September 08, 2018 10:00 pm


Histamine and estrogen are intrinsically linked.

It is no coincidence that a high incidence of people who acquire histamine intolerance are women. The common link is estrogen.

Whether the ovaries produce too much estrogen or the body is processing the hormones well, both profoundly impact histamine levels.

And how we process estrogen has everything to do with histamine intolerance.

The Role of Hormones

Hormones are chemical messengers that regulate cells.

This is why we look and feel our best when hormones are in balance, and when they are not, we can have widespread symptoms like histamine intolerance.

While we typically think of hormones as steroidal hormones (such as estrogen, progesterone, and testosterone), these are just one class of hormones. Amines (including histamine) are another class of hormone.

estrogen, histamine intolerance, mast cell activation, alison vickery, health, Australia

Estrogen Stimulates Hormones

Hormones act on specific targeted tissues.

Which hormones affect which cells depends on whether the “key” or hormone fits the “lock” or receptor on the cell. Receptors interact with and bind to specific hormones.

Both histamine and estrogen attach to the H1 receptor.

When excess estrogen attaches to the cell, it stimulates the H1 receptor and releases histamine from the cell. The more estrogen that is circulating, the more histamine will be released.

At the same time, histamine stimulates estrogen, leading to a vicious circle.

Estrogen and Histamine Intolerance

Histamine intolerance occurs when there is an excess of histamine.

Either there is too much histamine (due to estrogen excess) or the reduced ability to degrade histamine (due to reduced diamine oxidase).

Excessive estrogen has been shown to modify intestinal permeability, which can, in turn, reduce diamine oxidase (the enzyme that degrades histamine)

So not only does excessive estrogen stimulate the release of histamine, but it also can reduce the ability to degrade histamine.

Ovarian Estrogen Levels

In pre-menopausal, non-pregnant women, the primary source of estrogen is the ovaries. After menopause, the primary source of estrogen is the adrenals. Practically, this means that if you have adrenal fatigue going into menopause, it is harder to transition to menopause.

A menstruation cycle lasts approximately 28 days and has three phases:

Phase 1 is the follicular phase, during days 1 – 10, in which the top lining of the uterus is shed, and menstrual bleeding commences. During this stage, there are rising estrogen levels, and histamine intolerance symptoms seem to worsen.

Phase 2 is the mid-cycle phase, during days 11 – 14, in which hormones begin to release eggs from the ovaries for conception.

Phase 3 is the luteal phase, during days 15 – 28, in which hormones alter the endometrial lining to protect an embryo (if conceived). During this phase, there are rising levels of progesterone. 

In women, progesterone balances estrogen. It puts the “brakes” on estrogen.

Histamine intolerant women often suffer from headaches, dysmenorrhea, and increased symptoms of histamine intolerance, based on the menstrual cycle phase.  When estrogen dominates relative to progesterone, symptoms ensue.

Also, as we age, progesterone is the 1st hormone to decline, then estrogen, then testosterone.  This decline takes a couple of years until homeostasis (at a lower balanced menopausal level) is restored.

It is, therefore, no coincidence that middle-aged women are susceptible to histamine intolerance. Supporting progesterone that balances estrogen can be helpful.

estrogen, estrogen dominance, histamine intolerance, Alison Vickery, Health, Australia

Assessing Estrogen Levels

There are four steps to assessing histamine dominance as follows:

Step 1: Total Estrogen Level

The steroidal hormone pathway is the system the body uses to produce estrogen.

DHEA is necessary for the production of both testosterone and estrogen.

High estrogen may be due to high DHEA or high testosterone, not just due to high estrogen.

2. Is Estrogen In Balance

When evaluating the hormone pathway, we are also concerned about hormone relationships. Hormones act in tandem to establish homeostasis.

In women, progesterone balances estrogen. It puts the “brakes” on estrogen via the E2 receptor.

Estrogen dominance can occur if estrogen is high or higher than progesterone.

3. Phase 1 Estrogen Clearance

However, the ultimate biological effect of estrogen in the body depends on how it is cleared.

