HISTAMINE 101 ”The scientific link between histamine, oestrogen, progesterone & cortisol from a Functional Medicine Clinicians perspective”

Headaches, itching, hives, swelling, flushing, racing heart, nasal congestion, digestion problems, irritability… do any of these sound familiar to you?

If you’ve been living inside your irritating, allergic, itchy little bubble, not knowing what causes your symptoms then there’s a chance you may be been dealing with histamine intolerance.

The line between allergies and histamine intolerance is a thin one. If you found yourself confused by the conflicting theories online, then hopefully this should shed some scientific light on that topic for you.

Let’s dive deep into the essence of the amino acid called “histamine “, why do we need it, how to know if we have too much of it, and what to do if your body cannot no longer degrade it.

So what exactly is ‘Histamine’?

Well, in the majority of cases people usually hear or talk about this compound in an unpleasant, problematic way, when they are told by doctors that they cannot quite tolerate it, (and often given pharmaceutical drugs such as antihistamines to supposedly address the issue), but that doesn’t mean that histamine is not important to our overall health – far from it. Histamine is a chemical classified as an ‘amine’ hence it forming the second half of the word itself.

In more technical terms, histamine is a ‘pleiotropic’ biogenic amine required for the normal function of many processes in the body including inflammation, immunity, neuromodulation and gastric acid secretion. Normally, the formation, storage, utilisation and breakdown of histamine is tightly controlled by several measures due to its capacity to stimulate significant biological effects. However, the integrity of such measures can be adversely influenced by a number of endogenous and exogenous factors.

Histamine is essentially a chemically active biological substance that can be found in almost every living organism. It is produced by the mast cells, (which will go on to discuss in my next article), and plays a very important part in the bodies immune response.

The reason histamine is chemically classified as an amine is due to it being formed as a result of the decarboxylation of the amino acid ‘Histadine’. This extremely important compound was first discovered in 1910 in the plant fungus ‘ergot’. year later, scientist also found that histamine was present in animal tissues as well. Think of histamine as the “irritating “chemical. It is found in stinging nettles, and also founded the venom of many insects, such as bees and wasps. It is thanks to histamine that you each and swell when you make contact with nettle leaves. In the human body, histamine is found in almost every tissue, and most of it is stored as granules in the mast cells, as well as in the basophils and eosinophils, or otherwise known as white blood cells (WBC’s). Once the histamine gets released from these granules, it immediately starts producing different effects (such as muscle contraction, blood vessel dilation, gastric acid stimulation, etc.) Within the body. But that’s not the only reason why he is doing super significant for overall health. It acts as a neurotransmitter, and is in charge of transferring chemical messages to the nerve cells.

Histamine also helps the body to defend itself from invaders such as viruses, bacteria, or other harmful foreign bodies, hence why it is highly essential – despite people cursing it when they are suffering with histamine intolerance.

Additionally, in defending the body from harmful pathogens and being a huge part in any vital process, histamine also serves as the most important mediator in allergy symptoms, which means that in order to protect the body from this inflammatory reaction, the body must released histamine (as well as other anti inflammatory mediators) or respond to the allergens.

To better understand the importance of histamine during an allergic reaction let’s look at this example. Imagine yourself having a picnic in nature during allergy season in spring. You’re sitting on fresh grass, surrounded with beautiful blooming flowers. If you’re prone to allergies, then you know what’s about to happen. Not long after you start enjoying your time in nature you start sneezing, your nose will start running, and you suddenly become itchy. Have you ever wondered why this happens? And more importantly, what does histamine have to do with a pollen allergy?

When something foreign like pollen enters your body it triggers your immune system to respond for an intruder. The pollen is microscopic grains, which in this case, are treated as the enemy, and your body does its best to get rid of these attackers. In order to start the defending process, the body sends a signal to the mast cells and request that they release it secret weapon – histamine. The release of histamine to the site where the irritation is happened activates the proper response. This means that after, for example, your nose has been attacked by pollen, histamine stimulates the membranes to produce more mucus, and as a result, you will get a runny nose followed by a couple of sneezes. Chemically, histamine works only when bound to other receptors on the cell surface. When histamine arrives at the irritation site, it does not cause one but multiple important effects.

