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

 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

 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

 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

 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

 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

 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

 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

 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

 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

 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

 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

 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