So, while it’s helpful to know how much estrogen someone is making and how the total estrogen level compares to total progesterone, it’s even more important to know how estrogen is being cleared.

Estrogen is transformed repeatedly throughout the body before elimination. Problems can occur at many points in the process, and once again, the point at which the dysfunction occurs gives us clues as to the root cause.

Phase 1 activates estrogen by adding a hydroxyl group and splits it into three pathways:

2 hydroxy (2-OH), the healthiest form of estrogen.

4 hydroxy (4-OH) has the most potential to damage the DNA.

16 hydroxy (16OH) has the potential to proliferate any DNA damage.

Because phase 1 turns estrogen into an active substance, which of the three detoxification pathways estrogen takes is essential.  Ideally, we want the vast majority (70% or more) to go down the 2-OH pathway.

While the activity of the CYP1A1, CYP1B1, and CYP3A4 genes regulate these pathways, environmental factors primarily determine the outcome.

Gut dysbiosis, inflammation, heavy metals, mycotoxins, environmental chemicals, and nutrient status influence these pathways.

4. Phase 2 Estrogen Clearance

However, the body has compensatory mechanisms, and sub-optimal phase 1 clearance may not be a problem, provided there is good phase 2 clearance.

Phase 2 deactivates  4-OH estrogen (16-OH relies on a different pathway) via the methylation, glucuronidation, or sulfation pathways.

Some intestinal bacteria (mostly bacteroides, which are also histamine-producing) have an enzyme, beta-glucuronidase, that breaks the bond between estrogen and glucuronic acid, allowing it to re-enter circulation.

The beta-glucuronidase marker is not available on the Dutch Test but is picked up on a comprehensive gut test.

Glutathione is a backup system for phase 1 and phase 2. It also neutralizes the 16-OH pathway and other remaining toxins. It relies on adequate levels of glutathione.

Other Factors

Other reasons that estrogen may be dominant include:

Bile insufficiency – estrogen is fat-soluble; therefore, the amount of estrogen excreted is limited to the amount of bile.  The steocrit marker on a gut test is usually a good indicator of insufficient bile.

Insufficient fiber in diet – needed to eliminate fat-soluble hormones and toxins.

Reduced sex hormone binding globulins – made in the liver and impacted by hypothyroidism, insulin resistance, PCOS, obesity, and birth control pills.

Aromatase upregulation – due to inflammation, obesity (fat stores estrogen), insulin resistance, viruses, or mycotoxins.

Endocrine disruptors –  including phytoestrogens (plant-derived – particularly diets exceptionally high in isoflavones, lignans, and certain flavonoids), xenoestrogens (chemically derived – mainly the “Dirty Dozen” fruit and vegetables), Metaloestrogens (heavy metal derived – particularly mercury, lead, and unbound copper), and mycoestrogens (mold derived).


The fact that some conditions (such as histamine intolerance, SIBO, and auto-immunity) are more prevalent in women than men indicates how important our hormones are to our overall health.

When our hormones are unbalanced, we can experience wide-ranging symptoms, including histamine intolerance.

While our production of hormones can be affected, how we process hormones within our body has as much, if not more, to do with our overall health.

Estrogen dominance may be the root cause of histamine intolerance. If that is the case, then addressing estrogen levels can reduce, if not reverse, histamine intolerance.

Equally, hormones have a lot to do with our environment. Addressing the underlying cause can re-establish healthy hormone levels and improve histamine tolerance.

The right solution, however, will depend upon the individual, including the root cause.

Further Reading

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Fogel, W. A. “Diamine oxidase (DAO) and female sex hormones.” Agents and actions 18.1-2 (1986): 44-45.

Maintz, Laura, et al. “Effects of histamine and diamine oxidase activities on pregnancy: a critical review.” Human reproduction update 14.5 (2008): 485-495.

Maintz, Laura, and Natalija Novak. “Histamine and histamine intolerance–.” The American journal of clinical nutrition 85.5 (2007): 1185-1196.

