Prevention of menstrual migraine with perimenstrual transdermal 17-β-estradiol: a randomized, placebo-controlled, double-blind crossover study
2011; Elsevier BV; Volume: 96; Issue: 2 Linguagem: Inglês
10.1016/j.fertnstert.2011.05.089
ISSN1556-5653
AutoresAnna Almén-Christensson, Mats Hammar, Lotta Lindh‐Åstrand, Anne‐Marie Landtblom, Jan Brynhildsen,
Tópico(s)Ophthalmology and Eye Disorders
ResumoThe effect of treatment with percutaneous E2 (100 μg/24 h) during 2 weeks perimenstrually on the number and severity of menstrual migraine attacks was studied in 27 women in a randomized, placebo-controlled, double-blind, crossover trial. We were not able to demonstrate any difference between E2 supplementation and placebo on the number or severity of migraine attacks, but both regimens showed significant effects compared with before treatment.Clinical Trial Identification NumberNCT00204074. The effect of treatment with percutaneous E2 (100 μg/24 h) during 2 weeks perimenstrually on the number and severity of menstrual migraine attacks was studied in 27 women in a randomized, placebo-controlled, double-blind, crossover trial. We were not able to demonstrate any difference between E2 supplementation and placebo on the number or severity of migraine attacks, but both regimens showed significant effects compared with before treatment. NCT00204074. After puberty, migraine is approximately three times more common in women than in men, and ∼18% of all women of fertile ages suffer from migraine (1Lipton R.B. Stewart W.F. Diamond S. Diamond M.L. Reed M. Prevalence and burden of migraine in the United States: data from the American Migraine Study II.Headache. 2001; 41: 646-657Crossref PubMed Scopus (1809) Google Scholar). The gender difference of migraine and the nature of menstrual migraine suggest a hormonal trigger. Pure menstrual migraine is defined by the International Headache Society (IHS) as migraine attacks that occur 2 days before to 3 days after the onset of bleeding and at no other times of the menstrual cycle. Attacks should be without aura and present in two out of three menstrual cycles (2Headache Classification Committee of the International Headache SocietyThe international classification of headache disorders: second edition.Cephalalgia. 2004; 24: 9-160PubMed Google Scholar).Sommerville (3Somerville B.W. The role of estradiol withdrawal in the etiology of menstrual migraine.Neurology. 1972; 22: 355-365Crossref PubMed Google Scholar, 4Somerville B.W. Estrogen-withdrawal migraine. I. Duration of exposure required and attempted prophylaxis by premenstrual estrogen administration.Neurology. 1975; 25: 239-244Crossref PubMed Google Scholar) concluded that the rapid decrease in serum concentrations of E2 triggered migraine attacks in certain women. The E2 drop also requires a preceding high serum concentration of more than a few days to be able to trigger a migraine attack, explaining why E2 drops after ovulation are seldomly associated with migraine attacks (3Somerville B.W. The role of estradiol withdrawal in the etiology of menstrual migraine.Neurology. 1972; 22: 355-365Crossref PubMed Google Scholar, 4Somerville B.W. Estrogen-withdrawal migraine. I. Duration of exposure required and attempted prophylaxis by premenstrual estrogen administration.Neurology. 1975; 25: 239-244Crossref PubMed Google Scholar). In women with menstrual migraine, the stability rather than the concentrations of E2 might be crucial to avoid and prevent attacks. Treatment may cause stability at low estrogen concentrations with the use of GnRH analogues or danazole (5Lichten E.M. Bennett R.S. Whitty A.J. Daoud Y. Efficacy of danazol in the control of hormonal migraine.J Reprod Med. 1991; 36: 419-424PubMed Google Scholar, 6Murray S.C. Muse K.N. Effective treatment of severe menstrual migraine headaches with gonadotropin-releasing hormone agonist and "add-back" therapy.Fertil Steril. 