Hormones and Migraine Part 1: Glutamate and Histamine

You probably already know that three times more women than men suffer from migraine. And if you are one of those many women, you have also probably asked why. The typical and obvious answer is that it’s our hormonal differences that make us more susceptible to migraine than men. But since not all women get migraines, we need to take a closer look at some of the factors that lead some women’s hormones to get out of balance in such a way that this imbalance manifests as migraine – especially “hormonal” migraine or menstrual migraine.

Since I am not an endocrinologist, the inquiry for this blog post will be fairly general and necessarily simplified (for example, there are many types of estrogen but I will just refer to “estrogen” as though it is one thing).  I think that this simplicity will still be accurate for the purposes of providing a general understanding for the following key concepts:

  1. Migraine is a mineral imbalance issue which leads to enzymatic deficiencies and inability to properly break down histamine, glutamate, and tyramine – ie, it is a metabolic disorder.
  2. High estrogen levels at ovulation affect histamine, while low estrogen and progesterone levels raise glutamate levels and contribute to menstrual migraine.

There are surely additional factors that go into why women get more migraine at ovulation and menstruation, and there are other inflammatory molecules besides histamine, glutamate, and tyramine that play a role in migraine pathology, but these two are certainly big players in menstrual migraine.

This is part 1 of a 3 part series, so be sure to continue reading for further insights into hormonal migraine.

The Fluctuation of Estrogen and Progesterone at Ovulation and Menstruation

One very basic explanation for why migraine occurs during ovulation and menstruation has to do with the sudden spikes and drops of hormones during these times.  Women who have reached menopause do not have such intense hormonal fluctuations.

Notice in the graph below of a “normal” menstrual cycle that estrogen is high at ovulation while progesterone only starts to rise a little at this point.  Progesterone peaks in the week after ovulation (and estrogen is at its lowest point), then starts to plummet again leading up to menstruation. Both estrogen and progesterone get very low right before and during menstruation.

It is most common for women to get migraine directly prior to and during menstraution – more common than women getting migraine during ovulation.  This is because both levels of estrogen and progesterone are low at this time.

The graph above does not illustrate finer fluctuations in estrogen prior to and during menstruation, however – and these sudden drops in estrogen especially, along with food triggers, are what some researchers believe cause the “menstrual” migraines, which are most likely to occur 2 days before and 3 days after menstruation.

“In an analysis of data collected as part of the long-term longitudinal Study of Women’s Health Across the Nation (SWAN), migraineurs’ estrogen levels declined in the 2 days before luteal peak at a faster absolute rate than non-migraineurs, and at a higher percent change than non-migraineurs, Jelena Pavlovic, MD, PhD, of the Albert Einstein College of Medicine in New York City, and colleagues reported in Neurology.

As part of a secondary analysis within the migraineurs’ group, the study authors determined that hormone patterns were similar regardless of whether the woman had a migraine that cycle. As a result, Pavlovic and her team formed a “two-hit” hypothesis in which women with rapid estrogen level dips before menstruation are more sensitive to migraine triggers, such as stress, lack of sleep or a glass of wine. It’s a combination of the estrogen drop and the additional trigger that result in a migraine.” (Source)

As interesting as this insight is, it doesn’t provide an explanation for WHY the group with the migraines had a more sudden drop of estrogen and were more prone to triggers resulting in migraine.

The question becomes: What do estrogen, progesterone, histamine, tyramine, and glutamate have in common? Is there a common mineral needed for the enzymatic processes that help to break down the amino acid neutrotransmitters glutamate, histamine, and tyramine that are also needed in the synthesis of estrogen and progesterone?  The answer is yes.  These two minerals are copper and zinc.

My hypothesis is that in the study cited above, the women with migraine have less bio-available copper needed to make the enzymes that break down histamine and tyramine – and which make estrogen.  They have less copper because their digestive, kidney, adrenal and liver function is more compromised, which in turn makes it harder for them to absorb and retain minerals and efficiently detoxify pollutants, convert amino acids, or make hormones as efficiently as women who are not compromised in these organ systems.

Ditto with zinc.  When major organ systems like the kidney and liver aren’t working optimally, zinc will not be assimilated or utilized for glutamate or progesterone, or for the removal of heavy metals in the body.  Once heavy metal buildup occurs (usually in the very organs that are already strained), these heavy metals will further disrupt mineral balance by displacing zinc and copper.  More on zinc and copper in part 2. Now that you’re familiar with my basic hypothesis, let’s get back to histamine and glutamate.

Histamine, Glutamate and Menstrual Migraine

Both histamine and glutamate are excitatory neurotransmitters implicated in migraine, and levels of these two amino acids in the gut and brain are affected directly by hormones as they shift at different times of the menstrual cycle.

