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


The human placenta produces the majority of estrogen and progesterone necessary for a successful pregnancy. Serum levels of estradiol and progesterone begin to rise in the mother during the 6th to 8th weeks of pregnancy as the placenta begins to produce steroids and they continue to gradually increase to their highest levels during the third trimester.[77] During the third trimester, serum estradiol levels are 30 to 40 times higher and progesterone levels are 20 times higher than peak levels during native menstrual cycles (Figure 4). Other hormones may also be increased during pregnancy and include human chorionic gonadotropin, human placental lactogen, inhibin, atrial natriuretic peptide, and α-fetoprotein as well as others.[78]

Mean plasma estrogen and progesterone levels during pregnancy. Plasma estradiol (- -) and progesterone (- -) levels rise abruptly during the second and third trimesters (weeks 14 to 40) of pregnancy. Note that serum estradiol levels during the third trimester of pregnancy are 30 to 40 times higher and progesterone levels are 20 times higher than their peak levels during natural menstrual cycles. (Adapted with permission from Tulchinsky D. Am J Obstet Gynecol 1972;112(8):1095-1100.)

Preexisting migraine most often improves with pregnancy. Sances et al[79] conducted a prospective study of 47 female migraineurs to investigate the course of migraine headache during pregnancy. Migraine improved in 46.8% of women during the first trimester, 83% during the second trimester, and 87% during the third trimester. The complete remission rate increased from 11% during the first trimester to 53% and 79% during the second and third trimesters, respectively. Other retrospective studies have also confirmed that 48% to 79% of women with a history of preexisting migraine improve during pregnancy, particularly during the second and third trimesters[9,80,81,82,83] ( Table 2 ). Aura symptoms in particular appear to occur quite frequently during pregnancy in those with a past history of migraine. Ertresvag et al[84] demonstrated that 40.9%, 20.3%, and 15.5% of migraineurs, respectively, had visual, sensory, or motor symptoms during pregnancy.

Migraine has also been reported to develop for the first time during pregnancy in 1.3% to 18% of migraineurs.[9,81] Several studies[85,86] have reported "new onset" visual, sensory, and motor aura during pregnancy. Some of the patients had experienced complicated pregnancies with accompanying thrombocytopenia, pre-eclampsia, and threatened abortions.[85] One might postulate that the "high estrogen milieu" of pregnancy could play a role in initiating attacks of MWA.

Studies have attempted to identify clinical predictors that would allow identification of migraineurs more or less likely to experience improvement during pregnancy. Granella et al[9] reported that a complete remission with pregnancy was more likely in those with a history of onset of migraine during menarche. Sances et al[79] found that a pathological pregnancy course (eg, toxemia) and prior history of menstrual migraine were negative predictors of improvement during the first and the third trimesters. Kelman[87] noted that female migraineurs with "exclusively" MWA were less likely to have an improvement in migraine during pregnancy.

Pregnancy induces a state of antinociception that has been termed the "analgesia of pregnancy." The "analgesia of pregnancy" is likely mediated through the opiatergic system as intrathecal administration of antagonists of κ and δ opioid receptors can abolish this antinociception within pregnant rats.[88] Spinal cord levels of enkephalin and dynorphin levels are also increased in pregnant rats.[88] High serum levels of both estrogen and progesterone are necessary to produce the "analgesia of pregnancy," as administration of either hormone alone fails to induce antinociception. It is not known if similar mechanisms exist within the trigeminal pain pathways of female migraineurs to explain an improvement in migraine headache during pregnancy.


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