1997; 67: 390-393Abstract Full Text PDF PubMed Scopus (77) Google Scholar) or at higher concentrations with the use of combined oral contraceptives or estrogen supplementation perimenstrually (7DeLignières B. Vincens M. Mauvais-Jarvis P. Mas J.L. Touboul P.J. Bousser M.G. Prevention of menstrual migraine by percutaneous estradiol.Br Med J. 1986; 293: 1540Crossref PubMed Scopus (175) Google Scholar, 8Dennerstein L. Morse C. Burrows G. Oats J. Brown J. Smith M. Menstrual migraine: a double-blind trial of percutaneous estradiol.Gynecol Endocrinol. 1988; 2: 113-120Crossref PubMed Scopus (123) Google Scholar, 9Smits V.G. van der Meer Y.G. Pfeil J.P.J.M. Rijnierse J.J.M.M. Vos A.J.M. Perimenstrual migraine: effect of Estraderm TTS and the value of contingent negative variation and exteroceptive temporalis muscle suppression test.Headache. 1993; 34: 103-106Crossref Scopus (72) Google Scholar, 10Pfaffenrath V. Efficacy and safety of percutaneous estradiol vs placebo in menstrual migraine.Cephalalgia. 1993; 13: 244Google Scholar). There seems to be a dose-response pattern, because better results have been reported with use of a higher E2 dose, which also suggests a critical concentration (11Pradalier A. Vincent D. Beaulieu P. Baudersson G. Launey J.-M. Correlation between estradiol plasma level and therapeutic effect on menstrual migraine.in: Rose F. New advances in headache research. Smith-Gordon, London1994: 129-132Google Scholar).The aim of this study was to test the hypothesis that a high dose of E2 administered perimenstrually would reduce the number, duration, and severity of migraine attacks in women with pure menstrual migraine.Pure menstrual migraine was defined according to the IHS (2Headache Classification Committee of the International Headache SocietyThe international classification of headache disorders: second edition.Cephalalgia. 2004; 24: 9-160PubMed Google Scholar). There were two study centers (University Hospital, Linköping, Sweden, and County Hospital, Jönköping, Sweden). The women had to be 18–45 years old, be otherwise healthy, and have regular menstrual cycles (26–30 days). No hormonal contraception was allowed, and adequate wash-out periods were demanded if the women had used contraceptive injectables, implants, or intrauterine progestin.At the screening visit and end of trial, a thorough general medical examination and a gynecologic examination, including ultrasound, was conducted. Each woman was informed in both writing and orally and thereafter gave her written informed consent.After screening, the woman filled in a diary prospectively to confirm regular menstrual periods and the diagnosis of pure menstrual migraine. An experienced neurologist (A.-M.L.) confirmed the diagnosis.The treatment was administered transdermally as two patches with 50 μg E2/24 h (Climara; Schering Nordiska) or placebo in 7-day patches. Seven days before the estimated onset of the menstrual bleeding the woman started treatment. Two new patches replaced these patches after 7 days and were then followed by 2 weeks without treatment, i.e., 2 weeks of treatment each menstrual cycle.This procedure was repeated three times (i.e., during three consecutive menstrual cycles). After 1 month of wash-out, women crossed over to the treatment they had not received during the first three consecutive cycles (Supplemental Fig. 1, available online at www.fertstert.org). The research nurse delivered the patches before the start of each treatment period.The women recorded menstrual data, use of patches, number of migraine attacks, and severity of the attacks (mild, moderate, or severe) (12MacGregor E.A. Hackshaw A. Prevalence of migraine on each day of the natural menstrual cycle.Neurology. 