Low Estrogen Levels Trigger Menstrual Migraine

OJAI, CA—Attacks of menstrual migraine are triggered by decreasing serum estrogen levels during the perimenstrual time period, which can influence neurotransmitter systems and neuropeptide synthesis within trigeminal pain networks, creating a pronociceptive state, suggested Vincent T. Martin, MD. The modulation of neurotransmitter systems by ovarian hormones, specifically estrogen, may account for the migraine prevalence disparity between women and men and could be a key factor in developing treatments for those with menstrual migraine.

Migraine is two to three times more common in women than men, according to Dr. Martin. Approximately 16% of women have migraines, but the prevalence may approach 25% to 30% between the ages of 35 to 40. “You can argue about what causes an increased prevalence of migraine in women, but what probably happens is that they inherit a genetic predisposition to migraine, and fluctuating sex hormones that occur as part of the emale menstrual cycle might bring out this genetic predisposition,” stated Dr. Martin at the Headache Cooperative of the Pacific’s 2009 Winter Colloquium.

DISTRIBUTION OF ESTROGEN RECEPTORS WITHIN TRIGEMINAL PAIN PATHWAYS

Estrogen receptors are found throughout the entire nervous system and trigeminal pain pathways, which are important in migraine pathogenesis. The two predominant types of nuclear estrogen receptors (ER) are alpha (ERα) and beta (ERβ). Both affect transcriptional activity within cells, though ERα produces greater transcriptional activity. Estrogen receptors dimerize prior to binding the estrogen response element of DNA. “Many people believe there’s a yin yang between ERα and ERβ,” noted Dr. Martin, who is a Professor of Medicine at the University of Cincinnati College of Medicine. “If you have alpha combined with beta, beta actually inhibits the transcription activity of alpha,” he explained. In addition, because ERα and ERβ receptors are found within the raphe nuclei and locus coeruleus, it is feasible that estrogen could play a role in neurotransmitter synthesis (eg, serotonin, norepinephrine). Ultimately, the receptors’ effects may depend on what the target organ is.

MODULATION OF MIGRAINE

“If you look at the effect of reproductive events on migraine without aura, virtually every reproductive life event modulates migraine headache,” Dr. Martin said. The severity of women’s migraine often worsens during the perimenstrual time period. However, approximately 60% to 70% of women experience improvement in their migraines during their second or third trimesters of pregnancy, when estrogen and progesterone levels can be anywhere from 15 to 30 times greater than their peak levels during the menstrual cycle. The “sky-high” levels may create analgesia of pregnancy. Animal models have shown that elevated levels of estrogen or progesterone alone do not produce this effect. “But somehow, when you combine the two, it creates the analgesia of pregnancy,” Dr. Martin pointed out. “It’s probably nature’s way to provide some pain relief to women.”

Dr. Martin and colleagues conducted a study in which a gonadotropin-releasing hormone agonist was administered to premenopausal female migraineurs (most experienced attacks of migraine without aura) to create a medical menopause and then randomized women to a 100-μg estradiol or placebo patch. Headache outcome measures improved in those randomized to the 100-μg estradiol patch as compared to baseline, but there was no change in those receiving placebo patches. Dr. Martin added that “estrogen can have a preventative effect on migraine headache when administered in a formulation that maintains stable and minimally fluctuating serum levels of estradiol. However, it may be necessary to keep serum estradiol levels above a threshold (eg, >40 pg/mL) to attain this preventative benefit.”

Ovarian hormones have a different effect on migraine with aura, which suggests that “the two types of migraine may have a different pathogenesis,” Dr. Martin stated. Aura can be triggered by high levels of estrogen or birth control pills that contain a high potency of estrogen. Epidemiologic studies have not shown increased amounts of aura during the perimenstrual time period. “Although, in my practice, I have had several women whose attacks of migraine with aura reproducibly occurred during perimenstrual time periods,” Dr. Martin commented. One study in postmenopausal women demonstrated that 100-μg ethanol estradiol patches worsened aura, but when doses were cut in half, the aura went away.

“How sensitive can the female brain be to changes in estrogen?” Dr. Martin asked. “This is really key, because there are changes in estrogen occurring on a day-by-day, if not minute-by-minute, basis in women.” In the above-mentioned study, Dr. Martin and colleagues showed that headache outcome measures worsened by 50% during the first two days after an estradiol patch change compared with those obtained during the last two days before a patch change. Yet, serum levels of estradiol were maintained in a narrow range by the estrogen patch (40 to 55 pg/mL). Dr. Martin stated that if similar fluctuations were to precipitate attacks of migraine during natural menstrual cycles, estrogen could modulate migraine not just in the perimenstrual stage but throughout the entire cycle.

CONTROLLING AND PREDICTING MIGRAINE ATTACKS

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.”

NEUROTRANSMITTER IMBALANCE THEORY OF MENSTRUAL MIGRAINE

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.”