Probably the most important one is the effect of dilating the blood vessels, which is followed by swelling. This is the inflammatory response. Have you ever been stung by a bee? The fact that the skin gets immediately puffy around the place where you got stung thanks to the fact that histamine forces blood vessels to dilate. And although we know how uncomfortable a bee sting can be, this inflammation response is how your body heals. Passed the blood flow leads to the immediate delivery of white cells. The degree of inflammation in this case, or the allergic reaction that you will most likely experience in the pollen example, depends on how much histamine has been released, and this is something that varies from person to person.

Histamine works when it’s bountiful receptors H1, H2, H3, and H4. In this, as well as in the majority of cases, histamine binds to H1, which is the most important of all the receptors and is involved in allergic reactions. (See image above)

The H1 receptor is expressed on smooth muscle tissue, vascular endothelial cells and the brain. It is involved in immune- (IgE) and inflammatory-mediated processes initially due to the activation of this receptor. The classic histamine-associated effects include vasodilation, erythema and oedema, as well as symptoms such as allergic rhinitis, dermatitis, urticaria, asthma and anaphylaxis. H1 also mediates adrenal catecholamine-release and central nervous system (CNS) neurotransmission.

The H2 receptor is located on immune, gastric mucosal, brain, adipocyte, vascular and uterine smooth muscle cells. Its activation is involved in the regulation of gastric acid secretion, gastrointestinal motility, and cell growth and differentiation. It is also suggested to have an immune-suppressive affect via inhibition of white blood cell chemotaxis (i.e. neutrophils, basophils, eosinophils).

The H3 receptor has a significant presence on CNS histaminergic neurons, eosinophils, dendritic cells and monocytes. It regulates the secretion of neurotransmitters, nerve supply to the heart and blood vessels and smooth muscle contraction.

Lastly, the H4 receptor is mainly expressed on haematopoietic cells, as well as on various immune cells (i.e. mast cells, eosinophils, T cells, basophils and monocytes), keratinocytes and dendritic cells. Its activation thought to be involved in inflammation and allergic processes.

Another internal measure that influences histamine’s biological effects is its stimuli-induced release by either immune- or non-immunological processes.

Immune-mediated (‘classic’) histamine release involves mast cells and basophils, which degranulate stored histamine after antigen-induced IgE antibodies bind to membrane receptors.

Non-immunological histamine release involves the degranulation of stored histamine from mast cells and basophils or the passive transport of histamine in non-storing cells, which can be induced by endogenous (neuropeptides, cytokines, complement) or exogenous (alcohol, food, medication) factors.

At first glance, histamine may seem likely not so important biological compound, even the fact that it’s built with only 17 atoms, but histamine is indeed essential for our body, and not only for the reasons we have talked about earlier in this article. The chemical properties the histamine has, allow it to be extremely versatile in binding, which is why it is involved in 23 physiological functions. It is super flexible and confirmational, which allows it to easily interact.

I want to go on to just touch upon some of the things that histamine is part of or affects either directly or indirectly.

Due to the fact histamine can force blood  vessels to dilate, this can lead to a decrease in blood pressure. This is why people with high blood pressure often receive histamine intravenously.

As was previously mentioned, histamine is a great neurotransmitter. It’s cell bodies can be found in the hypothalamus (a portion of the brain in charge of mini metabolic processes), from where the histamine neurons are projected throughout the brain in order to support wakefulness and lower symptoms of sleep. This is why the antihistamines are traditionally known to cause drowsiness (although new ones are designed in a way that doesn’t allow them to cross the blood brain barrier (BBB) and cause sedative effects.