2004; 63: 351-353Crossref PubMed Scopus (211) Google Scholar). A severe attack was defined as an attack that prevented the patient from work or other scheduled activities.Compliance to treatment was evaluated from unused patch count, and the number of migraine attacks in each cycle as well as the average number of attacks was calculated.Statistical evaluation was performed using Wilcoxon signed rank test. To be able to detect a difference between treatments of one attack per cycle or one-step decrease in severity at a 5% significance level with a 90% power, 29 patients had to fulfill the treatment. Estimating a 20% dropout rate, 36 patients were planned to be included.The Regional Ethical Review Board in Linköping and the Swedish Medical Products Agency approved the study, which was conducted according to Good Clinical Practice.A total of 83 patients were screened for inclusion, and 38 patients were included. Eleven patients were excluded from the study. Three women did not fulfill the criteria for inclusion, and one woman used the patch incorrectly. Six women did not complete the study owing to adverse events (Supplemental Fig. 1). The women were on average 39.6 ± 4.3 years old. Both E2 and placebo treatment reduced the number of migraine attacks compared with before treatment. There were, however, no significant differences between E2 and placebo on the number of migraine attacks or the severity of migraine attacks (Table 1). Neither were there any differences in the number of days of sick leave from work between the treatment period and the placebo period.Table 1Number of migraine attacks, severity of headache, intensity of attack, and sick leave.Before treatmentE2PlaceboBefore treatment vs.E2 vs. PlaceboE2PlaceboNo. of menstrual migraine attacks/cycle1.5 (1–3)1.0 (0–2)1.0 (0–2.5)P=.0001P=.0004P=.92Severity of headache in migraine attacks/cycle1.75 (1–3)1.67 (0–3)1.67 (0–2.5)P=.13P=.12P=.96Intensity of the migraine attacks/cycle1.5 (1–2.5)1.5 (0–3)1.6 (0–2.5)P=.15P=.40P=.82Note: Values are presented as median and range. P values determined by Wilcoxon signed-rank test. Intensity means the patients' subjective rating of the attack, including not only headache but also related symptoms, such as nausea, vomiting, etc. Open table in a new tab Patch count yielded a result slightly above 100%, because some patients used an extra patch when the originally placed patch was lost.Six women discontinued due to adverse events. Two of these women reported increased headache, and two discontinued because of local skin reactions, one because of nausea, and one because of increased blood pressure. One woman became pregnant and was therefore excluded. Two women reported minor disturbances of the menstrual cycle, but both of these women continued. No serious adverse events occurred.In this study, we were not able to demonstrate any difference between treatment with 100 μg transdermal 17β-estradiol and placebo on the number, duration, or severity of menstrual migraine attacks. Both treatments had significant effect on migraine attacks compared with before treatment.The strict inclusion criteria made it difficult to recruit patients. Therefore, we decided to break the code and stop the study when only 27 patients had fulfilled the study. As a consequence, we did not reach the planned sample size and statistical power. However, when estimating two more patients with maximum effect of active treatment, the lack of difference between E2 and placebo would have remained.Earlier placebo-controlled studies have shown conflicting results. Studies of treatment with 25–50 μg E2/24 h have failed to demonstrate any effect compared with placebo (9Smits V.G. van der Meer Y.G. Pfeil J.P.J.M. Rijnierse J.J.M.M. Vos A.J.M. Perimenstrual migraine: effect of Estraderm TTS and the value of contingent negative variation and exteroceptive temporalis muscle suppression test.Headache. 1993; 34: 103-106Crossref Scopus (72) Google Scholar, 10Pfaffenrath V. Efficacy and safety of percutaneous estradiol vs placebo in menstrual migraine.Cephalalgia. 1993; 13: 244Google Scholar, 11Pradalier A. Vincent D. Beaulieu P. Baudersson G. Launey J.-M. Correlation between estradiol plasma level and therapeutic effect on menstrual migraine.in: Rose F. New advances in headache research. Smith-Gordon, London1994: 129-132Google Scholar), whereas 100 μg E2/24 h has been reported to be effective (11Pradalier A. Vincent D. Beaulieu P. Baudersson G. Launey J.