Defining the Relationship Between Ovarian Hormones and Migraine Headache


  • Vincent T. Martin MD,

  • Suzanne Wernke MD, PhD,

  • Karen Mandell PharmD,

  • Nabih Ramadan MD,

  • Lily Kao MS,

  • Judy Bean PhD,

  • James Liu MD,

  • Willie Zoma MD,

  • Robert Rebar MD

  • From the Department of Internal Medicine, University of Cincinnati, Cincinnati, OH (Drs. Martin, Wernke, and Mandell); Department of Neurology, Rosalind Franklin University of Medicine and Science, Chicago, IL (Dr. Ramadan); Department of Obstetrics and Gynecology, University of Cincinnati College of Medicine, Cincinnati, OH (Ms. Kao); Centers for Epidemiology and Biostatistics, Children's Hospital Medical Center, Cincinnati, OH (Dr. Bean); Departments of Obstetrics and Gynecology and Reproductive Biology, University Hospitals of Cleveland and Case Western University School of Medicine, Cleveland, OH (Dr. Liu); Department of Obstetrics and Gynecology, University of Texas Medical Branch, Galveston, TX (Dr. Zoma); and American Society for Reproductive Medicine, Birmingham, AL (Dr. Rebar).

Address all correspondence to Dr. Vincent T. Martin, Division of General Internal Medicine, University of Cincinnati College of Medicine, 231 Albert Sabin Way ML 6603, Cincinnati, OH 45267-4217.


Objective.—(1) To determine whether the attack characteristics of migraine differ between different intervals of the menstrual cycle; (2) To ascertain whether the “rate of change,”“magnitude of change,” or “total burden” of urinary hormone metabolites correlates with headaches outcome measures during different intervals of the menstrual cycle.

Background.—The mechanisms through which migraines are influenced by ovarian hormones remain unclear. No previous studies until now have identified “hormonally defined” time intervals within the female menstrual cycle and compared headache outcome measures among these intervals in female migraineurs.

Methods.—Daily headache diary data were obtained from 21 female migraineurs during three native menstrual cycles. Daily urine samples were collected and later assayed for estrogen and progesterone metabolites. Seven 3-day time intervals were identified within each menstrual cycle based on urine hormone measurements. Primary (headache index) and secondary (disability index, headache severity, and headache frequency) outcome measures were compared between intervals using the mixed model approach. “Rates of change,”“magnitude of change,” and the “total burden” of ovarian hormones were estimated from urine hormone metabolites and correlated with headache outcome measures.

Results.—The headache index was significantly different across different intervals of the menstrual cycle (P values <.001) and was higher during menstrual intervals (first 6 days of the menstrual cycle) than during mid-cycle and mid-luteal intervals (P < .002). Similarly, secondary outcome measures were highest during the menstrual intervals. “Higher burdens” of urinary progesterone metabolites were positively correlated with headache outcome measures during the luteal intervals of the menstrual cycle. “Rates of change” and the “magnitude of change” of urinary hormone metabolites did not correlate with headache outcome measures.

Conclusions.—Migraine headache is more severe, disabling, and frequent during the menstrual intervals of the female reproductive cycle than during mid-luteal or mid-cycle intervals. Progesterone metabolites may play a role in modulating migraine headaches during luteal intervals of the menstrual cycle.