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In part 1 of this series I explored the idea that:
- 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.
- High estrogen levels at ovulation affect histamine, while low estrogen and progesterone levels raise glutamate levels and contribute to migraine around menstruation.
While metabolic processes require many nutrient cofactors to take place, I will focus on copper and zinc in this article, as balancing these two minerals is the biggest leverage point in transforming migraine.
From my studies into migraine and mineral balancing, I have come to believe that there are at least two important things to consider in regard to copper zinc balance as it relates to glutamate, histamine, and hormone imbalances:
- Excesses of histamine and glutamate in the body from food and gut flora imbalances place a greater demand on mineral stores of copper and zinc which are also needed for hormonal balance. This means that even if someone has copper and zinc levels within the “normal” range, there may insufficient amounts to meet the increased demand.
- Insufficient amounts of these two minerals will result in a reduced ability to regulate hormones at key times throughout the cycle, lower levels overall of estrogen and progesterone, and higher levels of histamine and glutamate.
- As a result, women will be more prone to food triggers from an overload of these two amino acids at key times during their menstural cycle – right after ovulation, 2 days prior to menstruation, and on day 3 of menstruation.
A Quick Recap from Part 1
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 optimally utilized for glutamate or progesterone (or serotonin), 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.
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 following is also true: too little copper, too little zinc, too little estrogen, and too little progesterone all lead to migraine.
It isn’t helpful to demonize estrogen or copper. Both estrogen and copper are vitally needed to be free from migraine. So are zinc and progesterone. They just need to be balanced.
Zinc, Copper, and Migraine
Zinc and copper are both synergistic and antagonistic – I like to think of them as like husband and wife, with copper (estrogen) as the wife and zinc (testosterone) as the husband. Of course, both men and women need copper and zinc because both men and women have estrogen and testosterone.
Copper and zinc compete for absorption in the intestine and are very close in atomic weight, so are easily swapped out for each other in various metabolic functions. This is why too much of either mineral can cause a deficiency in the other, and why maintaining a good balance and harmony between them is crucial for physical health.
Copper zinc balance can’t be accomplished by just fixing deficiencies in copper and zinc, or assuming that if you are within normal range on a blood serum test that your copper and zinc are fine. Copper zinc balance has to do with looking at optimal ratios of zinc to copper, and not just the total amount of copper or zinc.
A relative imbalance can exist in this ratio even when there is a sufficient level of both minerals on an absolute level. The converse is also true: in the case of someone who is deficient in both copper and zinc, a copper excess can still occur from too much copper in relation to zinc, or vice versa.
A deficiency of copper in relation to zinc can lead to connective tissue problems, especially connective tissue in the lining of the endothelium of the blood vessels so needed for blood flow to the brain. A deficiency of zinc in relation to copper can lead to low stomach acid, depression and heavy metal buildup.
Most migraineurs are deficient in both minerals. In a study done in Turkey measuring blood serum levels for various minerals and heavy metals, researchers found that
There were 25 migraine patients with an average age of 36.4±8.9 years and 25 healthy controls with a mean age of 42.4±9.5 years. Cadmium, iron, manganese and lead levels were significantly elevated in the patients compared to the controls (p<0.05 each), while copper, magnesium and zinc were decreased and cobalt demonstrated no change. (Source)
Copper is needed for hundreds of enzymatic processes in the body, but most importantly for migraineurs, it is needed for DAO (diamine oxidase) in the breakdown of histamine and in the breakdown of tyramine, as well as for enzymes needed to synthesize estrogen.
Copper is needed for:
- reducing histamine via DAO
- blocking glutamate receptors, reducing excitotoxicity (Source)
- ATP production in the cell (ie, energy)
- nerve conduction
- fatty acid metabolism (and by extension, brain health)
- neurotransmitter function (norepinephrine)
- liver health (and by extension, detoxification)
- bile flow (and by extension, gallbladder health)
- connective tissue health of blood vessels, bone, skin, and tooth enamel in the formation of elastin (via the lysyl oxidase enzyme)
- combating oxidative stress
- release of luteinizing hormone follicle-stimulating hormone (Source)
- signalling in the anterior pituitary (Source)
Copper and Estrogen
Copper is so closely linked to estrogen as estradiol that most sources state that copper mirrors it’s fluctuations (Source) – ie, that when estrogen levels rise, so does copper. If this is true, then it could be that the body regulates copper levels alongside estrogen as an adaptive mechanism to help protect the body from too much histamine (since copper is needed for DAO, an enzyme that breaks down histamine).
