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Table 2 Summary of Findings

From: The complex relationship between estrogen and migraines: a scoping review

Article # of particpants Patient characteristics Intervention Outcome/conclusions Study design GRADE
Amir, 2005 [9] 98 Menstruating women undergoing IVF and being treated with GnRH agonist (mean age 33.5) Use of GnRH agonist Use of GnRH agonist reduced estradiol levels to nearly undetectable and was associated with increased risk of migraine by 28.6% (95% CI 19.7-37.5%) Cross sectional (Soroka medical center in Israel) Moderate
Brandes, 2006 [5] 18221 Postmenopausal Estrogen dosing in HRT; low (< 0.3 mg/day), intermediate (0.625 mg/day), high (> 0.9 mg/day) Intermediate dose estrogen in HRT had a significantly lower risk of migraine occurrence (OR 1.28, 95% CI 1.10-1.48, p=0.001) than low (OR 2.00, 95% CI 1.51-2.65, p=0.001) or high (OR 1.72, 95% CI 1.39-2.13, p=0.002) dose compared to general population Cross sectional (Part of Women’s Health Study) High
Cachrimanidou, 1993 [7] 300 Menstruating women age 18-39 that attended a family planning clinic to request oral contraceptives Study group took combined OCP with 30 ug ethinyl estradiol (low dose) with a 9 weeks on, 1 week off regimen. Control group took same OCP with a 3 weeks on, 1 week off traditional regimen Women on the 9 weeks on, 1 week off regimen reported a 9.7% incidence of migraine complaints compared to 17.3% in women on the traditional 3 weeks on, 1 week off regimen (p < 0.01). Concluded that estrogen replacement delayed estrogen withdrawal menstrual migraine RCT (multicenter study of three clinics in Sweden) High
Calhoun, 2004 [14] 20 Menstruating women with history of menstrual related migraine (< 14 days of headache per month) 20 ug ethinyl estradiol on days 1-21 of menstrual cycle (percutaneous and oral) with 0.9 mg conjugated equine estrogens on days 22-28 (the placebo week for OCPs) Estrogen replacement during placebo week of OCP treatment significantly reduced migraines experienced per month by 76%, from 7.6 headache days per month to 1.6 after treatment. Concluded that estrogen replacement prevented estrogen withdrawal migraine Open-label clinical trial Low
Calhoun, 2008 [4] 229 Menstruating women that were referred to an academic center for intractable menstrual migraines (mean age 35.6) Ethinyl estradiol-containing oral contraceptive dosed to prevent premenstrual ethinyl estradiol decline by more than 10 mcg In women that experienced resolution of menstrual migraine after treatment, there was a 55.8% reduction in the number of headache days per month (p < 0.001) compared to the 36% of women that continued to experience persistent menstrual migraine with no reduction in frequency Prospective cohort (single-center uncontrolled study) Moderate
de Lignieres, 1986 [10] 20 Menstruating women that experienced menstrual migraines in last 12 menstrual cycles (mean age 42.5) Percutaneous administration of 1.5 mg estradiol in 2.5 g gel 48 hours prior to expected migraine 31% of women treated experienced a menstrual migraine after treatment compared to 96% of women in placebo group (p < 0.01). Concluded that physiologic withdrawal of estrogen precipitates menstrual migraine and that treatment with supplemental estrogen can prevent withdrawal migraine. Double blind placebo-controlled crossover (single-center study in UK) Moderate
Facchinetti, 2002 [11] 38 Postmenopausal women with history of migraine (mean age 51.1) HRT with estradiol hemi- hydrate 1 mg/day plus norethisterone 0.5 mg/day for 28 days, in a continuous combined scheme; oral conjugated estrogens 0.625 mg/day for 28 days plus medroxyprogesterone acetate 10 mg/day in the last 14 days, in a sequential continuous scheme; and estradiol valerate 2 mg/day for 21 days plus cyproterone acetate 1 mg/day from day 12 to 21 in a sequential cyclical scheme All 3 HRT treatments significantly increased migraine attack frequency (2.2 days per month vs 3.8, p < 0.001), (3.4 days per month vs 4.9, p < 0.001), (3.4 days per month vs 5.6, p < 0.001) over the course of 6 months. Patients also reported increased severity of headache after starting therapy RCT (single-center study in Italy) Moderate
Johannes, 1995 [15] 74 Menstruating women age 22–29 with history of menstrual migraine Relation of migraine timing to menstrual cycle There was a significantly higher incidence of migraine during the first 3 days of menses compared to remainder of menstrual cycle (OR 1.66, 95% CI 1.21–2.26) Self-reported 4-month diary Low
Lichten, 1995 [16] 29 Menstruating women with recurrent, medically unresponsive, menstrual migraine Treatment for 2 months, first with placebo, then depo-leuprolide acetate 3.75 mg. Those who remained migraine free at 2 months continued therapy for 12 months with added transdermal estradiol 17/29 women remained migraine free at 2 months, 14/29 remained migraine free at one year. The initial 17 women had an average 50% improvement in headache index while taking therapy compared to placebo. Concluded that ovarian hormones are responsible for migraine pathogenesis and that reducing physiologic fluctuations in estrogen can reduce migraine incidence Crossover Low