-M. Correlation between estradiol plasma level and therapeutic effect on menstrual migraine.in: Rose F. New advances in headache research. Smith-Gordon, London1994: 129-132Google Scholar). Also studies using 1.5 mg E2 transdermal gel have reported good effects (7DeLignières B. Vincens M. Mauvais-Jarvis P. Mas J.L. Touboul P.J. Bousser M.G. Prevention of menstrual migraine by percutaneous estradiol.Br Med J. 1986; 293: 1540Crossref PubMed Scopus (175) Google Scholar, 8Dennerstein L. Morse C. Burrows G. Oats J. Brown J. Smith M. Menstrual migraine: a double-blind trial of percutaneous estradiol.Gynecol Endocrinol. 1988; 2: 113-120Crossref PubMed Scopus (123) Google Scholar, 13MacGregor E.A. Frith A. Ellis J. Aspinall L. Hackshaw A. Prevention of menstrual attacks of migraine. A double-blind placebo-controlled crossover study.Neurology. 2006; 67: 2159-2163Crossref PubMed Scopus (127) Google Scholar). The serum concentrations of E2 in women using patches with 100 μg estradiol may produce even higher serum concentrations of E2 (14Pharmaceutical Agents in Sweden (FASS). Elanders, Kungsbacka, Sweden2005Google Scholar, 15Taggart W. Dandekar K. Ellman H. Notelowitz M. The effect of site application on the trancutaneous absorption of 17-β estradiol from a transdermal delivery system (Climara).J North Am Menopause Soc. 2000; 7: 364-369Crossref PubMed Scopus (14) Google Scholar, 16Piippo S. Lenko H. Kainulainen P. Sipilä I. Use of percutaneous estrogen gel for induction of puberty in girls with Turner syndrome.Endocrinol Metabol. 2004; 89: 3241-3247Crossref PubMed Scopus (68) Google Scholar) than 1.5 mg E2 gel, and the lack of difference in results between E2 and placebo could most probably not be explained by an insufficient dose of E2.MacGregor et al. (13MacGregor E.A. Frith A. Ellis J. Aspinall L. Hackshaw A. Prevention of menstrual attacks of migraine. A double-blind placebo-controlled crossover study.Neurology. 2006; 67: 2159-2163Crossref PubMed Scopus (127) Google Scholar) used a fertility monitor to establish the time of ovulation for timing of the treatment. Such a regimen is more reliable regarding the timing but is difficult to use in everyday life. We relied on the women's self reported menstrual data, and the pretreatment diaries confirmed regular cycles.The women in our study were treated during a prolonged time (14 days, starting 7 days before estimated start of the menstrual bleeding) to maintain a higher serum concentration of E2 and to avoid influence of a variation in cycle length, whereas other studies generally treated women for 7 days totally (7DeLignières B. Vincens M. Mauvais-Jarvis P. Mas J.L. Touboul P.J. Bousser M.G. Prevention of menstrual migraine by percutaneous estradiol.Br Med J. 1986; 293: 1540Crossref PubMed Scopus (175) Google Scholar, 8Dennerstein L. Morse C. Burrows G. Oats J. Brown J. Smith M. Menstrual migraine: a double-blind trial of percutaneous estradiol.Gynecol Endocrinol. 1988; 2: 113-120Crossref PubMed Scopus (123) Google Scholar, 13MacGregor E.A. Frith A. Ellis J. Aspinall L. Hackshaw A. Prevention of menstrual attacks of migraine. A double-blind placebo-controlled crossover study.Neurology. 2006; 67: 2159-2163Crossref PubMed Scopus (127) Google Scholar). The aim of the present regimen was to make sure that serum concentrations of E2 would be stable at the time of the anticipated start of the bleeding and migraine attacks. This regimen minimizes the risk of insufficient timing of the treatment owing to variable menstrual cycle length.According to IHS guidelines for controlled clinical trials of drugs in migraine (17International Headache Society Clinical Trials SubcommitteeGuidelines for controlled trials of drugs in migraine: second edition.Cephalalgia. 