When bound to the H2 receptor, histamine can stimulate the parietal cells found near the stomachs gastric glands by supporting the acceptance of the water and carbon dioxide from the blood, and converting it to carbon acid. Inside the parietal sales, the carbon acid separates into bicarbonate and hydrogen irons, from where the hydrogen irons are pumped into the stomach lumen, and HCO3 irons once again diffused into the bloodstream. When the stomachs pH level start decreasing, the release of histamine is stopped. In certain cases of infections of the stomach such as H. pylori, The stomachs pH can become alkaline by way of the pathogenic mechanism of H. pylori converting your ear into urease which has a pH of 11 which is highly alkaline. It is this environment that can increase the levels of histamine as it tries to counteract lack of acidity or lack of low pH.

Then there is protection. When I say protection, I don’t mean just defending the body from foreign invaders. Histamine is known to have some amazing effects that protects from stress, drug sensitisation, and convulsion. Histamine has also been discovered to have an affect on those mechanisms by which we tend to forget learn to memorise things.

Otherwise known as intrinsic histamine, histamine is present in all mammals – humans included – and serves the role of a biogenic mean. This type of histamine is produced when the enzyme Histidine Decarboxylase can be found in the cells that contain granules (such as mast cells and basophils). When the amino acid Histidine comes into contact with the enzyme in the cells, it gets converted into histamine, and is stored in the cell structures waiting for signal to be released. That is why histamine is present in the mast cells in the basophils.

Although the mast cells aware histamine is primarily stored, that is not the only place where it can be found. There are also a number of other microorganisms that can produce histamine. For example, there are a lot of bacteria in the human: they are perfectly capable of producing histamine. How? The bacteria also produce histidine decarboxylase, and once protein with his content enters the large bowel and comes into contact with the enzyme histidine decarboxylase, he gets converted into histamine. Once there is histamine in the large bowel it can quickly and easily get transported through the bowel to many different parts of the body.

Histamine is also present in a variety of natural foods, and this type of histamine which enters our body from an outside source is called extrinsic histamine. The microorganisms that convert histidine into histamine also exist in nature, and so histamine can appear in our body from many outer sources.

Foods relevant to histamine intolerance include those that: contain high levels of histamine (fermented foods such as sauerkraut, processed meat, dried anchovies, fish sauce, spinach, tomatoes, cocoa, eggplant, fish, chicken, yoghurt, soy, red wine); induce histamine release from mast cells (citrus foods, pineapple, bananas, strawberries, papaya, tomatoes, additives); or other biogenic amines that may interfere with the binding of histamine to mucosal mucine resulting in more histamine in circulation.

Shortly after a fish dies, the bacteria in the gut begins to break down the tissue proteins while releasing histidine. This is the reaction that produces histamine. It is important to know that the longer the fish stays ungutted after has been caught, the higher the level of histamine. In fact, the histamine levels can double every 20 minutes or so. Fish that are not gutted after being caught, such as shellfish, will continue producing histamine until the moment they become cooked. There are also many other foods that contain histamine or are known to have histamine releasing properties which are come onto later.

There are also many food manufacturing processes that mostly rely on the production of all sorts of chemicals in a means for the sake of flavour of the food. Many of these processes, especially fermentation, will produce a rather high amount of amines, and with them, histamine.

When people have a “intolerance”, it usually means that their bodies are sensitive to something. Take lactose intolerance for example. It simply means that the body cannot quite digests the natural sugar lactose, and therefore becomes extremely sensitive when milk or other dairy products consumed. Histamine intolerance, on the other hand, means something different. Despite what the name suggests, when a person is histamine intolerance, it does not mean that they are sensitive and cannot tolerate histamine; it simply means that they have too much of it circulating.

Histamine intolerance is the consequence of excess levels of endogenous histamine inducing a broad range of systemic physiological effects in the body It has a complex clinical presentation, with variability observed in the type and severity of signs and symptoms that occur within and between individuals.

This is due in part to the range of organs and tissues that express histamine receptors, with symptoms of histamine intolerance presenting in gastrointestinal (diarrhoea, abdominal pain, cramps, bloating, reflux), respiratory (sneezing, rhinorrhoea, nasal congestion or swelling, phlegm, cough, asthma), cardiovascular (arrhythmias, tachycardia, palpitations), integumentary (urticarial, pruritis, flushing), CNS (headache, dizziness, anxiety, sleep disturbances) and reproductive tissues or organs (dysmenorrhoea, menstrual headache)

Like we said, histamine is an extremely important compound in our body that plays one of the key roles in keeping us healthy. However, when histamine levels pileup in the mast cells histamine has a counter effect on our health. Excess histamine can make us feel sick.

