The Confirmation of a Biochemical Marker for Women's Hormonal Migraine: The Depo-Estradiol Challenge Test


  • Edward M. Lichten MD,

  • Jason B. Lichten BS,

  • Albert Whitty PhD,

  • David Pieper PhD


Precis: Will estrogen withdrawal cause migraines in post-menopausal women?

Objective: To record the changes in serum estradiol and total estrogen levels after an intramuscular estradiol injection in menopausal subjects and then record any subsequent migraine occurrence.

Design: Open selection process, comparative trial.

Patients: Twenty-eight postmenopausal women volunteers were given 5 mg depo-estradiol cyprionate as an intramuscular injection. Sixteen (migraine group) had a history of severe, cyclic, menstrually related migraine attacks before becoming menopausal. Twelve (control group) had no history of migraine or headache. All volunteers were on continuous estrogen replacement therapy at the beginning of the study. Progestins were not used in the study.

Main Outcome Measures: Serum estradiol and total estrogen levels were measured prior to the depo-estradiol injection and on subsequent days 4, 7, 14, 21, and 28.

Results: Total estrogen and estradiol levels varied greatly at every measured interval. Menopausal complaints of vasomotor symptoms were relieved for at least the first 2 weeks of the study. No member of the control group reported a migraine during the month. However, a severe migraine was reported by all 16 women with a history of migraine. The average day of the migraine occurrence was 18.5 ± 2.8. The serum level of estradiol on the day of the worst migraine was 46.4 ±± 5.6 pg/mL. The significance of these findings was at the 95% confidence level.

Conclusions: This study confirms two factors about menopausal hormonal migraine: (1) it can be precipitated by a drop in serum estrogen levels, and (2) a period of estrogen priming is a necessary prerequisite. This study also identifies that there are two biologically different populations of postmenopausal women: (1) those who developed migraine after a single depo-estradiol injection, and (2) those who did not. By understanding that in addition to the biological predisposition to migraine there exists the biochemical cofactor of falling estrogen levels, we may better understand this phenomenon and develop means to prevent its occurrence.