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Category: Hormone imbalance

When addressing a hormone imbalance we are allowing our body to restore normal function in an area controlled by the Autonomic Nervous System. Functions of the body controlled by hormones are:

• menstrual cycle

• reproductive health

• circadian rhythm

• cardiovascular function

• metabolism

• mental health.

When looking into hormone imbalances there are a number of factors we need to take into consideration :

a. ratio between different hormones and metabolites of the same hormone

b. production, signal and breakdown (the entire life cycle) of the hormone

There are 3 areas one can use to assess and monitor hormones: symptoms, laboratory tests, genetic testing. When addressing hormonal imbalances I use a 3-angled approach abbreviated: FOC (Fuel, Oxygenation, Challenge).

Articles in this category:

Cold exposure


histamine intolerance

What helps Histamine Intolerance?

Updated: 28 Jan 2019


Histamine is a hormone involved in digestion, immune & nervous system function. While anti-histamine drugs are often prescribed for asthma, they are also given to those with food allergies.


Anti-histamine drugs can be life-saving in times of crisis. At the same time if one doesn’t deal with what causes the reaction at 1st place she/he is trying to put off a fire by removing the battery from the fire alarm.
Which raises the question “What helps histamine intolerance?”


What is histamine intolerance?

Histamine is a hormone with varying functions in different tissues.

histamine intolerance


Histamine intolerance symptoms are due to histamine’s relation with the immune system. Histamine activates immune cells (basophils & mast cells) while causing blood vessels to dilate so that immune cells can be quickly transferred to kill pathogens. In that sense you can think of histamine as a fire alarm.

“Histamine intolerance is a fire alarm going on when there is no fire.”


To be more precise histamine intolerance results from an imbalance between accumulated histamine and the capacity to break it down. In most cases it is due to limited histamine breakdown capacity. Like all hormones histamine needs to be eliminated from the body when it has done its job. While it is broken down by a few different enzymes (HNMT, NAT1,2 & DAO), it is the DAO (Maintz, L. and Novak, N., 2007) responsible for the breakdown of ingested histamine.

histamine intolerance


Digestion & histamine

Gastrointestinal problems are very common among those with histamine intolerance.

While histamine is necessary for proper gut function excess levels can cause digestive complications. Below are a few facts highlighting the link between histamine intolerance and gut health:

a. all 4 histamine receptors H1R-H4R are found in the digestive tract and they have excitatory actions there (Breunig E. et al., 2007).

b. In a study conducted in Italy, 13 out of 14 subjects (with food intolerances) reported benefits in at least 1 food after DAO supplementation (Manzotti G. et al., 2015).

c. The capacity of both histamine breakdown pathways: HNMT and DAO have been reported to be reduced in those with food intolerances (Kuefner MA et al., 2004).

histamine intolerance

d. Elevated levels of histamine in the brain have been shown to suppress appetite. (Malmlöf, K. et al., 2005)


“Diet can help histamine intolerance in 2 ways: i. reduce the histamine load ii. support histamine breakdown”


Histamine intolerance: foods to avoid

There are 2 categories of foods those with histamine intolerance need to avoid: a. Those that contain histamine & b. those that can cause the release of histamine in the body although they don’t contain histamine (Maintz, L. and Novak, N., 2007)


Histamine intolerance : diet

The fresher the food the lower it is in histamine. Vitamin C supplementation has also been shown to reduce histamine levels (Hemilä, H., 2014).


Blood sugar regulation and histamine intolerance

The link between histamine and diabetes goes back to 1950 (Pini A et al., 2016).

Plasma histamine was shown to reduce after insulin administration in diabetic rats (Hollis T. et al., 1985). Two of the mechanisms through which insulin and histamine interact was that the activation of histamine 3 receptors (H3R) in pancreatic beta cells was shown to: a. inhibit insulin secretion (Nakamura T et al., 2014) b. reduce glucagon production in non-hyperglycemic state (Nakamura T et al., 2015). While the mechanisms of interaction between diabetes and histamine intolerance are currently not clear the correlation appears to be positive (Pini A et al., 2016).