In order for histamine to function effectively, and to fight for and bacteria or viruses, it needs to be broken down. If our body fails to break down the histamine quickly or officially, it will begin to pile up in the mast cells. Think of it as a glass filled with water. Everything is fine till the water is below the top. You can lift the glass and drink it. But, if the water exceeds the top it is impossible not to spill it. The same goes for histamine. Everything is fine until your body has the ability to work with the histamine that has been stored inside your body. Once the histamine levels exceed your body is comfort zone and your body can no longer use this compound efficiently, histamine intolerance occurs.

But how much is too much…?

Now that we’ve mentioned that your body works fine until the histamine exceeds the levels which your body is comfortable functioning with, I’m sure that you cannot help but wonder what is the standard level. How much histamine do you need to have piled up in your mast cells of basophils.

Generally speaking, it’s considered the functional levels of history in between 0.3 and 1.0 ng/ml (nanograms per millimetre) in the plasma are normal. However, not everyone is built the same way and just because you, for example, have histamine level that is higher than 1ng/ml that doesn’t mean that you necessarily start experiencing symptoms. Some people are better at tolerating excessive histamine levels and others. However, that doesn’t mean that having over 1ng/ml of histamine the body is healthy. Try to keep the levels within the normal range. There’s also other factors at play which can affect how someone can tolerate histamine in conjunction with histamine being within functional ranges.

There are a number of underlying physiological conditions/factors I see regularly working with patients in Functional Medicine Practice that often lead to and/or are contributing to an individual’s histamine intolerance. I’ve listed & expanded on some of them below.

  • Diamine Oxidase (DAO) blocking

As previously discussed earlier, the body first needs to break down the histamine in order for it to be able to travel to the irritation site and do its job. Under normal conditions, the histamine is broken down by two enzymes.

1 – N-Methyltransferase (HMT) which is in charge of breaking down the histamine inside the central nervous system (CNS).

The HNMT pathway metabolises the majority (50-80%) of endogenous histamine and consequently the expression of this cytosolic protein is widespread, including in kidney, liver, spleen, intestinal, spinal cord, placental and ovarian tissues.

Histamine inactivated by this pathway is derived from cellular synthesis or transported from the extracellular space, whereupon it is converted to N-tele-methylhistamine with the addition of a methyl group from S-adenosyl-L-methionine and then to M-methylimidazole acetic acid before leaving the body via the urine.

Across the population, the levels of both HNMT and DAO expression and activity have been observed to exhibit significant inter-individual variability, making the establishment of ‘normal’ levels challenging.

2 – Diamine Oxidase (DAO) which is in charge of breaking down the histamine in the stall intestine.

The latter of the two has definitely received the most attention, since a deficiency or blockage of the DAO enzyme in the body can lead to histamine intolerance. If a person is DAO deficient, there will not be enough of this enzymatic protein to break down the excess histamine levels that are either invested through food or have been stored in the body. Based on my clinical experience, DAO deficiency is the leading cause of histamine intolerance.

Because this pathway inactivates exogenous histamine, DAO is largely expressed and released following a stimulus by intestinal epithelial cells, with a smaller presence in kidney and placental tissues.

The intestinal absorption of histamine is largely inhibited by DAO, while any histamine that is absorbed is deaminated (removal of an amine group) to imidazole acetaldehyde, ammonia and hydrogen peroxide by the intestinal epithelial cells.