Lichten, 1996 [19] 28 Postmenopausal women with history of severe menstrual migraine prior to menopause and taking HRT One-time dose of 5 mg depo-estradiol cypionate intramuscular injection All participants experienced a severe migraine on day 18 ± 4 of the study with average serum estradiol level on day of migraine between 45 and 50 pg/mL. No control group participants experienced a migraine during the course of the study. Concluded that there may be a genetic component to migraine pathogenesis and that estradiol levels falling below 50 pg/mL after a period of priming with higher estradiol levels can be a trigger for migraine Open-label clinical trial Very low
MacGregor, 2006 [13] 35 Menstruating women with menstrual migraine in last 3 menstrual cycles Daily administration of percutaneous estradiol gel (1.5 mg estradiol) from 6 days prior to onset of menses until day 2 of menses 22% reduction in migraine incidence while using percutaneous estradiol gel (RR 0.78, 95% CI 0.62–0.99, p = 0.04) with 40% increase in migraine occurrence in the 5 days after discontinuing the intervention (RR 1.40, 95% CI 1.03–1.92, p = 0.03). Concluded that estrogen replacement can delay onset of estrogen withdrawal menstrual migraine Double blind placebo-controlled crossover Moderate
Marcus, 1999 [20] 49 Pregnant women with history of chronic headache (mean age 29.4, mean headache duration 9.1 years) History of chronic headache Women with history of chronic headache reported a 30% decrease in headache frequency during the 2nd and 3rd trimesters of pregnancy. This was not a statistically significant difference compared to women with no history of chronic headache. Concluded that women with chronic headache in the 1st trimseter of pregnancy would likely continue to have headaches through pregnancy and postpartum Prospective cohort Very low
Martin, 2003 [12] 21 Menstruating women with history of menstrual migriane (mean age 39) Both groups treated with GnRH agonist to simulate medical oophorectomy, with one group getting estrogen add-back therapy to maintain estradiol at > 50 pg/mL (prior studied threshold for triggering menstrual migraine) In the group that recieved estrogen add-back therapy to maintain estradiol levels at > 50 pg/mL, the rise in estradiol on days 1 and 2 of the study increased headache index by 45% compared to day 6. During the overall study duration, estrogen add-back therapy reduced headache index by 33.7% compared to the control group (95% CI, 3.0–64.4%). Concluded that small rises in estrogen can precipitate migraine in some patients, and preventing estrogen withdrawal can prevent migraine in some patients. Patients with history of menstrual migraine are very sensitive to changes in estrogen levels RCT Moderate
Mattsson, 2003 [17] 728 Women aged 40–74 with history of menstrual migraine Relation of migraine timing to menstrual cycle 75% of women reported that their menstrual migraines occurred within day -2 to +3 of menstrual cycle Survey Low
Misakian 2003 [8] 17107 Postmenopausal Use of HRT HRT use significantly increased risk of experiencing a migraine in postmenopausal women (13% vs 9%, p < 0.001) Cross sectional (Part of Women’s Health Study) High
Murray, 1997 [21] 5 Menstruating women with repetitive severe migraines limited only to the perimenstrual period 3.75 mg IM depot-leuprolide acetate monthly injections for 10 months with 0.1 mg daily transdermal ethinyl estradiol added from month 5 onwards 74% decrease in headache index when being treated with only GnRH analog and 80% decrease after estrogen was added back. Concluded that stabilization of fluctuations in estrogen decreases incidence of menstrual migraine Prospective cohort Very low
Pringsheim, 2004 [6] 50 Male-to-female transgenders taking antiandrogen and estrogen therapy with history of migraine Male-to-female transgender vs. general population Prevalence of migraines in male-to-female transgenders (26%) was significantly higher than genetic males (7.5%) in the population (p < 0.05), but was not significantly different from prevalence of migraines in genetic females (25%) in the population Survey Low
Somerville, 1972 [22] 6 Menstruating women with history of menstrual migraine Administration of estradiol valerate (10 mg) to maintain high plasma estradiol level during premenstrual and menstrual phases Migraines attacks were delayed by 3 to 9 days (relative to usual timing during each patient's menstrual cycle) when treated with estradiol valerate, suggesting that migraines are precipitated by a fall in estradiol levels, particularly when they fall below 45-50 pg/mL during the perimenstrual period Crossover (case series) Very low
Stewart, 2000 [18] 81 Menstruating women age 18–55 with history of menstrual migraines Relation of migraine timing to menstrual cycle There was an increased incidence of migraine perimenstrually. Days 0 and 1 had OR 2.04 (95% CI 1.49–2.81). Days -1 and -2 had OR 1.80, 95% CI 1.40–2.30) Self-reported 98 day diary Low