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Table 3 Studies evaluating estrogen and progestogen strategies in women of reproductive age

From: Effect of exogenous estrogens and progestogens on the course of migraine during reproductive age: a consensus statement by the European Headache Federation (EHF) and the European Society of Contraception and Reproductive Health (ESCRH)

Study Study design (recruitment period) Setting (diagnostic criteria) Women included (n) Treatment Duration Outcome Findings
Desogestrel progestogen-only pill
 Merki-Feld, 2017 [41] Retrospective, observational, (2009–2013) MO, MA (ICHD-2); women who required treatment for contraception or medical reasons 64; 6 dropped out (on treatment analysis) Desogestrel 75 μg/day 90 days of observation and 90 days of treatment Migraine days, headache intensity, days with headache score 3, analgesic use Reduced migraine days, headache intensity, days with headache and use of pain medications
 Nappi, 2011 [42] Prospective, observational MA (ICHD-2); women who required treatment for contraception or medical reasons 30; 2 dropped-out after 3-month (analysis on treatment at 6 months) Desogestrel 75 μg/day 3 months of observation and 6 months of treatment Migraine attacks, duration of aura, duration and severity of headache pain, occurrence of focal neurological symptoms or associated symptoms, analgesic use Reduced number of migraine attacks in previous COCs users and nonusers
Desogestrel progestogen-only pill and extended regimen of combined oral contraceptives
 Morotti, 2014 [14] Retrospective, observational (2009–2013) MO (ICHD-2); women who required treatment for contraception or medical reasons 53; 21 dropped-out (on treatment analysis) Desogestrel 75 μg/day vs continuous EE 20 μg plus oral desogestrel 150 μg 6 months of treatment (pre-treatment observation period not-defined) Migraine and headache days, headache intensity, days with headache score 3, pain medication, triptan use, quality of life Reduced migraine days, headache days pain intensity, number of days with severe pain and days with pain medication in POP users; reduced number of headache days and in days with pain medication in COCs users; reduced number of days with pain medication in the POP group compared to the COC group
 Morotti 2014 [13] Prospective, observational (2009–2013) MO (ICHD-2) and endometriosis; women who required treatment for contraception or medical reasons 144; 27 dropped-out (on treatment analysis) desogestrel 75 μg/day vs sequential (21/7) EE 20 μg plus desogestrel 150 μg 6 months of treatment (pre-treatment observation period not-defined) Severity, number and duration of migraine attacks, associated symptoms Decreased number and intensity of migraine attacks in POP users
Extended regimen of combined oral contraceptive
 Coffee, 2014 [30] Non-randomized, open-label* MRM without aura (modified ICHD-2 criteria); women specifically treated for headache 32; 2 dropped-out (on treatment analysis) Extended regimen of EE 30 μg + levonorgestrel 150 μg 2 cycles of observation and 168 days of treatment Headache severity, MIDAS score, analgesic use Decrease in daily headache scores
 Sulak, 2007 [15] Prospective, observational Women with and without headache (no ICHD criteria; MA excluded); women who required treatment for contraception or medical reasons 114; 12 dropped-out (on treatment analysis) EE 30 μg plus drosperinone 3 mg Standard 21/7-day cycles for 3 months followed by a 168-day extended placebo-free regimen Presence and severity of headaches, analgesic use, impact of headaches on work, housework, social, recreational, and family events Improved headache scores with the extended regimen
Combined oral contraceptives with shortened pill-free interval
 De Leo, 2011 [39] Randomized, parallel group PMM (ICHD-2); women who required treatment for contraception or medical reasons 60 EE 20 μg + drospirenone 3 mg
21 active + 7 placebo vs 24 active + 4 placebo
3 cycles of observation and 3 months of treatment Duration and severity of headache Both treatments associated with reduction in intensity and duration of attacks; greater reduction in intensity and duration in patients taking 24 active + 7 placebo vs 21 active + 7 placebo
 Nappi, 2013 [43] Non-randomized, open-label MRM (ICHD-2); women who required treatment for contraception or medical reasons 32; 4 dropped-out (analysis on treatment on 29 women at cycle 3 and on 28 women at cycle 6) Estradiol valerate + dienogest pill using an estrogen step-down and progestogen step-up approach 26 days + 2 placebo 3 cycles of observation and 6 cycles of treatment Number of headache attacks, numbers of hours of headache pain, number of hours of severe headache pain, associated phenomena, analgesic use Reduction in the number and duration of migraine attacks, in hours of severe pain, and in use of analgesics
Combined oral contraceptives with oral estradiol supplementation during the pill-free interval
 Calhoun, 2004 [44] Retrospective and prospective, observational MO (ICHD-1 criteria) associated with menses; indication not specified 11 EE 20 μg (days 1–21) and conjugated equine estrogen 0.9 mg (days 22–28) 1 cycle of treatment Number of headache days, headache intensity score Decrease in the number of headache days and in weighted headache score
Combined oral contraceptives with estradiol supplementation with patch during the pill-free interval
