivity to pain mediated by PGs may represent one of the common clue linking pelvic pain with head pain in women suffering from both medical conditions [38]. Therefore, in women with predictable pain at the time of menstruation, there may be a role for hormonal preventive strategies to both relieve the symptom and effectively treat the underlying gynecologic conditions such as dysmenorrhea, menorrhagia, endometriosis and irregular cycles [39]. Both the strengths and weaknesses of our study should be acknowledged. It is a prospective study conducted with a validated diary to assess MRM in a specialized headache center [13,25]. However, the lack of a comparator arm is a relevant limitation, and further controlled studies need to be designed to confirm our data. In addition, it has to be demonstrated if the effect of E2V/DNG on MRM is maintained during longer use. In conclusion, the present diary-based pilot study indicates that the use of a pill containing EV2/DNG for six cycles may have a positive effect in women with MRM who choose to use oral contraception for birth control and suggests the persistence of dysmenorrhea under COCs as a potential feature of refractory head pain. Acknowledgments This study was supported by a grant of the Italian Ministry of Public Health RC2010-2011 assigned to a project entitled “Migraine and reproductive life: the role of sexual hormones.” References [1] Nappi RE, Berga SL. Migraine and reproductive life. Handb Clin Neurol 2010;97:303–22. [2] The international classification of headache disorders, 2nd ed. Cephalalgia 2004;(suppl 1). [3] MacGregor EA, Hackshaw A. Prevalence of migraine on each day of the natural menstrual cycle. Neurology 2004;63:351–3. [4] Stewart WF, Lipton RB, Chee E, et al. Menstrual cycle and headache in a population sample of migraineurs. Neurology 2000;55:1517–23.

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