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 World Health Organization has defined menopause as the "permanent cessation of menstruation, determined retrospectively after 12 consecutive months of amenorrhea without any pathological or physiological cause."[92] Menopause represents a time period during which women have depleted their supply of follicles from the ovaries resulting in a permanent cessation of ovulation. Serum levels of estradiol typically range from 10 to 20 pg/mL in most postmenopausal women. Postmenopausal women often experience symptoms such as hot flashes, fatigue, forgetfulness, loss of memory, inability to concentrate, anxiety, depression, irritability, and headache.[96] Many of these symptoms can be improved with estrogen replacement therapy.[97,98]

The clinical course of migraine headache is quite variable at the time of menopause. Unfortunately, there have been no longitudinal cohort studies of migraine patients transitioning through menopause to determine the true effect of menopause on migraine. Most past studies have been retrospective questionnaire studies querying patients of the effect of menopause on their headaches. These studies suggest that preexisting migraine improves in 8% to 36%, worsens in 9% to 42%, and remains unchanged in 27% to 64% at the time of menopause[9,11,57,99,100,101] ( Table 3 ). Eight to 13% of female migraineurs may develop migraine for the first time during menopause.[9,11] Patients with a surgical menopause may fare worse than those with a natural menopause, with 38% to 87% experiencing a worsening of existing migraine.[9,101] These data could suggest that an abrupt withdrawal of estrogen such as that occurring with surgical oophorectomy may be more provocative for migraine headache than a gradual withdrawal such as that occurring with a natural menopause. Another potential explanation may be that the dose of estrogen replacement therapy used in surgically oophorectomized patients was too low to prevent migraine (see below).

"Estrogen withdrawal" and its effects on the central nervous system are thought to be the primary mechanism through which symptoms are provoked during the menopausal time period (eg, hot flashes, headaches, etc.). In fact, many of the same neurotransmitter systems altered during menstrual migraine secondary to "estrogen withdrawal" may also be affected by menopause. Decreased opioid tonus within hypothalamic nuclei, decreased blood serotonin levels, and up-regulation of certain serotonin receptors (eg, 5-HT 2A) have been demonstrated within studies of postmenopausal women.[102,103,104,105]

While the effects of a natural menopause on migraine headache can be quite variable, there appears to be a subgroup of women in which migraine arises "de novo" or worsens with the onset of menopause. These headaches have been termed "estrogen withdrawal" headaches and share some common features with hot flashes. "Estrogen withdrawal" headaches and hot flashes may not resolve for months to years after a natural menopause and both improve with estrogen treatment. This could suggest that the changes in the central nervous system induced by "estrogen withdrawal" during a natural menopause may not resolve immediately after removal of the offending stimulus. A long-standing menopause (>2 years), however, generally leads to an improvement in the clinical course of migraine headache.


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