HISTAMINE AND ESTROGEN

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 excess estrogen.

When I first became histamine intolerant the information available on hormones was fairly limited.

Since then our understanding of hormones has expanded rapidly with our ability to test not only estrogen levels but estrogen clearance.

In reality, the question is not only whether the ovaries are producing too much estrogen, but whether the body is processing the hormones well.

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

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

ESTROGEN STIMULATES HISTAMINE

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.

Estrogen stimulates the release of histamine from mast cells in the uterus and ovaries in a dose-dependent manner.

The more estrogen that is circulating the more histamine will be released. At the same time, histamine stimulates estrogen, leading to a vicious circle.

So the key is estrogen, the lock is the H1 receptor, and when excess estrogen attaches to the cell, it not only stimulates the H1 receptor but releases histamine from the cell.

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.

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

ESTROGEN AND SIBO

Estrogen signals to cells. One of its key signals is intestinal motility.

Studies show that high estrogen is linked to irritable bowel syndrome (IBS) and small intestinal bacterial overgrowth (SIBO) and develops in response to slowed intestinal motility.

This suggests, that optimizing estrogen levels, can be important in finally resolving SIBO.

ESTROGEN AND MYCOTOXINS

Zearalenone (from Fusarium fungi) resembles estrodial and binds to  steroid receptors.  Alternaria species are also estrogenic.

They can lead to excessive levels of estrogen in the body and severe reproductive and infertility problems.

This suggests, that reducing mycotoxin levels may also be important to resolving histamine intolerance.

ESTROGEN AND VIRUSES

High estrogen levels reactivate viruses.

Viruses can interfere with the hormone process to ensure a favorable environment (they can accelerate the conversion of testosterone into estrogen to increase estrogen levels).

Numerous botanicals have both anti-viral and anti-estrogenic actions (for example DIM).

Practically, I have seen estrogen normalize on treatment of viruses.

This suggests that optimizing estrogen levels is crucial to resolving viruses.

OVARIAN ESTROGEN LEVELS

In pre-menopausal, non-pregnant, women, the main source of estrogen is the ovaries. After menopause, the main source of estrogen is the adrenals.

Word of warning, if you have adrenal fatigue going into menopause, it makes the transition harder.

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

Phase 1, 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 levels of estrogen.

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

Phase 3, 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 phase of their menstrual cycle.  When estrogen dominates relate 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 with progesterone that balances estrogen can be helpful.

Step 1: Point of Dysregulation

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

The point at which hormones became dysregulated give us clues as to the root cause of any dysregulation.

Downstream hormones are less important as they are affected by anything happening upstream. Also as hormones act in unison, addressing downstream issues alone, can cause further dysregulation.

Hormones are produced by healthy fats and b vitamins from our diet. If our diet or digestion is compromised then our body may not have the raw materials it needs to make or indeed detoxify our hormones.

From these nutrients, pregnenolone is produced. Pregnenolone is the "mother of all hormones" or the hormone from which all hormones are produced.

From there, pregnenolone is diverted to one of two pathways.

The first pathway is the progesterone pathway that is necessary for the production of cortisol. The second pathway is DHEA. DHEA is necessary for the production of testosterone and estrogen.

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

Step 2: Relationship Between Hormones

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 actually high or if estrogen is simply higher than progesterone.

Both of the examples below had symptoms of estrogen dominance and severe histamine intolerance.

Example: High Estrogen with Estrogen Dominance


Example: Normal Estrogen with Estrogen Dominance

Step 3: Clearance of Hormones

The ultimate biologic effect of estrogen in the body, however, 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 prior to 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.

Here are the key points of transformation.

Issue: Sluggish Liver Clearance

Source: Heartfixer.com

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 important.  Ideally, we want the vast majority (70% or more) to go down the 2-OH pathway.

Whilst the activity of the CYP1A1, CYP1B1, and CYP3A4 genes regulate these pathways it is environmental factors which primarily determine the outcome.

Gut dysbiosis and inflammation, heavy metals, mycotoxins, environmental chemicals, and nutrient status all heavily influence these pathways. The example below was primarily due to extensive gut dysbiosis.

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.

COMT (catechol oxygen methyltransferase) is the primary enzyme that methylates estrogen. If COMT activity is good, Phase 1, 4-OH metabolites are deactivated, rendering them harmless. The sulfation pathway is a secondary pathway used if the COMT methylation pathway is unable to keep up.

COMT Clearance Markers on DUTCH Test

Estrogen is also deactivated via the phase 2 glucuronidation pathway by attaching glucuronic acid.

Some intestinal bacteria (mostly bacteroides which are also histamine producing) has 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.

Issue: Insufficient Bile

Estrogen is a fat-soluble substance.

As such, the liver excretes estrogen into the gallbladder, where it binds with bile, in order to prepare it for elimination.

Therefore the amount of estrogen that can be excreted is limited to the amount of bile available. When individuals have insufficient bile, estrogen can be reabsorbed in the gut and re-circulated in the body.

A steocrit marker on a gut test is usually a good indicator of insufficient bile.

Issue: Low Fiber Diet

After estrogen is bound to bile, it binds to fiber in the gastrointestinal tract, to eliminate it via the stool.

If there is not enough soluble fiber, then estrogen laden bile cannot be bound and eliminated. As such it will be reabsorbed.

Constipation, that is not having at least one bowel movement per day, may be an indicator of insufficient fiber.

