Hormones' Role in Migraine Continues to Unfold

BY CHARLES BANKHEAD
Contributing Writer

ORLANDO, FLA. - ECCC) Improved understanding of how ovarian hormones trigger migraine would likely improve knowledge about migraine in general, said Dr. Vincent T. Martin on July 19 at a headache symposium sponsored by the Diamond Headache Clinic Research and Educational Foundation.

"This is one of the most crucial questions in the entire migraine field, for several reasons," said Dr. Martin, professor of medicine at the University of Cincinnati. "First of all, migraine is two to three times more common in women than in men. Second, the perimenstrual time is a hot point for triggering migraine headaches."

Migraine prevalence in women spikes dramatically upward between the ages of 25 and 55, reaching a peak at about age 40. The spike coincides with the peak reproductive years of women, who have large fluctuations in levels of ovarian hormones.

Examination of the menstrual cycle provides some clues about the possible mechanisms involved in hormonal triggering of migraine headaches. Estradiol levels are low during the first two days of the cycle, followed by a sharp increase in mid-cycle. Levels then decline for several days before rising again during the luteal phase. Finally, estradiol levels plunge abruptly and dramatically during the final two days before the onset of menstruation.

"This perimenstrual fall in estradiol is thought to be one of the main triggers for menstrual migraine," said Dr. Martin.

One of the most controversial issues in the migraine field relates to the concept of mid-cycle migraine. Population-based studies have generally produced no evidence of mid-cycle headaches. However, Dr. Martin and colleagues recently presented data at the American Headache Society meeting suggesting the existence of three patterns of mid-cycle headache.

"Some headaches may be triggered by a rise in estrogen, some by a fall in estrogen, and progesterone may modulate others," he said.

More than 35 years ago the "estrogen withdrawal" theory of menstrual migraine was postulated. In one particular test of the theory, women with a history of menstrual migraine were given estradiol valerate, which artificially elevated estradiol levels and delayed the onset of menstrual migraine until day 2 or 3 of menstruation instead of two days before the onset of menstruation.

Other evidence of estrogen withdrawal as a migraine trigger relates to use of exogenous hormones. As examples, Dr. Martin noted that migraines often occur during:

• The placebo week of oral contraceptive use
• Interrupted use of postmenopausal estrogen replacement therapy
• Periods of low serum estrogen levels after fertility treatment

The plausibility of estrogen withdrawal as a migraine trigger has support in the fact that ovarian hormones affect multiple neurotransmitters thought to play a role in migraine, said Dr. Martin. For example, estrogen enhances glutamatergic tone, and glutamate is the major excitatory neurotransmitter in the brain. Progesterone also modulates GABA receptors, which are the principal neuroinhibitory receptors in the brain.

Progestins have a variable effect on migraine. In a recent review of ovarian hormones and migraine, Dr. Martin stated that daily oral progestin can prevent migraine in menstruating women. On the other hand, injectable medroxyprogesterone and levonorgestrel implants can precipitate migraine, and episodic administration of progestins as hormone replacement therapy can trigger migraine in some women (Headache 2006;46:365-86).

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