 MacGregor, 2002 [34] Double-blind, placebo-controlled, randomized, crossover study MM (ICHD-1); women specifically treated for headache 14 Estradiol 50 μg vs placebo (all patients were on combined hormonal contraceptive pill) 2 cycles of active treatment and 2 cycles of placebo Number of pill-free intervals with migraine; number of days of migraine; severity of migraine; number of days of migraine with associated symptoms Trend towards reducing the frequency and severity of migraine with the patch
Combined hormonal contraceptive patch
 LaGuardia, 2005 [40] Randomized (2002–2003) Women with and without headache; women who required treatment for contraception or medical reasons 239 EE 20 μg + norelgestromin 150 μg patch Extended (12 weekly patch, 1 patch-free week, 3 weekly patch) vs cyclic regimen (4 cycles of 3 weekly patch and 1 patch-free week) Headache occurrence Less headache days in the patch on than in the patch off weeks; decrease in the headache rate during the patch-on weeks over the 16-week study period
Combined hormonal contraceptive vaginal ring
 Calhoun, 2012 [45] Retrospective, observational (2004–2010) Migraine with aura + MRM (modified ICHD criteria); indication not specified 28; 5 dropped out (on treatment analysis) EE 15 μg + etonogestrel 0.120 mg 7.8 months (range: 2 to 30 months) Aura frequency, headache frequency and intensity, resolution of MRM, headache index Aura frequency reduced; MRM eliminated in 91.3% of subjects
Transdermal estradiol supplementation with gel
 de Lignieres, 1986 [31] Randomized, placebo-controlled, double-blind, crossover MM (No ICHD; migraine without aura occurring exclusively not earlier than 2 days before menstruation and no later than the last day of the menses); women specifically treated for headache 20; 2 dropped-out Estradiol gel 1.5 mg for 7 days vs placebo 26 cycles of treatment, 27 cycles of placebo Occurrence, duration, severity of migraine attacks, aspirin use Reduction in the occurrence and severity of attacks and in the use of aspirin
 Dennerstein, 1988 [32] Randomized, placebo-controlled, double-blind, crossover MM (No ICHD; regular migraine in the paramenstruum); women specifically treated for headache 22; 4 dropped-out (on treatment analysis) Estradiol gel 1.5 mg for 7 days vs placebo 2 cycles of treatment, 2 cycles of placebo, and 1 cycle of follow-up (no treatment) Occurrence of migraine, moderate to severe intensity migraine, analgesic use No difference in the occurrence of attacks; reduction of moderate to severe intensity attacks
 MacGregor, 2006 [35] Randomized, double-blind, placebo-controlled, crossover PMM or MRM (ICHD-2); women specifically treated for headache 37; 2 dropped-out (on treatment analysis) Estradiol gel 1.5 mg for 6 days vs placebo 3 cycles of placebo, 3 cycles of treatment Migraine days and severity, duration of attacks, associated symptoms, occurrence of aura, analgesic use Reduction in migraine days and attacks severity; increase in migraine occurrence in the 5 days immediately after estradiol use
Transdermal estradiol supplementation with patch
 Almen-Christensson, 2011 [29] Randomized, placebo-controlled, double-blind crossover PMM (ICHD-2); women specifically treated for headache 38; 6 dropped-out (on treatment analysis) Estradiol 100 μg vs placebo 2 weeks of treatment for 3 cycles for placebo and 3 cycles for active treatment Number, severity and intensity of migraine attacks No differences between active treatment and placebo
 Guidotti, 2007 [33] Prospective, observational MM (ICHD-2); women specifically treated for headache 38 (10 treated with EE) Estradiol 25 μg vs frovatriptan vs naproxen sodium 1 cycle of treatment (6 days before expected menstruation) Number and severity of migraine attacks Reduction in number of migraine attacks and severity of attacks with frovatriptan than with estradiol or naproxen sodium
 Pradalier, 1994 [37] Randomized, open-label study MM (ICHD-1); women specifically treated for headache 24 Estradiol 25 μg vs estradiol 100 μg 1 cycle of observation, 2 cycles of treatment Occurrence and severity of MM Reduction in number of attacks with the higher dose
 Smite, 1993 [38] Randomized, placebo-controlled (1989–1990) PMM (ICHD-1); women specifically treated for headache 20 Estradiol 50 μg vs placebo 6 days of treatment for 3 cycles (estradiol-placebo-estradiol or placebo-estradiol-placebo) Presence, duration, severity of migraine attacks, analgesic use No differences between active treatment and placebo
Transdermal estradiol supplementation with patch in women induced in pharmacological menopause
 Martin, 2003 [12] Randomized, placebo- controlled, parallel group (1997–2001) MO, MA (ICHD-1); women specifically treated for headache 23; 2 dropped-out (on treatment analysis) goserelin 3.6 mg implant with estradiol 100 μg patches every 6 days vs goserelin 3.6 mg implant with placebo patches 1 lead-in month, 2.5 months of placebo, 1 month of goserelin injection, 2 months of randomization Headache index, disability index, headache frequency and severity Reduced headache and disability index and in headache frequency in the GRH agonist/estradiol group
Subcutaneous estrogen implant plus cyclical progestogen
 Magos, 1983 [36] Retrospective, observational; women specifically treated for headache MM with and without aura (No ICHD; attacks immediately before or during menstruation) 24 Estradiol (100 mg then decreased to 50 mg) + norethisterone 5 mg/day for 7 days per month 2.5 years (mean duration) of treatment Improvement of menstrual migraine 95.8% of patients with improvement in MM; 46% became headache-free and 37.5% gained almost complete symptomatic relief
  1. MO migraine without aura, MA migraine with aura, ICHD International Classification of Headache Disorders, EE ethinylestradiol
  2. PMM pure menstrual migraine, MRM menstrually related migraine, MM menstrual migraine