2000; 20: 765-786Crossref PubMed Scopus (582) Google Scholar), at least 48 hours of freedom from symptoms should have occurred for the headache to be identified as a new migraine attack. Otherwise, it should be considered to be a relapse. In the present study, the exact hour of the onset of the attack was not recorded, only the day and the duration of the attack. Therefore we have included both new attacks and attacks that might have been relapses. We consider it unlikely that this slight modification would have had any effect on the interpretation of the results, because we used the same classification during all cycles and consequently the same method for both active and placebo treatment.In conclusion, we found no benefit in treating women with menstrual migraine with transdermal E2 (100 μg/24 h) versus placebo; however, both treatments improved migraine headache in the group of women studied. The results are in contrast to previous studies. After puberty, migraine is approximately three times more common in women than in men, and ∼18% of all women of fertile ages suffer from migraine (1Lipton R.B. Stewart W.F. Diamond S. Diamond M.L. Reed M. Prevalence and burden of migraine in the United States: data from the American Migraine Study II.Headache. 2001; 41: 646-657Crossref PubMed Scopus (1809) Google Scholar). The gender difference of migraine and the nature of menstrual migraine suggest a hormonal trigger. Pure menstrual migraine is defined by the International Headache Society (IHS) as migraine attacks that occur 2 days before to 3 days after the onset of bleeding and at no other times of the menstrual cycle. Attacks should be without aura and present in two out of three menstrual cycles (2Headache Classification Committee of the International Headache SocietyThe international classification of headache disorders: second edition.Cephalalgia. 2004; 24: 9-160PubMed Google Scholar). Sommerville (3Somerville B.W. The role of estradiol withdrawal in the etiology of menstrual migraine.Neurology. 1972; 22: 355-365Crossref PubMed Google Scholar, 4Somerville B.W. Estrogen-withdrawal migraine. I. Duration of exposure required and attempted prophylaxis by premenstrual estrogen administration.Neurology. 1975; 25: 239-244Crossref PubMed Google Scholar) concluded that the rapid decrease in serum concentrations of E2 triggered migraine attacks in certain women. The E2 drop also requires a preceding high serum concentration of more than a few days to be able to trigger a migraine attack, explaining why E2 drops after ovulation are seldomly associated with migraine attacks (3Somerville B.W. The role of estradiol withdrawal in the etiology of menstrual migraine.Neurology. 1972; 22: 355-365Crossref PubMed Google Scholar, 4Somerville B.W. Estrogen-withdrawal migraine. I. Duration of exposure required and attempted prophylaxis by premenstrual estrogen administration.Neurology. 1975; 25: 239-244Crossref PubMed Google Scholar). In women with menstrual migraine, the stability rather than the concentrations of E2 might be crucial to avoid and prevent attacks. Treatment may cause stability at low estrogen concentrations with the use of GnRH analogues or danazole (5Lichten E.M. Bennett R.S. Whitty A.J. Daoud Y. Efficacy of danazol in the control of hormonal migraine.J Reprod Med. 1991; 36: 419-424PubMed Google Scholar, 6Murray S.C. Muse K.N. Effective treatment of severe menstrual migraine headaches with gonadotropin-releasing hormone agonist and "add-back" therapy.Fertil Steril. 1997; 67: 390-393Abstract Full Text PDF PubMed Scopus (77) Google Scholar) or at higher concentrations with the use of combined oral contraceptives or estrogen supplementation perimenstrually (7DeLignières B. Vincens M. Mauvais-Jarvis P. Mas J.L. Touboul P.J. Bousser M.G. Prevention of menstrual migraine by percutaneous estradiol.Br Med J. 1986; 293: 1540Crossref PubMed Scopus (175) Google Scholar, 8Dennerstein L. Morse C. Burrows G. Oats J. Brown J. Smith M. Menstrual migraine: a double-blind trial of percutaneous estradiol.Gynecol Endocrinol. 