If you are wondering what may cause a person to be DAO deficient, or to have a blocked DAO enzyme that essentially inactivates the biochemical pathway for histamine to be cleared from the system, here is some answers…

  • The enzymes can be reduced as a result of underlying gastrointestinal conditions
  • Certain medications cause the blockage of the DAO enzyme
  • Consumption of foods high in amines such as tyramine or histamine promoting foods that cause DAO dysfunction or histamine overload
  • Consumption of foods that block the DAO enzyme
  • Consumption of non-histamine containing foods that have the ability to trigger the release of histamine. When the DAO enzymes are blocked and histamine production is supported indirectly, dysfunction may occur.
  • Immune system dysregulation such as Mast Cell Activation Syndrome (MCAS) which triggers the release of histamine

If you suffer from a certain GI disorder, then chances are it is an underlying cause of your histamine intolerance. The majority of individuals I work with who suffer with an intolerance to histamine have one or more of the following issues:

  • Allergies/immune dysfunction
  • Crohn’s Disease (CD)
  • Inflammatory Bowel Disease (IBS)
  • Intestinal hyper-permeability/Leaky gut
  • Gluten Sensitivity
  • Small intestinal Bacterial Overgrowth (SIBO)
  • Ulcerative Colitis (UC)

When you have an allergic reaction, your body produces more histamine. This means that when you are experiencing an overreaction of your immune system to a particular substance, your body, in order to defend itself, will be forced to frequently request the release of histamine, which will result in a massive production of this compound.

Histamine, ad mentioned earlier, is beneficial during allergy season as it helps the body defend itself, but when you are allergic to something and you expose yourself frequently to that substance (without knowing that you are allergic) you can also cause your histamine levels to become dysregulated, and eventually become intolerant to the substance in question with amplified reactions as a result. In cases like this, identifying the & avoiding the triggers for a number of months is important to allow the immune system to calm & reset, and thus stop the excessive histamine production.

There are also some rare cases, usually when there is a drug, venom, or food allergy, where the entire body is forced to produce an overwhelming amount of histamine which leads to anaphylactic shock, and is mostly life threatening. This is often followed by difficulties in breathing, wheezing, nasal congestion, abdominal pain, coughing, anxiety, panic & a feint pulse.

Another common thing I see in clinical practice that i touched upon earlier that caused histamine intolerance is the building up of the bacteria that is consumed through those foods that cannot be easily digested. The bacteria are known to produce histamine, and since it has disproportionately overgrown, it ends up producing excess histamine. When the body produces more histamine than the enzymes can degrade & clear, you are not only a prime candidate for histamine intolerance but also many different allergies, as well as an array of GI disorders. Let’s not forget that this is an inflammatory response which inflames tissues and creates a favourable environment for pathogenic activity & microbial imbalances.

Believe it or not, many studies indicate that UV light is also among the common cause of histamine intolerance. UV light triggers the release of histamine, and if exposed to frequently, your have an increased chance of becoming histamine intolerant over time.

Stress can also play a role due to the activation of mast cells by stress-induced hormones. The impact of chronic stress on the integrity of the intestinal epithelial lining, adversely influencing the histamine-inactivating capacity of intestinal DAO, is another process potentially contributing to increased levels of circulating histamine.

Many over-the-counter & prescribed pharmaceutical drugs can also cause disruption in histamine balance and block the DAO enzymes. Histamine-associated mechanisms associated with medication include inhibition of DAO activity (muscle relaxants, narcotics, analgesics, local anaesthetics, antihypnotics, antihypertensives, antiarrhythmics, diuretics, antibiotics, antiemetics, bronchodilators, antiseptics, mucolytics, H2-receptor antagonists, antidepressants); stimulation of histamine release (painkillers, antibiotics, anti-hypotensives, anti-hypertensives, antitussives, cytostatics, diuretics, local anaesthetics, muscle relaxants, narcotics) or inactivation of vitamin B6 (antihypertensives, antibiotics, hormonal contraceptives).

Any patient that comes to work with me who is experiencing allergies and has been prescribed or on any of the following medications is functionally assessed for histamine intolerance:

  • Immune modulators
  • Non-Steroidal Anti-inflammatory Drugs (NSAIDS)
  • Anti-depressants and Antipsychotics
  • Antiarrhythmics

When there is an excessive amount of histamine built up in the mast cells, the body is unable to break it down affect deeply, and so, a range of symptoms may appear. It’s worth noting that most of the symptoms on the list below are also symptoms of allergic reactions.