To that extent a state of insulin resistance should be addressed in cases of histamine intolerance together with any other protocol.


Breathing & histamine

Histamine release is involved in seasonal allergies. A recent novel clinical trial (Casale E. et al., 2018) has shown that the inhalation of small dosages of COcan suppress the symptoms of seasonal allergies.


histamine intolerancehistamine intolerance

histamine intolerance COcan suppress histamine release in mast cells by increasing intracellular Calcium levels (Strider J et al., 2011). While no studies so far has tested the use of breathing exercises to suppress seasonal allergies, it is well documented and clinically confirmed that certain breathing exercises can increase the levels of COin the body. Based on that it is well worth considering to use breathwork for histamine intolerance.


How to test for histamine intolerance?

Prior to treating any condition it is wise to diagnose it first. By measuring the levels of DAO enzyme in your blood you can assess your body’s capacity to breakdown histamine. The cut-off level of serum DAO activity (for probable histamine intolerance) is <10 U/mL (Manzotti G. et al., 2015)


Labs that offer this service are:

Smart Nutrition in UK

ImmunoPro in Australia

Dunwoody Labs in US & UK (via Invivo clinical)  – In my opinion the best test for gut integrity currently available.


23andme results & histamine intolerance

23andme results can be useful in identifying potential blockages in the pathway of histamine. At the same time it is dangerous to drive conclusions solely from one’s genetic makeup, let alone one gene. In many cases a person may have no SNPs in the gene that produces the DAO enzyme (AOC1 gene) and at the same time experience histamine-like reactions after the consumption of red wine for instance. The case bellow is such an example.

The woman is in her mid-40s, vegetarian with a more or less healthy lifestyle. She carries only 1 homozygous polymorphism in the AOC1 gene which has been shown to be beneficial.


Source: Opus23


While there seems to be no burden on the production of DAO if you look at the entire pathway you will see that she carries SNPs in the HNMT and MAOB genes. Both of which can tax DAO’s function.


Source: Opus23


How can this information be useful? 

For this woman supporting the function of HNMT and MAOB can help with histamine symptoms. For HNMT methylation support as well Salacia Oblonga (Oda, Y et al., 2015)  can be used while for MAOB vit B2.


Source: Opus23


This Nutrigenomics analysis would not be possible without access to Opus23 analytics.




Breunig, E., Michel, K., Zeller, F., Seidl, S., Weyhern, C.W.H.V. and Schemann, M., 2007. Histamine excites neurones in the human submucous plexus through activation of H1, H2, H3 and H4 receptors. The Journal of physiology583(2), pp.731-742.


Casale, T. B., Onder, R. F., Berkowitz, R. B., & Korenblat, P. E. (2018). Nasal Carbon Dioxide Used As Needed in the Symptomatic Treatment of Seasonal Allergic Rhinitis. The Journal of Allergy and Clinical Immunology: In Practice6(1), 183-189.


Hemilä, H., 2014. The effect of vitamin C on bronchoconstriction and respiratory symptoms caused by exercise: a review and statistical analysis. Allergy, Asthma & Clinical Immunology10(1), p.58.


Hollis, T.M., Kern, J.A., Enea, N.A. and Cosgarea, A.J., 1985. Changes in plasma histamine concentration in the streptozotocin-diabetic rat. Experimental and molecular pathology, 43(1), pp.90-96.


Kuefner, M.A., Schwelberger, H.G., Weidenhiller, M., Hahn, E.G. and Raithel, M., 2004. Both catabolic pathways of histamine via histamine-N-methyltransferase and diamine oxidase are diminished in the colonic mucosa of patients with food allergy. Inflammation Research, 53, pp.S31-S32.