1988; 2: 113-120Crossref PubMed Scopus (123) Google Scholar, 9Smits V.G. van der Meer Y.G. Pfeil J.P.J.M. Rijnierse J.J.M.M. Vos A.J.M. Perimenstrual migraine: effect of Estraderm TTS and the value of contingent negative variation and exteroceptive temporalis muscle suppression test.Headache. 1993; 34: 103-106Crossref Scopus (72) Google Scholar, 10Pfaffenrath V. Efficacy and safety of percutaneous estradiol vs placebo in menstrual migraine.Cephalalgia. 1993; 13: 244Google Scholar). There seems to be a dose-response pattern, because better results have been reported with use of a higher E2 dose, which also suggests a critical concentration (11Pradalier A. Vincent D. Beaulieu P. Baudersson G. Launey J.-M. Correlation between estradiol plasma level and therapeutic effect on menstrual migraine.in: Rose F. New advances in headache research. Smith-Gordon, London1994: 129-132Google Scholar). The aim of this study was to test the hypothesis that a high dose of E2 administered perimenstrually would reduce the number, duration, and severity of migraine attacks in women with pure menstrual migraine. Pure menstrual migraine was defined according to the IHS (2Headache Classification Committee of the International Headache SocietyThe international classification of headache disorders: second edition.Cephalalgia. 2004; 24: 9-160PubMed Google Scholar). There were two study centers (University Hospital, Linköping, Sweden, and County Hospital, Jönköping, Sweden). The women had to be 18–45 years old, be otherwise healthy, and have regular menstrual cycles (26–30 days). No hormonal contraception was allowed, and adequate wash-out periods were demanded if the women had used contraceptive injectables, implants, or intrauterine progestin. At the screening visit and end of trial, a thorough general medical examination and a gynecologic examination, including ultrasound, was conducted. Each woman was informed in both writing and orally and thereafter gave her written informed consent. After screening, the woman filled in a diary prospectively to confirm regular menstrual periods and the diagnosis of pure menstrual migraine. An experienced neurologist (A.-M.L.) confirmed the diagnosis. The treatment was administered transdermally as two patches with 50 μg E2/24 h (Climara; Schering Nordiska) or placebo in 7-day patches. Seven days before the estimated onset of the menstrual bleeding the woman started treatment. Two new patches replaced these patches after 7 days and were then followed by 2 weeks without treatment, i.e., 2 weeks of treatment each menstrual cycle. This procedure was repeated three times (i.e., during three consecutive menstrual cycles). After 1 month of wash-out, women crossed over to the treatment they had not received during the first three consecutive cycles (Supplemental Fig. 1, available online at www.fertstert.org). The research nurse delivered the patches before the start of each treatment period. The women recorded menstrual data, use of patches, number of migraine attacks, and severity of the attacks (mild, moderate, or severe) (12MacGregor E.A. Hackshaw A. Prevalence of migraine on each day of the natural menstrual cycle.Neurology. 2004; 63: 351-353Crossref PubMed Scopus (211) Google Scholar). A severe attack was defined as an attack that prevented the patient from work or other scheduled activities. Compliance to treatment was evaluated from unused patch count, and the number of migraine attacks in each cycle as well as the average number of attacks was calculated. Statistical evaluation was performed using Wilcoxon signed rank test. To be able to detect a difference between treatments of one attack per cycle or one-step decrease in severity at a 5% significance level with a 90% power, 29 patients had to fulfill the treatment. Estimating a 20% dropout rate, 36 patients were planned to be included. The Regional Ethical Review Board in Linköping and the Swedish Medical Products Agency approved the study, which was conducted according to Good Clinical Practice. A total of 83 patients were screened for inclusion, and 38 patients were included. Eleven patients were excluded