Low Estrogen Levels Trigger Menstrual Migraine




Prior research has examined the effects of capsaicin when applied to a rat’s hind paw. A control vehicle or an ERβ agonist was administered prior to the application of capsaicin, and a drastic reduction in the number of flinches occurred within 15 minutes in rats that were given an ERβ agonist. Dr. Martin said that estrogen preparations that agonize the ERβ receptor may have an analgesic effect. “The other thing about the ERβ receptor is that it’s thought to be very important to anxiety and mood disorders,” Dr. Martin noted. “So, ERβ may be very important in pain, anxiety, and depression—three of the most important components to our migraine patients.”

Dr. Martin and colleagues attempted to develop an animal model of trigeminal activation during the different stages of the rat estrous cycle. Capsaicin was applied to the dura to activate trigeminal nociceptors during the four stages of the estrous cycle, each of which has a distinct hormonal milieu. They recorded from second-order neurons located in the trigeminal nucleus caudalis and dorsal horns of C1-C3 that had both cutaneous and dural receptive fields. They found that the largest percent increase in receptive field size occurred during late proestrous stage, which is a time period of rapid decline in serum estradiol levels. “What this suggests is that different hormonal milieus can modulate how the trigeminal nucleus caudalis may sensitize,” Dr. Martin theorized. “If you can apply such a paradigm to migraine headache, one might predict that menstrual migraine may be more severe and disabling than nonmenstrual attacks, because it’s during this time period of estrogen withdrawal.”

Additional human studies have also confirmed that estrogen withdrawal may modulate trigeminal sensitization. Capsaicin was applied to the forehead of women during the midluteal time period (hormonal milieu of high estrogen and progesterone levels) and during the menstrual time period (hormonal milieu of low estrogen and progesterone levels). The investigators then mapped the area of brush-induced allodynia during the two phases. “In the midluteal phase, the brush-induced allodynia was much less than during the menstrual phase,” Dr. Martin stated. “This confirmed the finding of the above animal study, suggesting that sensitization of the trigeminal system is greatest during time periods of estrogen withdrawal. Interestingly, previous studies pinpointed the midluteal time period as the lowest for headache pain.”


Estrogen has both excitatory and inhibitory effects on the trigeminal pain pathways. It may produce an excitatory effect through an increase in glutamatergic neurotransmission or synthesis of neuropeptides such as brain-derived neurotrophic factor or nerve growth factor. It could be inhibitory through enhancement of opiatergic or serontonergic tonus within modulatory brainstem nuclei (eg, periaqueductal gray or dorsal raphe); activation decreases neurotransmission within second-order trigeminal neurons.

Dr. Martin used the “burning rubber analogy” to further demonstrate his theory of neurotransmitter imbalance leading to menstrual migraine. “We hypothesize that during high estrogen levels, inhibitory and excitatory neurotransmitter systems of trigeminal pain pathways are directly counter-balanced by one another. It’s like one foot is on the accelerator and the other is on the break,” he stated. “What happens? Your car doesn’t go anywhere—but, when estrogen levels fall, we believe that inhibitory tone reverses faster than excitatory tone and this enhances nociception.”


—Laura Sassano


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