One thing that is important to note here is that an overload of histamine and/or glutamate can come from many directions. Many intestinal bacteria also produce both histamine and glutamate, so those who have a history of antibiotics may have an environment in their gut lending to overproduction of these two amino acid neurotransmitters.  The overload occurs when there is a simultaneous excess of inflammatory gut bacteria, and deficiency of minerals needed to break down or convert them, leading to excitotoxicity on a brain level via the gut-brain axis. It has now been established that the gut and brain communicate not only via the vagus nerve, but also by way of electrical signalling from gut biome to brain biome (ie, bacterial, viral, and fungal colonies).

Below is a rundown of some of the ways that hormones, glutamates, and histamine affect each other.

  • Many hormones are processed by the liver, so anyone with an overwhelmed liver will necessarily have more of a tendency towards hormonal imbalances. (Source)
  • Estrogen and progesterone are glutamate transporters, ie, they help to reduce glutamate buildup. Excitotoxicity from glutamate is one key feature of migraine. Therefore, low levels of estrogen or progesterone (at menstruation) contribute to excitotoxicity. (Source)
  • Histamine intolerance or overload is a feature of migraine. Estrogen levels trigger mast cells to release histamine, so estrogens (including xenoestrogens and environmental pollutants that mimic estrogen), especially the estrogen spike at ovulation, will contribute to histamine overload. (Source) However, for reasons explained further in this article, this histamine and estrogen connection is mitigated by copper levels which also rise with estrogen.
  • Because most menstrual migraines occur at menstruation when both estrogen and progesterone are low, I hypothesize that glutamates are playing an even larger role in migraine than histamine.
  • Estrogen also down-regulates DAO (diamine oxidase), one enzyme that breaks down histamine. Estrogen replacement therapy and “the pill” increase estrogen levels and deplete progesterone – which may be one reason why headache is a known side-effect of the pill. (Source)
  • Progesterone is also needed to upregulate DAO (diamine oxidase), one enzyme that breaks down histamine. (Source)
  • Progesterone is used by the body to make cortisol.  Therefore excessive amounts of stress will deplete progesterone levels, and thereby raise glutamate.
  • Hormones are processed by the liver, so anyone with an overwhelmed liver will necessarily have more of a tendency towards hormonal imbalances. (Source)
  • Stress depletes zinc, which is needed to make progesterone. (Source). Zinc and copper have a reciprocal relationship. When zinc is depleted, copper levels rise, leading to more estrogen and histamine.
  • When both zinc and copper are low, hormonal function of both estrogen and progesterone is compromised.
  • Sudden drops in estrogen or progesterone during ovulation or directly prior to menstruation may account for migraines coming on at these times. (Source)

Because histamine intolerance or overload is a feature of migraine, and estrogen raises histamine, it is therefore tempting to demonize estrogen.  However, if high histamine triggered by estrogen were playing the dominant role in migraine, we would see more hormonal migraines occurring at ovulation than at menstruation.  And that is not the case.  More migraines occur at menstruation – and in those women who get migraine during ovulation as well, they often tend to not be as severe as the migraines at menstruation. So what is going on here?

Copper and Estrogen

Perhaps not so incidentally, copper levels rise when estrogen rises.  This may be the body’s adaptive mechanism to provide the copper that will allow the body to break down the excessive histamine. This means that those women who are low in copper, low in estrogen, or who have too much biounavailable copper or environmental estrogens will experience migraine more than those who have sufficient bioavailable copper and sufficient estrogen.

” . . . Dietary copper deficiency increases the mast cell population but does not alter the mast cell histamine content or sensitivity to degranulation in the rat. This increase in the number of mast cells may be a mechanism by which acute inflammation is enhanced in copper deficiency.” (Source)

Furthermore, since the liver processes estrogen, a stagnant or congested liver will also affect how frequently a woman gets migraines.  As it turns out, copper is vitally needed for proper bile flow, which is the way that these excess estrogens are removed.

So, while it is true that copper toxicity in the form of biounavailable copper built up in tissues contributes to migraine, and it is true that many women have an excess of estrogen in relation to progesterone (ie, an excess of copper in relation to zinc) – nevertheless, the opposite is also true: too little copper, too little zinc, too little estrogen, and too little progesterone leads to migraine.

What I’ve discovered in my practice is that balancing copper and zinc is THE LEVERAGE POINT for healing migraine.  I adore copper and zinc.  And I want to tell you more about them.  Continue on to Part 2.

About Marya Gendron
Marya Gendron is a biodynamic craniosacral therapist and health coach specializing in chronic migraine headache relief and alleviation of brain fog, indigestion, and histamine intolerance through plant-based solutions and hair mineral analysis. She practices out of White Salmon, Washington.

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