  • Anxiety
  • Abdominal Cramps
  • Acid Reflux
  • Breathing Problems
  • Conjunctivitis
  • Digestive Disturbances
  • Dizziness
  • Fatigue
  • Flushing
  • Headaches or Migraines
  • Hives
  • Hypertension or Hypotension
  • Itching
  • Sinus Problems
  • Sneezing
  • Tachycardia
  • Temperature Dysregulation
  • Tissue Swelling and Inflammation
  • Trouble Falling Asleep/Sleep Issues
  • Vertigo
  • Vomiting

The main complications behind histamine intolerance is when it travels throughout the bloodstream and gets transferred every part of the body. This is extremely useful when we need immediate immune response to defenders from foreign bodies, but not so much when you have piled up histamine. Because of the fact that travels throughout the body, histamine can easily affect the brain, skin, gut, lungs, as well as our entire cardiovascular system. When we pilot histamine the body, this can contribute to the occurrence of some hazardous conditions. If left on treated, histamine intolerance and cause a broad range of complications such as some of the following:

OSTEOPOROSIS

Most of the cells that are in charge of release of histamine extremely important to her bone health. When we have excess histamine levels the cells become unable to function properly and this can further lead to osteoporosis. In fact, many experts suggest that inhibiting the mast cells may actually treat osteoporosis.

BRAIN DEGENERATION

When histamine is pulled up in the brain, they can easily damage the neurons through inflammation or neuro-inflammation. This can lead to brain degeneration and even Parkinson’s disease. A study performed on patients with Parkinson’s disease showed that patients were unable to do great histamine in the brain.

CANCER

Recent studies have found a strong link between excess histamine and cancer. probably the greatest discovery regarding the histamine and cancer link is the fact that melanoma skin cancer is actually stimulated by histamine, based on lab tests.

MULTIPLE SCLEROSIS (MS)

It has been scientifically proven that histamine receptors are indeed involved in the occurrence of multiple sclerosis (MS); something promote the disease, while others inhibit it.

MENIERES DISEASE

Chronic dizziness, hearing loss, and tinnitus appear as a result of this disease of symptoms that can be caused by excessive amount of histamine the body.

DISEASE VULNERABILITY

Histamine has a tendency to increase the penetrability of the barrier of the blood brain barrier (BBB). When you have high histamine levels, they significantly affect the BBB and can leave the door open for mini bacterial infections and other diseases to sleeping. Note that disruption of the BBB contributes to the development of Alzheimer’s disease, MS, epilepsy, and meningitis.

Besides the fact that high levels of histamine can cause certain illnesses to occur, it can also worsen many already pre-existing conditions.

Eczema, medically known as a topic dermatitis, is an inflammatory condition of the skin can be irritating. If you suffer from this condition and you have been experiencing the worst symptoms and severity of your eczema, it may be as a result of being histamine intolerance, which worsens the condition. Studies have shown that the majority of people who are vulnerable to severe allergic reaction is, also known as recurring anaphylactic reactions, most likely victims of histamine intolerance, as well. This combination of severe allergies and histamine intolerance can be severe and life-threatening.

The complexity of histamine intolerance extends to the interaction between histamine, oestrogen and progesterone in the female body.

Mast cells are a key factor underlying these interactions, with the presence of both oestrogen and progesterone receptors on mast cells and mechanistic evidence (in vitro and in vivo) suggesting a regulatory role of these steroid hormones on mast cell functionality and activity. It has also been suggested that mast cell reactivity and histamine concentrations vary between males and females.

The binding of oestrogen to mast cell receptors stimulates the expression of H2 and H3 receptors, and induces rapid histamine degranulation, synthesis and release.

Histamine, within female reproductive tissue, is derived from uterine- and ovarian epithelial and mast cells, and endometrial and myometrial endothelial cells. It can also be derived from monoamine transporters in endometrial tissue, as these have a high affinity for histamine uptake. Oestrogen can also influence endogenous histamine levels by downregulating DAO activity.