Malmlöf, K., Zaragoza, F., Golozoubova, V., Refsgaard, H.H.F., Cremers, T., Raun, K., Wulff, B.S., Johansen, P.B., Westerink, B. and Rimvall, K., 2005. Influence of a selective histamine H3 receptor antagonist on hypothalamic neural activity, food intake and body weight. International journal of obesity, 29(12), pp.1402-1412.


Manzotti, G., Breda, D., Di Gioacchino, M. and Burastero, S.E., 2015. Serum diamine oxidase activity in patients with histamine intolerance. International journal of immunopathology and pharmacology, p.0394632015617170.
Maintz, L. and Novak, N., 2007. Histamine and histamine intolerance. The American journal of clinical nutrition, 85(5), pp.1185-1196.


Nakamura, T., Yoshikawa, T., Noguchi, N., Sugawara, A., Kasajima, A., Sasano, H. and Yanai, K., 2014. The expression and function of histamine H3 receptors in pancreatic beta cells. British journal of pharmacology, 171(1), pp.171-185.


Nakamura, T., Yoshikawa, T., Naganuma, F., Mohsen, A., Iida, T., Miura, Y., Sugawara, A. and Yanai, K., 2015. Role of histamine H 3 receptor in glucagon-secreting αTC1. 6 cells. FEBS open bio, 5, pp.36-41.


Oda, Y., Ueda, F., Utsuyama, M., Kamei, A., Kakinuma, C., Abe, K. and Hirokawa, K., 2015. Improvement in Human Immune Function with Changes in Intestinal Microbiota by Salacia reticulata Extract Ingestion: A Randomized Placebo-Controlled Trial. PloS one, 10(12), p.e0142909.


Pini, A., Obara, I., Battell, E., Chazot, P.L. and Rosa, A.C., 2016. Histamine in diabetes: is it time to reconsider?. Pharmacological research111, pp.316-324.


Strider, J. W., Masterson, C. G., & Durham, P. L. (2011). Treatment of mast cells with carbon dioxide suppresses degranulation via a novel mechanism involving repression of increased intracellular calcium levels. Allergy66(3), 341-350.



Type 2 Diabetes & Alzheimer's

The link between type 2 diabetes and Alzheimers Disease


The 1st case of Alzheimer’s Disease (AD) was reported in 1906 in Germany [53]. According to Alzheimer’s Association (www.alz.org) as of Oct 2016 there are more than 5 mil. Americans living with AD while in 2017 it is estimated to cost US $274 billion.

Over the last decade there has been a lot of research associating the development of Alzheimer’s Disease with Type 2 Diabetes.

There are 2 ways in which T2D influences the risk of AD:

1. by contributing to small vessel disease. T2D can disrupt the healthy function of brain vasculature and lead to dementia and AD [47]

2. by interacting with key proteins & pathways (such as Aβ and tau), T2D influences the development of AD.

In this article I will discuss the 2nd link.




Alzheimer’s Disease (AD) is a neurodegenerative disease characterised by selective neuronal cell death. Two hallmarks of AD are:

– the intracellular neurofibrillary tangles (NFTs)

– extracellular amyloid deposits forming senile plaques.

The accumulation of neurotoxin amyloid β peptide (Aβ) in the hippocampus and cerebral cortex appears to be a major pathological step in the progression of AD [1, 10]. Based on the tau hypothesis excess phosphorylation of tau proteins result in the transformation of normal tau proteins to NFTs.


Diabetes mellitus is a metabolic disorder characterised by hyperglycaemia. In type 2 diabetes (T2D) the main effect is insulin resistance causing relative insulin deficiency. Pancreatic β-cells co-secrete insulin and amylin (also known as islet amyloid polypeptide IAPP). One of the hallmarks of T2D is:

– β-cell loss [11] due to amyloid deposits (composed primarily of amylin) [2].

Similar with AD in T2D degeneration of pancreatic islets has been associated with NFTs formation [12].