Step 4: Blocking Factors

Blocking factors are other systems and feedback loops that when out of balance can interfere with the transport and bioavailability of estrogen. These include:

Issue: Low Levels of SSHBG (Sex Hormone Binding Globulin)

SHBG is a protein made by the liver, that binds to testosterone and estrogen, to enable it to be transported through the blood to the cells.

When SHBG is low, the levels of circulating estrogens that are unbound is high

Common causes of low SHBG include:

Hypothyroidism,

Insulin resistance,

PCOS,

Obesity, and

Birth control pills (including for several years after cessation).

Issue: Aromatase Upregulation

The process that converts testosterone to estrogen is called aromatization.

If aromatization is upregulated it will convert testosterone to estrogen at a rapid rate.  So estrogen may be high and testosterone low simply because of this interference.

Aromatase can be upregulated due to:

Inflammation (due to food, pathogens, and toxins)

Obesity (fat stores estrogen)

Insulin resistance

Viruses, or

Mycotoxins.

 

Issue: Estrogen Receptor Activity

Hormone tests measure estrogens made by the body or bio-identical estrogen taken via supplements.

Other estrogens that are not bio-identical, will not show up on a hormone test. They will, however, cause havoc by binding to the estrogen receptor sites and competing with estrogen for detoxification.

As a result, these types of non-biological estrogens are typically called endocrine disruptors. These are also often classified into:

Phytoestrogens (plant derived - particularly diets extremely high in isoflavones, lignans, and certain flavonoids),

Xenoestrogens (chemically derived - particularly the “Dirty Dozen” fruit and vegetables)

Metaloestrogens (heavy metal derived - particularly mercury, lead, and unbound copper).

The "Environmental Working Group’s “Dirty Dozen Endocrine Disruptors” list provides a good summary of the most common endocrine disruptors.

 

Step 5 - Solutions

By now you have probably gathered that a lot can go off the rails when processing estrogen.

Simply supplementing individual hormones is not the whole answer. Likewise, the antidote needs to be implemented at the right place so as not to upset the apple cart.

It is therefore important to test and not guess.  I use the DUTCH test.

Also, as the microbiome plays a crucial role in this detoxification process, I also usually run a GI-Map.

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

However, there are also many supplements and nutrients, which can support estrogen clearance.  The right solution, however, will depend upon the individual including the root cause.

I am providing you with this information to help you engage with your health practitioner,  not to take things at random without testing.

That said here are a few examples. This list is not complete:

Conclusion

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

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

Whilst it is possible for our production of hormones to be affected, how we process hormones within our body, has as much if not more to do with our overall health.

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

Further Reading

Bodis, J., et al. "The effect of histamine on progesterone and estradiol secretion of human granulosa cells in serum-free culture." Gynecological Endocrinology 7.4 (1993): 235-239.

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.

Szelag, A., A. Merwid-Lad, and M. Trocha. "Histamine receptors in the female reproductive system. Part I. Role of the mast cells and histamine in female reproductive system." Ginekologia Polska 73.7 (2002): 627-635.

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.

Jarisch, Reinhart, and Felix Wantke. "Wine and headache." International archives of allergy and immunology 110.1 (1996): 7-12.

Zierau, Oliver, Ana Claudia Zenclussen, and Federico Jensen. "Role of female sex hormones, estradiol, and progesterone, in mast cell behavior." Frontiers in Immunology 3 (2012): 169.

Mulak, Agata, Yvette Taché, and Muriel Larauche. "Sex hormones in the modulation of irritable bowel syndrome." World journal of gastroenterology: WJG 20.10 (2014): 2433.

Diamanti-Kandarakis, Evanthia, et al. "Endocrine-disrupting chemicals: an Endocrine Society scientific statement." Endocrine reviews 30.4 (2009): 293-342.

Cornish, Julie A., et al. "The risk of oral contraceptives in the etiology of inflammatory bowel disease: a meta-analysis." The American journal of gastroenterology 103.9 (2008): 2394.

Jarisch, Reinhart. "Histamine intolerance in women." Histamine Intolerance. Springer, Berlin, Heidelberg, 2015. 109-115.

Pigrau, M., et al. "The joint power of sex and stress to modulate brain–gut–microbiota axis and intestinal barrier homeostasis: implications for irritable bowel syndrome." Neurogastroenterology & Motility 28.4 (2016): 463-486.

Cutolo M1, Brizzolara R, Atzeni F, Capellino S, Straub RH, Puttini PC.The immunomodulatory effects of estrogens: clinical relevance in immune-mediated rheumatic diseases. Ann N Y Acad Sci. 2010 Apr;1193:36-42.

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.

Chevrier, J., et al. "Body weight loss increases plasma and adipose tissue concentrations of potentially toxic pollutants in obese individuals." International journal of obesity 24.10 (2000): 1272.

Hue, Olivier, et al. "Increased plasma levels of toxic pollutants accompanying weight loss induced by hypocaloric diet or by bariatric surgery." Obesity Surgery 16.9 (2006): 1145-1154.

Jandacek, Ronald J., et al. "Effects of yo-yo diet, caloric restriction, and olestra on tissue distribution of hexachlorobenzene." American journal of physiology-Gastrointestinal and liver physiology 288.2 (2005): G292-G299.

Hall, D. "Nutritional influences on estrogen metabolism." Applied nutritional science reports 1 (2001): 1-8.

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).

Close

50% Complete

Two Step

Lorem ipsum dolor sit amet, consectetur adipiscing elit, sed do eiusmod tempor incididunt ut labore et dolore magna aliqua.