I began to get confused about this because I was not seeing this reflected in blood serum tests for copper, zinc, and ceruloplasmin, which I have clients test at ovulation and menstruation.
Below are two recent samples from two clients at ovulation and menstruation:
Ovulation (Blood Serum)
Copper: 12.5 umol/L (81.7 ug/dL) (70-140 ug/dL is the range)
Zinc: 8.88 umol/L (58 ug/dL) (65-110 ug/dL range)
Ceruloplasmin: 0.19 g/L (19 mg/dL) (20-35 mg/dL range)
% Unbound copper: 30.2% (range is 5-10% is optimal, <25% okay)
Copper Zinc Ratio: 1.4/1 (optimal is .7/1)
Menstruation (Blood Serum)
Copper: 13.4 umol/L (85 ug/dL) (70-140 ug/dL is the range)
Zinc: 8.22 umol/L (52 ug/dL) (65-110 ug/dL range)
Ceruloplasmin: 0.18 g/L (18 mg/dL) (20-35 mg/dL range)
% Unbound copper: 36.5% (range is 5-10% is optimal, <25% okay)
Copper/zinc ratio: 1.63/1 (optimal is .7/1)
Ovulation (Blood Serum)
Copper: 132 mcg/dL (70-140 mcg/dL is the range)
Zinc: 95 mcg/dL (65-110 mcg/dL range)
Ceruloplasmin: 38 mg/dL (20-35 mg/dL range)
% Unbound copper: 36% (range is 5-10% is optimal, <25% okay)
Copper/Zinc Ratio: 1.38/1 (optimal is .7/1)
Menstruation (Blood Serum)
Copper: 146 mcg/dL (70-140 mcg/dL is the range)
Zinc: 97 mcg/dL (65-110 mcg.dL range)
Ceruloplasmin: 28 mg/dL (20-35 mg/dL range)
% Unbound copper: 42% (range is 5-10% is optimal, <25% okay)
Copper/Zinc Ratio: 1.5/1 (optimal is .7/1)
Notice in these two clients that their copper levels are lower at ovulation (when estrogen is highest), and their zinc levels are higher at ovulation than at menstruation. Notice also that their ceruloplasmin levels (which bind copper and make it bioavailable), are higher at ovulation than at menstruation. This is as expected, since estrogen triggers ceruloplasmin. The free copper, or copper unbound to ceruloplasmin, is highest at menstruation, as is the level of copper overall.
Other researchers have also picked up on this – and their data confirms what mine does – that copper drops when estrogen rises. In a study titled “Changes in Copper and Zinc Plasma Concentrations During the Normal Menstrual Cycle in Women”, the researchers observe an inverse relationship between estrogen and serum copper levels:
Copper levels were highest during menstruation and lowest during the ovulation, thus exactly the opposite to [Estradiol] fluctuations. Our observations seem not to be in accordance to previous studies which suggested that higher plasma concentrations of estrogen resulted in higher concentrations of plasma C[opper]. . . (Source)
This tells me that estrogen levels are crucial to keep migraine in check, and estrogen’s ability to keep them in check may have a lot to do with estrogen’s ability to stimulate ceruloplasmin, keeping copper in bound form where it is able to get into the cells to metabolize histamine and glutamate and keep estrogen levels steady.
I believe that the lower levels of copper in the serum at ovulation actually translate to higher levels of cellular copper thanks to ceruloplasmin. I believe that the lower copper levels at this time reflect that the copper is getting where it’s supposed to go – ie, out of the serum and into the cells. I do not believe that this means lower levels of copper are needed to keep migraine at bay. It just needs to be bioavailable.
This would explain why taking supplemental copper is actually able to abort migraine in some individuals (usually fast oxidizers with sufficient cofactors for ceruloplasmin).
When estrogen levels around menstruation drop, so does ceruloplasmin, and this in turn causes an increase in free unbound copper, triggering migraine. This unbound copper cannot be used for enzymatic processes to break down histamine, and is damaging on a tissue level in this form.
Therefore, it is not copper per se that is the problem (indeed, copper is needed to make estrogen in the first place, and copper also triggers ceruloplasmin). Rather, the issue here is a compromised ability to produce ceruloplasmin due to adrenal burnout or liver congestion, and/or insufficient copper and other cofactors to make sufficient estrogen.
When women eat high histamine or glutamate-rich foods at the times when their estrogen levels are already dropping, they further exacerbate the intensity of the estrogen drop by increasing the demand on copper.