from the study. Three women did not fulfill the criteria for inclusion, and one woman used the patch incorrectly. Six women did not complete the study owing to adverse events (Supplemental Fig. 1). The women were on average 39.6 ± 4.3 years old. Both E2 and placebo treatment reduced the number of migraine attacks compared with before treatment. There were, however, no significant differences between E2 and placebo on the number of migraine attacks or the severity of migraine attacks (Table 1). Neither were there any differences in the number of days of sick leave from work between the treatment period and the placebo period. Note: Values are presented as median and range. P values determined by Wilcoxon signed-rank test. Intensity means the patients' subjective rating of the attack, including not only headache but also related symptoms, such as nausea, vomiting, etc. Patch count yielded a result slightly above 100%, because some patients used an extra patch when the originally placed patch was lost. Six women discontinued due to adverse events. Two of these women reported increased headache, and two discontinued because of local skin reactions, one because of nausea, and one because of increased blood pressure. One woman became pregnant and was therefore excluded. Two women reported minor disturbances of the menstrual cycle, but both of these women continued. No serious adverse events occurred. In this study, we were not able to demonstrate any difference between treatment with 100 μg transdermal 17β-estradiol and placebo on the number, duration, or severity of menstrual migraine attacks. Both treatments had significant effect on migraine attacks compared with before treatment. The strict inclusion criteria made it difficult to recruit patients. Therefore, we decided to break the code and stop the study when only 27 patients had fulfilled the study. As a consequence, we did not reach the planned sample size and statistical power. However, when estimating two more patients with maximum effect of active treatment, the lack of difference between E2 and placebo would have remained. Earlier placebo-controlled studies have shown conflicting results. Studies of treatment with 25–50 μg E2/24 h have failed to demonstrate any effect compared with placebo (9Smits V.G. van der Meer Y.G. Pfeil J.P.J.M. Rijnierse J.J.M.M. Vos A.J.M. Perimenstrual migraine: effect of Estraderm TTS and the value of contingent negative variation and exteroceptive temporalis muscle suppression test.Headache. 1993; 34: 103-106Crossref Scopus (72) Google Scholar, 10Pfaffenrath V. Efficacy and safety of percutaneous estradiol vs placebo in menstrual migraine.Cephalalgia. 1993; 13: 244Google Scholar, 11Pradalier A. Vincent D. Beaulieu P. Baudersson G. Launey J.-M. Correlation between estradiol plasma level and therapeutic effect on menstrual migraine.in: Rose F. New advances in headache research. Smith-Gordon, London1994: 129-132Google Scholar), whereas 100 μg E2/24 h has been reported to be effective (11Pradalier A. Vincent D. Beaulieu P. Baudersson G. Launey J.-M. Correlation between estradiol plasma level and therapeutic effect on menstrual migraine.in: Rose F. New advances in headache research. Smith-Gordon, London1994: 129-132Google Scholar). Also studies using 1.5 mg E2 transdermal gel have reported good effects (7DeLignières B. Vincens M. Mauvais-Jarvis P. Mas J.L. Touboul P.J. Bousser M.G. Prevention of menstrual migraine by percutaneous estradiol.Br Med J. 1986; 293: 1540Crossref PubMed Scopus (175) Google Scholar, 8Dennerstein L. Morse C. Burrows G. Oats J. Brown J. Smith M. Menstrual migraine: a double-blind trial of percutaneous estradiol.Gynecol Endocrinol. 1988; 2: 113-120Crossref PubMed Scopus (123) Google Scholar, 13MacGregor E.A. Frith A. Ellis J. Aspinall L. Hackshaw A. Prevention of menstrual attacks of migraine. A double-blind placebo-controlled crossover study.Neurology. 