NR

—Laura Sassano

OJAI, CA—Attacks of menstrual migraine are triggered by decreasing serum estrogen levels during the perimenstrual time period, which can influence neurotransmitter systems and neuropeptide synthesis within trigeminal pain networks, creating a pronociceptive state, suggested Vincent T. Martin, MD. The modulation of neurotransmitter systems by ovarian hormones, specifically estrogen, may account for the migraine prevalence disparity between women and men and could be a key factor in developing treatments for those with menstrual migraine.

Migraine is two to three times more common in women than men, according to Dr. Martin. Approximately 16% of women have migraines, but the prevalence may approach 25% to 30% between the ages of 35 to 40. “You can argue about what causes an increased prevalence of migraine in women, but what probably happens is that they inherit a genetic predisposition to migraine, and fluctuating sex hormones that occur as part of the emale menstrual cycle might bring out this genetic predisposition,” stated Dr. Martin at the Headache Cooperative of the Pacific’s 2009 Winter Colloquium.

DISTRIBUTION OF ESTROGEN RECEPTORS WITHIN TRIGEMINAL PAIN PATHWAYS

Estrogen receptors are found throughout the entire nervous system and trigeminal pain pathways, which are important in migraine pathogenesis. The two predominant types of nuclear estrogen receptors (ER) are alpha (ERα) and beta (ERβ). Both affect transcriptional activity within cells, though ERα produces greater transcriptional activity. Estrogen receptors dimerize prior to binding the estrogen response element of DNA. “Many people believe there’s a yin yang between ERα and ERβ,” noted Dr. Martin, who is a Professor of Medicine at the University of Cincinnati College of Medicine. “If you have alpha combined with beta, beta actually inhibits the transcription activity of alpha,” he explained. In addition, because ERα and ERβ receptors are found within the raphe nuclei and locus coeruleus, it is feasible that estrogen could play a role in neurotransmitter synthesis (eg, serotonin, norepinephrine). Ultimately, the receptors’ effects may depend on what the target organ is.

MODULATION OF MIGRAINE

“If you look at the effect of reproductive events on migraine without aura, virtually every reproductive life event modulates migraine headache,” Dr. Martin said. The severity of women’s migraine often worsens during the perimenstrual time period. However, approximately 60% to 70% of women experience improvement in their migraines during their second or third trimesters of pregnancy, when estrogen and progesterone levels can be anywhere from 15 to 30 times greater than their peak levels during the menstrual cycle. The “sky-high” levels may create analgesia of pregnancy. Animal models have shown that elevated levels of estrogen or progesterone alone do not produce this effect. “But somehow, when you combine the two, it creates the analgesia of pregnancy,” Dr. Martin pointed out. “It’s probably nature’s way to provide some pain relief to women.”

Dr. Martin and colleagues conducted a study in which a gonadotropin-releasing hormone agonist was administered to premenopausal female migraineurs (most experienced attacks of migraine without aura) to create a medical menopause and then randomized women to a 100-μg estradiol or placebo patch. Headache outcome measures improved in those randomized to the 100-μg estradiol patch as compared to baseline, but there was no change in those receiving placebo patches. Dr. Martin added that “estrogen can have a preventative effect on migraine headache when administered in a formulation that maintains stable and minimally fluctuating serum levels of estradiol. However, it may be necessary to keep serum estradiol levels above a threshold (eg, >40 pg/mL) to attain this preventative benefit.”

Ovarian hormones have a different effect on migraine with aura, which suggests that “the two types of migraine may have a different pathogenesis,” Dr. Martin stated. Aura can be triggered by high levels of estrogen or birth control pills that contain a high potency of estrogen. Epidemiologic studies have not shown increased amounts of aura during the perimenstrual time period. “Although, in my practice, I have had several women whose attacks of migraine with aura reproducibly occurred during perimenstrual time periods,” Dr. Martin commented. One study in postmenopausal women demonstrated that 100-μg ethanol estradiol patches worsened aura, but when doses were cut in half, the aura went away.

“How sensitive can the female brain be to changes in estrogen?” Dr. Martin asked. “This is really key, because there are changes in estrogen occurring on a day-by-day, if not minute-by-minute, basis in women.” In the above-mentioned study, Dr. Martin and colleagues showed that headache outcome measures worsened by 50% during the first two days after an estradiol patch change compared with those obtained during the last two days before a patch change. Yet, serum levels of estradiol were maintained in a narrow range by the estrogen patch (40 to 55 pg/mL). Dr. Martin stated that if similar fluctuations were to precipitate attacks of migraine during natural menstrual cycles, estrogen could modulate migraine not just in the perimenstrual stage but throughout the entire cycle.

CONTROLLING AND PREDICTING MIGRAINE ATTACKS

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.”

NEUROTRANSMITTER IMBALANCE THEORY OF MENSTRUAL MIGRAINE

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.”