Biounavailable Copper and Copper “Toxicity”
Many people avoid copper because of fear of copper toxicity. Common factors which can contribute to copper toxicity aside from having a slow metabolism include the use of (or historical use of) hormonal birth control, hormone replacement therapy, heavy metal toxicity – especially mercury toxicity – or the use of a copper IUD. Copper water pipes contribute to excessive copper intake when water is acidic, and Wilson’s disease is a rare example of genetic copper toxicity.
The body regulates copper levels by eliminating excess copper through the bile where it is then excreted in the stool.
In order for copper to be bioavailable to cells, it must be carried by the protein enzyme ceruloplasmin, which is manufactured in the liver. This is why liver health is so important, and why simply getting the right supplements and minerals is not always enough to heal migraine if the woman’s liver is being challenged by pharmaceutical medications or heavy metal toxicity.
Many things can help to trigger ceruloplasmin production (including copper and estrogen) but ultimately the signal for the liver to produce ceruloplasmin comes from the adrenal glands. Therefore adrenal gland health is crucial for healthy copper metabolism and balance. The thyroid also plays a role in signalling the liver to make ceruloplasmin.
A woman’s metabolic type plays a huge role in how her body utilizes or stores copper. Slow oxidizers (as compared to fast oxidizers, who burn up copper more quickly) tend to accumulate copper in biounavailable form in different parts of the body. This is a simultaneous copper toxicity AND copper deficiency, as this biounavailable copper is not able to make it inside the cells for enzymatic processes including the breakdown of histamine and the synthesis of estrogen.
The strategy here is to make the copper bioavailable with the appropriate nutrient cofactors, including whole food vitamin C, vitamin A as retinol, and boron.
A Hair Tissue Mineral Analaysis and/or a blood test checking serum ceruloplasmin, copper, and zinc is the best way to determine if someone is “copper toxic” or not. Copper toxicity is often indicated on a hair tissue mineral analysis by a high tissue calcium level or mercury toxicity.
I believe that for many of those with migraine (though not all), copper deficiency may be playing a greater role than copper toxicity. For most people some level of tissue copper buildup and simultaneous cellular deficiency is probably going on, and this is why increasing ceruloplasmin will benefit both fast and slow oxidizers.
Zinc is also critical, as it is needed to
- break down glutamate
- make progesterone and testosterone AND estrogen
- remove heavy metals from the body
- make serotonin
- diversify gut flora
- make stomach acid
transcription of DNA
oocyte maturation and reproduction
- regularity of menstrual cycle (Source)
Zinc is easily lost through stress. Vegetarians and vegans tend to be low in zinc.
Supplementing with zinc can be much more dangerous than supplementing with copper is, unless you have a genetic condition or pyrrole disorder which predisposes you to excessive zinc loss.
As it relates to migraine, zinc’s ability to convert glutamate and prevent its buildup in the brain is especially important.
The higher glutamate concentration that is found in zinc deficiency is thought to be due to enhanced activation of the hypothalamic-pituitary-adrenal (HPA) axis, the main mechanism involved in the stress reaction. Rodents receiving a zinc-deficient diet had significantly elevated corticosterone concentrations. It is thought that cortisol/corticosterone may mediate the blocking of glutamate transporter activity under zinc-deficient/stress conditions, leading to the accumulation of excess glutamate. (Source)
While zinc is clearly crucial for those with migraine (especially since it too is needed to make estrogen), it is extremely important to supplement zinc cautiously. This is because zinc depletes copper more readily than copper depletes zinc.
High dietary zinc intakes increase the synthesis of an intestinal cell protein called metallothionein, which binds certain metals and prevents their absorption by trapping them in intestinal cells. Metallothionein has a stronger affinity for copper than zinc, so high levels of metallothionein induced by excess zinc cause a decrease in copper absorption. In contrast, high copper intakes have not been found to affect zinc nutritional status. (Source)
To Sum Up . . .
Copper and zinc balance is crucial for those with migraine. When balanced, these minerals allow the body to build sufficient estrogen and progesterone, leading to fewer drastic spikes and drops of hormones that lead to migraine. When deficiencies in these minerals are corrected, the body is better able to eliminate heavy metals and convert glutamate and histamine into usable form so that they don’t build up and trigger a migraine.
Zinc and copper balance in the body is determined by a person’s dietary intake, metabolic type, organ health, pharmaceutical load, heavy metal load, and history of birth control or hormone replacement therapy. Hair Tissue Mineral Analysis and serum ceruloplasmin, copper, and zinc tests, as well as tests for pyrrole levels, are all crucial tools in customizing a plan to balance an individuals copper and zinc levels to heal migraine.
Stay tuned for Part 3 of this series
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The information in this article is for educational purposes only and not meant to replace diagnosis, treatment, or prescription by a qualified medical professional.