Ovarian Hormones and Migraine Headache: Understanding Mechanisms and Pathogenesis--Part 2

Vincent T. Martin, MD; Michael Behbehani, PhD


Headache. 2006;46(3):365-386. 

In This Article

Oral Contraceptives

OCPs are commonly used in women of child bearing age to prevent pregnancy. They are primarily composed of ethinyl estradiol and a progestin (a derivative of 19-nortestosterone). Ethinyl estradiol is a synthetic estrogen that has a high potency to inhibit gonadotropin release from the anterior pituitary gland. In the 1970s OCPs contained 50 to 100 mcg of ethinyl estradiol, while more recent pills contain 15 to 35 mcg.[53] Progestins also inhibit gonadotropin release and have been categorized as first (eg, norethisterone), second (eg, norgestrel, levonorgestrel), third (eg, desogestrel, gestodene, norgestimate), and fourth generation (eg, drospirenone). Third generation progestins are less androgenic and have less effect on plasma lipid levels than first or second generation progestins. Fourth generation progestins are less androgenic and also have an antimineralocorticoid effect similar to spironolactone.

OCPs exist in monophasic, triphasic, and extended duration formulations as well as those that contain progestins only. Monophasic OCPs have a fixed dosage of synthetic hormones for the first 3 weeks followed by a placebo week for the last week. Triphasic OCPs change the dose of synthetic hormones on a weekly basis for 3 consecutive weeks and then a placebo week follows. Extended duration OCPs contain a fixed dosage of synthetic hormones for 3 months followed by a placebo week. Progestin-only pills have a fixed dose of a progestin for 4 weeks.

Most of the past studies evaluating the effect of OCPs on preexisting migraine headache were conducted during the 1970s with the higher dose estrogen pills (eg, 50 to 100 mcg of ethinyl estradiol). Studies using the higher dose estrogen OCPs have generally demonstrated a worsening of migraine headache. Ryan[54] reported that headaches worsened in 70% and improved in 30% during treatment with OCPs (50 mcg of ethinyl estradiol/0.5 mg of norgestrel) in a randomized placebo-controlled crossover trial. Other case series[55,56] have reported that migraine headaches typically occur during the placebo week of the OCP, which would be expected if "estrogen withdrawal" triggers migraine in susceptible patients.

More recent studies have evaluated the impact of OCPs containing lower dosages of estrogen on migraine headache.[9,11,57] They have reported that the clinical course of migraine was unchanged in 44% to 67%, worse in 24% to 35%, and improved in 5% to 8% after administration of OCPs. These results suggest that migraine is most often unaffected by the use of OCPs. None of the above trials specified the type of OCP (eg, monophasic or triphasic) or the dosage of estrogen/progestin used, but they likely used monophasic OCPs with 30 to 35 mcg of ethinyl estradiol, since these were the predominant OCPs used at the time of these studies.

Loder et al[58] performed a literature review of existing OCP trials to determine if the incidence of "headache complaints" (not migraine) was higher in those taking monophasic OCPs when compared to a placebo group. They concluded the following: (1) most contraceptive trials do not demonstrate statistically significant differences in "headache complaints" between treatment and control groups, (2) women with a history of migraine or "troublesome" headaches may be at increased risk of "headache complaints" with OCPs, (3) the type and dosage of progestin does not influence headache activity, and (4) if headaches begin or worsen during the first month of OCP use, they will often improve during subsequent months. Others have demonstrated that the incidence of "headache complaints" may be reduced through the use of extended duration OCPs, which decrease the frequency of "estrogen withdrawal" by having only 1 placebo week every 3 months. Cachrimanidou et al[59] reported an incidence of headache complaints of 9.7% in participants receiving extended duration OCPs and 17.3% in those receiving standard OCPs.

Patients experiencing attacks of MWA are more likely to worsen with administration of OCPs than those with MWoA. Two past trials[10,11] noted that 50% to 57% of patients with MWA worsened with OCPs as compared to 25% to 35% of those with MWoA. In addition, case reports[11,60,61,62] have demonstrated that visual, sensory, and motor aura may develop for the first time in those receiving OCPs. Some patients with "new onset aura" or a "crescendo pattern" to their migraines after the start of OCPs have progressed to develop cerebrovascular accidents (CVAs).[62]

Scant research exists to explain the mechanisms through which migraine (particularly MWA) could be triggered by OCPs in some patients. Hanington et al[63] reported decreases in "platelet aggregation" after cessation of OCPs in patients who had developed "new onset migraine" with OCPs. The decreases in platelet aggregation seemed to parallel improvements in migraine headache. These data suggest that increased "platelet aggregation" induced by OCPs might play a role in the development of migraine headache. Another mechanism through which OCPs might trigger attacks of MWoA could be "estrogen withdrawal" during the placebo week of the pill.

Past studies[64,65,66,67,68] have reported an increased risk of CVAs in patients with migraine headache, particularly in young women and those with MWA. A recent meta-analysis[69] reviewed 14 studies (11 case control and 3 cohort studies) to determine the relationship between migraine and risk of ischemic CVA. They found relative risks of 2.27 (95% confidence intervals [CI] 1.61, 3.19) for patients with MWA and 1.83 (95% CI 1.06, 3.15) for those with MWoA, while migraineurs taking OCPs had a relative risk of 8.72 (95% CI 5.05, 15.05). Other studies[70,71] have suggested an increased risk of CVA in OCPs with higher estrogen dosages (eg, 30 to 50 mcg vs. 20 mcg) and those containing second and third generation progestins, while progestin-only pills were not associated with an increased risk. Cardiovascular risk factors (eg, smoking, hypertension) as well as prothrombotic conditions (eg, factor V Leiden, prothrombin, and methylenetetrahydrofolate mutations) may further increase the risk of CVAs in those consuming OCPs.[67,72,73] One study[67] reported an odds ratio of 34 for stroke in female migraineurs who smoked and used OCPs. These data has led some groups to recommend that OCPs not be used in patients experiencing MWA or in those with cardiovascular risk factors.[74,75,76]


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