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

Hormone Replacement Therapy

HRT refers to the administration of estrogens and/or progestins to women to ameliorate the symptoms encountered during perimenopausal or menopausal time periods. The estrogen preparations are categorized as those that contain natural, conjugated, and synthetic estrogens. Natural estrogen preparations contain estrogens normally found with women (eg, β-estradiol). Conjugated estrogens are produced from animal and/or plant sources, while synthetic estrogens are synthesized estrogen derivatives (eg, ethinyl estradiol). Both conjugated and synthetic estrogens are primarily composed of estrogen derivatives that are not typically found within humans. The estrogens within HRT have a much lower potency than those generally found in OCPs. The oral progestins include natural progesterone (eg, micronized progesterone) as well as synthetic progestins (eg, medroxyprogesterone). Oral progestins may be administered daily or for 10 to 12 days each month to prevent endometrial hyperplasia. The routes of delivery of HRT include pills, transdermal patches/gels, subcutaneous implants or injections, and vaginal suppositories.

HRT has been reported to improve migraine in 22% to 23%, worsen migraine in 21%, and leave it unchanged in 57%[100] ( Table 3 ). Hodson et al[100] reported that HRT was more likely to have no effect on migraine headache if a natural menopause left migraine unchanged. The PEPI trial[97] showed an improvement in headache with oral conjugated estrogens when compared with placebo in those with a history of headache at baseline, whereas if there was no history of headache they were more likely to develop headache as a side effect. In a cross-sectional study of 17,107 postmenopausal women from the Women's Health Study, Misakian et al[106] demonstrated that a diagnosis of migraine was 1.44 times more likely in current HRT users as compared to nonusers. This study could not ascertain, however, if the use of HRT led to the increased migraine prevalence or if migraine patients were simply more likely to be prescribed HRT.

Case reports have suggested that aura symptoms can develop secondary to estrogen replacement therapy in some patients.[107,108] They may develop "de novo" or may increase the frequency of existing attacks of MWA. Higher dosages of estrogen replacement therapy may be more prone to lead to the development of aura symptoms. MacGregor[108] reported that lowering the dosage or changing to another type of estrogen replacement may lead to an abatement of aura symptoms.

The dosage of estrogen replacement therapy may have an influence on the clinical course of migraine in postmenopausal women. Martin et al[109] reported that a 100-mcg transdermal estradiol patch produced a modest preventative benefit for migraine headache in 21 women (15 with MWoA; 6 with MWA) who had a medical menopause induced by a gonadotropin-releasing hormone agonist. A subsequent study[110] randomized the same group of patients to two different doses of transdermal estradiol (either 50 or 100 mcg) and found that only the 100-mcg dose was preventative of migraine. Since the 100-mcg patch maintains serum levels of estradiol in the 45 to 75 pg/mL range, these data could imply that a critical range of estradiol levels is necessary to prevent migraine headache.

The type and route of administration of estrogen replacement therapy could have an effect on migraine headache. Nappi et al[111] demonstrated that headache outcome measures worsened in headache patients receiving an oral conjugated estrogen and medroxyprogesterone, while they did not change as compared to baseline in those receiving a 50-mcg transdermal estradiol patch and medroxyprogesterone. These data could suggest that HRTs containing conjugated estrogens are provocative for migraine, while those containing natural estrogens have less effect on migraine. Alternatively, transdermal routes of delivery may be superior to oral routes, since they maintain a more constant serum estradiol level, which could prove advantageous if fluctuating estrogen levels trigger headache.[112]

The dosing regimens of combined estrogens/progestin therapy can also influence migraine headache. Facchinetti et al[113] found that patients receiving regimens of daily continuous HRT (eg, daily oral estrogens and progestins) had lower headache outcome measures than those receiving HRT regimens with intermittent dosing regimens (eg, regimens with no HRT for 1 week per month or those that gave progestins for only 2 weeks per month). These data would imply that HRT regimens using the same dosage of estrogens and progestins on a daily basis are superior to those using intermittent dosing of HRT.

HRT does carry some risk to postmenopausal women. The Women's Health Initiative[114] reported that oral conjugated estrogens administered daily along with a progestin significantly increased the risk of breast cancer (hazard ratio [HR], 1.26), stroke (HR, 1.41), pulmonary embolus (HR, 2.13), and coronary heart disease (HR, 1.29). This data has led several expert panels to discourage use of HRT for the prevention of chronic disease.[115,116,117,118,119] They recommended HRT for short-term use (<2 years) during the early menopausal time period to manage symptoms of hot flashes, but to discourage long-term use for other indications.


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