The degranulation and activity of histamine appears to fluctuate with menstrual hormonal secretions. During a healthy menstrual cycle, there is a characteristic hormonal pattern involving luteinising hormone (LH), follicle stimulating hormone (FSH), oestrogen and progesterone. Animal data has demonstrated that cellular histamine concentrations in ovarian and uterine mast cells varies across the menstrual cycle, and the activation of mast cells within endometrial tissue is most significant during the premenstrual phase following the decrease in progesterone and oestradiol.

A correlation between urinary histamine metabolites and plasma oestrogen levels in premenopausal women has been observed, as has significant associations between elevated midcycle serum oestradiol levels and skin prick test reactivity to histamine. Also, in healthy reproductive-age women, the application of histamine solution to the nasal mucosa induced a significant localised response, which correlated with peak midcycle oestradiol concentrations, that did not occur during the menstrual or luteal phases when oestrogen levels were significantly lower.

The interaction between histamine and oestrogen is a two-way process, with histamine able to induce dose-dependent oestradiol synthesis by ovarian granulosa cells through H1 activation, thereby having an additive effect on endogenous oestrogen levels.

Overall, this evidence demonstrates that: histamine can stimulate oestrogen production; oestrogen induces mast cell degranulation in female reproductive tissues; and elevated oestrogen levels during the menstrual cycle induces histamine release and may also influence tissue histamine responsiveness.

An association between oestrogen, histamine and progesterone, and also cortisol, further highlights the complexity of the relationship between these hormones in the body.

The interactive and somewhat regulatory relationship between oestrogen and progesterone that occurs during the menstrual cycle can be observed in relation to the effect of progesterone on histamine release. Progesterone has an inhibitory effect on histamine secretion following mast cell binding. However this effect is likely tempered by the regulation of progesterone expression and activity at a genomic level by oestrogen. This may be particularly relevant in women who present clinically with low progesterone and elevated oestrogen, in terms of the histamine-stimulating effect of oestrogen and the physiological impact of high histamine on the body.

The hypothalamic-pituitary-adrenal (HPA) hormonal response to stress results in mast cell degranulation and consequently elevated levels of histamine (i.e. stress à histamine). In the hypothalamus, H1 and oestrogen receptors sit together, so oestrogen can influence hypothalamic H1 receptor activity (i.e. oestrogen à histamine), while histamine can also stimulate cortisol synthesis by adrenal cells. (i.e. histamine à cortisol). Elevated histamine-induced cortisol may inhibit the synthesis of progesterone and oestrogen via the ‘cortisol or progesterone steal’ mechanism, however studies are required to confirm this effect of histamine in humans.

The relationship between oestrogen, progesterone and histamine may contribute to the experience in women with histamine intolerance of menstrual related headaches and dysmenorrhoea, partly due to the inflammatory and contractile effects of histamine.

This interactive association is also demonstrated by hormonal associated fluctuations in asthma severity that is more prevalent in reproductive-aged women. Plasma oestradiol and progesterone concentrations have been shown to correlate with clinical asthma symptoms and bronchial responsiveness, with women often experiencing more frequent and severe asthma symptoms during the preovulatory and premenstrual phases.

It has also been observed that allergies, in which histamine is closely involved, are more prevalent in women with hormonal-imbalance-related conditions such as endometriosis.

Overall it is clear that there is an interconnection in the body between histamine, oestrogen, progesterone and cortisol in regards to systemic functionality. It can also be stated that an endogenous imbalance in these substances can cause or contribute to many reproductive or non-reproductive issues. Further research is required to further clarify the mechanistic connection between histamine, oestrogen, progesterone and cortisol and determine the clinical relevance of this association in specific conditions or pathologies.

Thank you for your attention.

*By Steve Hawes

If histamine intolerance or allergies are one of a number of issues that have been plaguing you for years, and you’re looking for someone with targeted strategies to help identify & address the underlying functional causes which are either behind or contributing to these issues? If so then feel free to book a free 30 minute consult so we can discuss your individual case & see if we are the right fit to work together.