Hamada, Yasuhiro, et al. “Effect of the menstrual cycle on serum diamine oxidase levels in healthy women.” Clinical biochemistry 46.1-2 (2013): 99-102.

Kalogeromitros, D., et al. “Influence of the menstrual cycle on skin prick test reactions to histamine, morphine, and allergen.” Clinical & Experimental Allergy 25.5 (1995): 461-466.

Sabbah, A., et al. “Antihistaminic or anti-degranulating activity of pregnancy serum.” Allergie et immunologie 20.6 (1988): 236-240.

Morel, Françoise, Anny Surla, and Pierre V. Vignais. “Purification of human placenta diamine oxidase.” Biochemical and biophysical research communications 187.1 (1992): 178-186.

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Szelag, A., A. Merwid-Lad, and M. Trocha. “Histamine receptors in the female reproductive system. Part II. The role of histamine in the placenta, histamine receptors, and the uterus contractility.” Ginekologia Polska 73.7 (2002): 636-644.

Sessa, A., M. A. Desiderio, and A. Perin. “Estrogenic regulation of diamine oxidase activity in rat uterus.” Agents and actions 29.3-4 (1990): 162-166.

Fogel, W. A. “Diamine oxidase (DAO) and female sex hormones.” Agents and actions 18.1-2 (1986): 44-45.

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Ho, Pak-Chung, Grace WK Tang, and John WM Lawton. “Lymphocyte subsets in patients with oestrogen deficiency.” Journal of reproductive immunology 20.1 (1991): 85-91.

Janegova, Andrea, et al. “The role of Epstein-Barr virus infection in the development of autoimmune thyroid diseases.” Endokrynologia Polska 66.2 (2015): 132-136.

Miguel, Rodolfo D. Vicetti, et al. “17-? estradiol promotion of herpes simplex virus type 1 reactivation is estrogen receptor dependent.” Journal of Virology 84.1 (2010): 565-572.

Iizuka, Norio, et al. “Altered levels of cytochrome P450 genes in hepatitis B or C virus-infected liver identified by oligonucleotide microarray.” Cancer Genomics-Proteomics 1.1 (2004): 53-58.

Draborg, Anette Holck, Karen Duus, and Gunnar Houen. “Epstein-Barr virus in systemic autoimmune diseases.” Clinical and Developmental Immunology 2013 (2013).

Velmurugan, Ganesan, et al. “Gut microbiota, endocrine-disrupting chemicals, and the diabetes epidemic.” Trends in Endocrinology & Metabolism 28.8 (2017): 612-625.

Rajapakse, Nissanka, Elisabete Silva, and Andreas Kortenkamp. “Combining xenoestrogens at levels below individual no-observed-effect concentrations dramatically enhances steroid hormone action.” Environmental health perspectives 110.9 (2002): 917.

Lu, Kun, Ridwan Mahbub, and James G. Fox. “Xenobiotics: interaction with the intestinal microflora.” ILAR journal 56.2 (2015): 218-227.

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Ortizo, Ronald, et al. “Exposure to oral contraceptives increases the risk for development of inflammatory bowel disease: a meta-analysis of case-controlled and cohort studies.” European journal of gastroenterology & hepatology 29.9 (2017): 1064-1070.

Khalili, Hamed. “Risk of inflammatory bowel disease with oral contraceptives and menopausal hormone therapy: current evidence and future directions.” Drug safety 39.3 (2016): 193-197.

Looijer-van Langen, Mirjam, et al. “Estrogen receptor-? signaling modulates epithelial barrier function.” American Journal of Physiology-Gastrointestinal and Liver Physiology 300.4 (2011): G621-G626.

Vejdovszky, Katharina, et al. “Synergistic estrogenic effects of Fusarium and Alternaria mycotoxins in vitro.” Archives of toxicology 91.3 (2017): 1447-1460.

Zheng, Wanglong, et al. “Effects of zearalenone and its derivatives on the synthesis and secretion of mammalian sex steroid hormones: A review.” Food and chemical toxicology (2019).