Although this post describes interactions between female hormones and histamine, everything else discussed pertains to both men and women when experiencing histamine issues.

Migraine Mysteries and Misery

Migraines cause much misery and can be a mysterious health challenge to solve, This article covers one of the most common causes of migraines (and insomnia, brain fog, nasal congestion, low blood pressure, heart palpitations, anxiety, and more).

If you suffer from migraines (or insomnia, brain fog, nasal congestion, or anxiety), have you considered the possibilty that the migraines may be connected to an issue with controlling histamine?

If you are a woman, have you noticed migraines developing at certains of the month, when estrogen peaks at ovulation and just before your period?

And are the migraines accompanied by other symptoms like anxiety, insomnia, brian fog, nasal congestion, and/or hives?

Do the migraines seem to be triggered by high histamine foods?

Migraines, Female Hormones, and Histamine

Migraines often arise when estrogen peaks during the menstrual cycle because estrogen stimulates mast cells to release histamine and down-regulates the diamine oxidase (DAO) enzyme that clears histamine in the gut. And histamine stimulates the ovaries to produce estrogen, potentially creating a vicious cycle in which estrogen promotes histamine production, and histamine in turn promotes more estrogen production.

In contrast to the histamine-promoting and DAO-down-regulating actions of estrogen, progesterone stabilizes mast cells and upregulates DAO. During pregnancy, the placenta produces lots of DAO, so histamine tolerance tends to be better during pregnancy. 

Factors Affecting DAO Activity

Several common factors cause low DAO activity. DAO requires copper, vitamin C, and vitamin B6, so deficiencies in these would reduce DAO activity and your ability to control histamine via DAO. Small intestine bacterial overgrowth (SIBO) impairs the activity of the DAO enzyme. And a genetic variant in the DAO gene can also reduce DAO activity.

Methylation and Histamine Clearance

Aside from DAO, histamine is also cleared by the back-to-back action of two enzymes, histamine N-methyltransferase (HNMT) and monoamine oxidase (MAO). In the first step of this process, HNMT requires vitamin B6 as its cofactor and transfers a methyl group from S-adenosylmethionine (SAM, aka SAMe) to histamine to produce methylated histamine.

However, oversupplementing with B6 could cause HNMT activity to outpace MAO activity, causing an accumulation of methylated histamine, which is even more active than unmethylated histamine,. So although you need B6, do not oversupplement with B6, because it could potentially worsen a an issue with excess histaminic signaling.  Oversupplementing with B6 over time can also cause neuropathy.

Because the cleanance of histamine via HNMT and MAO depends on the supply of SAM to supply methyl groups to transfer to histamine, factors affecting the SAM supply affect your ability to clear histamine. 

SAM supply depends on how well the methylation cycle is functioning, and this is affected by a variety of genetic polymorphisms (variants) in genes like the infamous MTHFR gene. But there is much more to the methylation cycle than MTHFR. And it's important to know that a particular oxidant colled the hydroxyl radical inhibits the methionine adenosyltransferase (MAT) enzyme that forms SAM from the amino acid methionine.  So oxidative stress can impair the supply of SAM.

Other Histamine Clearance Pathways and Impediments

In addition to DAO and processes involving methylation, histamine can also be cleared by a phase 2 "detoxfication" process called glucuronidation, Glucoronidation is also involved with clearing steroid hormones like estrogen and toxins like mold toxins (mycotoxins). In particular, the UGT1A4 gene affects one's ability to conjugate histamine and mycotoxins via glucuronidation.

Mycotoxins and high levels of steroid hormones (e.g. estrogen) could overburden glucuronidation, thereby reducing the ability to clear histamine via this pathway. Excess steroid hormones like cortisol, the main stress hormone, could also overburden glucuronidation and reduce your ability to clear histamine.

Steroid hormones are also cleared from the body via methylation by another phase 2 pathway, the catechol-O-methyltransferase enzyme (COMT). So genetic variants that code for a slow COMT enzyme could slow the clearance of estrogen, potentially transferring more of the burden of estrogen clearance to glucuronidation, thereby creating problems with clearing histamine. The COMT enzyme requires SAM (the universal methyl donor), so the overall function of the methylation cycle comes into play again here.

Sources of Excess Histamine

The gastrointestinal tract releases histamine in response to some dysbiotic bacteria, parasites, fungal overgrowth, and food intolerances, which can be promoted by low levels of stomach acid, bile, and pancreatic enzymes. 

Mycotoxins (toxins produced by mold) are a particularly strong stimulator of histamine release by mast cells.

Deficiencies in selenium and vitamin A increase mast cells and potential histamine release. But be careful to not oversupplement with selenium because it's easy to become selenium toxic. When it comes to vitamin A status, realize that some people do not efficiently convert beta carotene from plant foods to vitamin A and need to get it from animal foods. Vitamin A requires sufficient zinc and exposure to ultraviolet light (sunlight or tanning beds) for activation, so sufficient zinc and exposure to ultraviolet light are also important to your ability to control histamine levels. 

Neuroinflammation can upregulate mast cell activity. Polymorphisms in certain genes (e.g. the KIT gene) can create a propensity for higher mast cell activity. Any many other factors can promote a hypervigilant immune system that can become trigger-happy with the histamine.

Summing Up

To summarize, a variety of factors can contribute to a problem controlling histamine, such as ...

• Elevated estrogen or "estrogen dominance" increases histamine and downregulate DAO.
• Low progesterone reduces the ability to balance the actions of estrogen.
• Genetic variants and other factors like deficiencies of vitamin B6, vitamin C, and copper limit the supply or efficiency of DAO, HNMT, and MAO.
• The methylation cycle and therefore the supply of DAO can be impacted by genetic polymorphisms, oxidative stress, B vitamin deficiencies, and more.
• Mycotoxins might compete with estrogen for clearance via glucoronidation pahways.
• Genetic variants in UGT1A4 and COMT genes could reduce the speed at which estrogen , other steroid hormones, and histamine are deactivated and cleared
• Small intestine bacterial overgrowth (SIBO) impairs DAO activity.
• Some dysbiotic bacteria produce histamine.
• Parasites, yeast overgrowth, and food intolerances (often caused by weak digestion) can increase histamine release by mast cells in the gut.
• Deficiencies in selenium and vitamin A (and indirectly, deficiencies in zinc and exposure to ultraviolet light) increase mast cells. 
• Mold toxins, neuroinflammation, and other factors can activate mast cells into a hypervigilant state.
• Genetic variants in the KIT gene can increase mast cell activity.

Escape "Histamine Hell"

Any of these factors could combine to create a "histamine hell" consisting of migraines, reactions to high-histamine foods, and other symptoms related to histamine. Many of the symptoms of "estrogen dominance" may actualy be symptoms of histamine intolerance or mast cell activation.

Whether you are a woman or a man, histamine hell is no fun at all, and it can be one of the most confusing of health mysteries to solve.

If you would like help with any of this, you can learn more about my general approach by downloading the Bio-Individual Blueprint Roadmap, watching the walkthrough video, and scheduling a meeting if it seems like we might be a fit to work together.