2006; 67: 2159-2163Crossref PubMed Scopus (127) Google Scholar). The serum concentrations of E2 in women using patches with 100 μg estradiol may produce even higher serum concentrations of E2 (14Pharmaceutical Agents in Sweden (FASS). Elanders, Kungsbacka, Sweden2005Google Scholar, 15Taggart W. Dandekar K. Ellman H. Notelowitz M. The effect of site application on the trancutaneous absorption of 17-β estradiol from a transdermal delivery system (Climara).J North Am Menopause Soc. 2000; 7: 364-369Crossref PubMed Scopus (14) Google Scholar, 16Piippo S. Lenko H. Kainulainen P. Sipilä I. Use of percutaneous estrogen gel for induction of puberty in girls with Turner syndrome.Endocrinol Metabol. 2004; 89: 3241-3247Crossref PubMed Scopus (68) Google Scholar) than 1.5 mg E2 gel, and the lack of difference in results between E2 and placebo could most probably not be explained by an insufficient dose of E2. MacGregor et al. (13MacGregor E.A. Frith A. Ellis J. Aspinall L. Hackshaw A. Prevention of menstrual attacks of migraine. A double-blind placebo-controlled crossover study.Neurology. 2006; 67: 2159-2163Crossref PubMed Scopus (127) Google Scholar) used a fertility monitor to establish the time of ovulation for timing of the treatment. Such a regimen is more reliable regarding the timing but is difficult to use in everyday life. We relied on the women's self reported menstrual data, and the pretreatment diaries confirmed regular cycles. The women in our study were treated during a prolonged time (14 days, starting 7 days before estimated start of the menstrual bleeding) to maintain a higher serum concentration of E2 and to avoid influence of a variation in cycle length, whereas other studies generally treated women for 7 days totally (7DeLignières B. Vincens M. Mauvais-Jarvis P. Mas J.L. Touboul P.J. Bousser M.G. Prevention of menstrual migraine by percutaneous estradiol.Br Med J. 1986; 293: 1540Crossref PubMed Scopus (175) Google Scholar, 8Dennerstein L. Morse C. Burrows G. Oats J. Brown J. Smith M. Menstrual migraine: a double-blind trial of percutaneous estradiol.Gynecol Endocrinol. 1988; 2: 113-120Crossref PubMed Scopus (123) Google Scholar, 13MacGregor E.A. Frith A. Ellis J. Aspinall L. Hackshaw A. Prevention of menstrual attacks of migraine. A double-blind placebo-controlled crossover study.Neurology. 2006; 67: 2159-2163Crossref PubMed Scopus (127) Google Scholar). The aim of the present regimen was to make sure that serum concentrations of E2 would be stable at the time of the anticipated start of the bleeding and migraine attacks. This regimen minimizes the risk of insufficient timing of the treatment owing to variable menstrual cycle length. According to IHS guidelines for controlled clinical trials of drugs in migraine (17International Headache Society Clinical Trials SubcommitteeGuidelines for controlled trials of drugs in migraine: second edition.Cephalalgia. 2000; 20: 765-786Crossref PubMed Scopus (582) Google Scholar), at least 48 hours of freedom from symptoms should have occurred for the headache to be identified as a new migraine attack. Otherwise, it should be considered to be a relapse. In the present study, the exact hour of the onset of the attack was not recorded, only the day and the duration of the attack. Therefore we have included both new attacks and attacks that might have been relapses. We consider it unlikely that this slight modification would have had any effect on the interpretation of the results, because we used the same classification during all cycles and consequently the same method for both active and placebo treatment. In conclusion, we found no benefit in treating women with menstrual migraine with transdermal E2 (100 μg/24 h) versus placebo; however, both treatments improved migraine headache in the group of women studied. The results are in contrast to previous studies. The authors thank Dr. Birgitta Gustafsson-Borg and Dr. Jan-Åke Åkesson for recruiting patients and nurses/midwives Gunn Johansson, Christina Ramsö, and Lena Skaring-Thorssén for help with handling the patients. Appendix
Referência(s)