NR

—Laura Sassano

OJAI, CA—Attacks of menstrual migraine are triggered by decreasing serum estrogen levels during the perimenstrual time period, which can influence neurotransmitter systems and neuropeptide synthesis within trigeminal pain networks, creating a pronociceptive state, suggested Vincent T. Martin, MD. The modulation of neurotransmitter systems by ovarian hormones, specifically estrogen, may account for the migraine prevalence disparity between women and men and could be a key factor in developing treatments for those with menstrual migraine.

Migraine is two to three times more common in women than men, according to Dr. Martin. Approximately 16% of women have migraines, but the prevalence may approach 25% to 30% between the ages of 35 to 40. “You can argue about what causes an increased prevalence of migraine in women, but what probably happens is that they inherit a genetic predisposition to migraine, and fluctuating sex hormones that occur as part of the emale menstrual cycle might bring out this genetic predisposition,” stated Dr. Martin at the Headache Cooperative of the Pacific’s 2009 Winter Colloquium.

DISTRIBUTION OF ESTROGEN RECEPTORS WITHIN TRIGEMINAL PAIN PATHWAYS

Estrogen receptors are found throughout the entire nervous system and trigeminal pain pathways, which are important in migraine pathogenesis. The two predominant types of nuclear estrogen receptors (ER) are alpha (ERα) and beta (ERβ). Both affect transcriptional activity within cells, though ERα produces greater transcriptional activity. Estrogen receptors dimerize prior to binding the estrogen response element of DNA. “Many people believe there’s a yin yang between ERα and ERβ,” noted Dr. Martin, who is a Professor of Medicine at the University of Cincinnati College of Medicine. “If you have alpha combined with beta, beta actually inhibits the transcription activity of alpha,” he explained. In addition, because ERα and ERβ receptors are found within the raphe nuclei and locus coeruleus, it is feasible that estrogen could play a role in neurotransmitter synthesis (eg, serotonin, norepinephrine). Ultimately, the receptors’ effects may depend on what the target organ is.

MODULATION OF MIGRAINE

“If you look at the effect of reproductive events on migraine without aura, virtually every reproductive life event modulates migraine headache,” Dr. Martin said. The severity of women’s migraine often worsens during the perimenstrual time period. However, approximately 60% to 70% of women experience improvement in their migraines during their second or third trimesters of pregnancy, when estrogen and progesterone levels can be anywhere from 15 to 30 times greater than their peak levels during the menstrual cycle. The “sky-high” levels may create analgesia of pregnancy. Animal models have shown that elevated levels of estrogen or progesterone alone do not produce this effect. “But somehow, when you combine the two, it creates the analgesia of pregnancy,” Dr. Martin pointed out. “It’s probably nature’s way to provide some pain relief to women.”

Dr. Martin and colleagues conducted a study in which a gonadotropin-releasing hormone agonist was administered to premenopausal female migraineurs (most experienced attacks of migraine without aura) to create a medical menopause and then randomized women to a 100-μg estradiol or placebo patch. Headache outcome measures improved in those randomized to the 100-μg estradiol patch as compared to baseline, but there was no change in those receiving placebo patches. Dr. Martin added that “estrogen can have a preventative effect on migraine headache when administered in a formulation that maintains stable and minimally fluctuating serum levels of estradiol. However, it may be necessary to keep serum estradiol levels above a threshold (eg, >40 pg/mL) to attain this preventative benefit.”

Ovarian hormones have a different effect on migraine with aura, which suggests that “the two types of migraine may have a different pathogenesis,” Dr. Martin stated. Aura can be triggered by high levels of estrogen or birth control pills that contain a high potency of estrogen. Epidemiologic studies have not shown increased amounts of aura during the perimenstrual time period. “Although, in my practice, I have had several women whose attacks of migraine with aura reproducibly occurred during perimenstrual time periods,” Dr. Martin commented. One study in postmenopausal women demonstrated that 100-μg ethanol estradiol patches worsened aura, but when doses were cut in half, the aura went away.

“How sensitive can the female brain be to changes in estrogen?” Dr. Martin asked. “This is really key, because there are changes in estrogen occurring on a day-by-day, if not minute-by-minute, basis in women.” In the above-mentioned study, Dr. Martin and colleagues showed that headache outcome measures worsened by 50% during the first two days after an estradiol patch change compared with those obtained during the last two days before a patch change. Yet, serum levels of estradiol were maintained in a narrow range by the estrogen patch (40 to 55 pg/mL). Dr. Martin stated that if similar fluctuations were to precipitate attacks of migraine during natural menstrual cycles, estrogen could modulate migraine not just in the perimenstrual stage but throughout the entire cycle.

CONTROLLING AND PREDICTING MIGRAINE ATTACKS

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.”

NEUROTRANSMITTER IMBALANCE THEORY OF MENSTRUAL MIGRAINE

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.”

NR

—Laura Sassano