Both Aβ peptide and insulin are amyloidogenic peptides sharing a common sequence recognition motif. Together with other amyloidogenic proteins (i.e. glucagon and amylin) they are degraded by Insulin Degrading Enzyme (IDE)* [3, 13]. IDE highest expression is in the liver, testes, muscles and brain [4]. Aβ is also broken down through Neprilysin (NEP) [5].

Both Aβ peptide and insulin compete with each other not only for their degeneration through IDE but also for binding to insulin receptors [6].

Insulin plays a key role in the healthy metabolism of Aβ peptides. It up regulates the transport of AβPP/Aβ from trans-Golgi to cellular membrane [13] promoting the transport of Aβ outside the cell [13] and has been shown through different mechanisms to contribute to the increase of extracellular Aβ levels and decrease of intracellular Aβ levels [13].

As I will discuss later insulin seems to counteract many of the toxic effects of Aβ in the mitochondria.


In the only study so far that measured insulin levels in the brain** it was shown that insulin reduces with age in both healthy subjects and patients with AD [8] indicating that low brain insulin is not a direct cause of AD pathology. On the other hand though there is consistency in the findings of insulin resistance in AD patients [49].


The following mechanism has been speculated to contribute to that:

1. IDE expression decreases with aging [7] reducing the breakdown capacity of Aβ peptides; leading to higher intracellular Aβ levels.

2. Sequentially the relatively higher levels of Aβ 1-40 & Aβ 1-42 peptides by binding on insulin receptors reduce insulin’s binding capacity and promote insulin resistance [5].

The fact that insulin resistance is not specific to insulin in AD brain is supported by the fact that both insulin-like growth factor (IGF) I & II (50,51) and lectin (52) are reported to be lower.

Type 2 Diabetes & Alzheimer's



Insulin also regulates the phosphorylation of tau proteins with insulin resistance been shown to cause [14] tau hyper-phosphorylation [15] and the formation of NFTs.

Type 2 Diabetes & Alzheimer's



In areas of the brain with high glucose demand and insulin resistance, AD patients have been shown to have compromised glucose metabolism [16]. 44% reduction in cerebral glucose metabolism has been reported in the early onset of AD [5].

Hypo metabolism of glucose leads to:

A. the inhibition of glutamine synthase, creatine kinase, aconitase, pyruvate dehydrogenase & α-ketoglutarate dehydrogenase [17,18,19] Sequentially the lower levels of pyruvate dehydrogenase lead to lower levels of acetyl-CoA, the compromised production of acetylcholine [20] and the decreased formation of intracellular cholesterol [21] (which is necessary for normal cell function).

B. reduced ATP production. In sporadic AD patients*** there is a 50% ATP decrease at the beginning of the disease [22]. Reduced ATP production leads to the activation of erk36 & erk40 [23] and subsequently tau hyperphosphorylation [24].

Glucose hypometabolism of early-onset AD was shown to be much more severe than in late-onset patients [25].

Type 2 Diabetes & Alzheimer's



Aβ42 protein was shown to inhibit cytochrome oxidase in human mitochondria in a dose depended manner [26]. The effect was dependent on the presence of Cu2+. Studies in cybrid cells demonstrated a deficit of cytochrome oxidase in AD platelets as well as impaired intracellular calcium buffering and elevated basal cytosolic calcium concentration in AD [27,28]

Mitochondria serve as a high capacity Ca2+ sinks, supporting cellular Ca2+ homeostasis [33]. Excess Ca2+ uptake in the mitochondria has been shown to [34, 35, 36]:

1. Increase ROS production

2. inhibit ATP synthesis

3. release cytochrome c

4. induce mitochondrial permeability transition (MPT)****

Type 2 Diabetes & Alzheimer's

The maintenance of Ca2+ homeostasis represents a major expenditure within neutrons [40]. In high oxidative stress there is an increase in cytoplasmatic Ca2+ [37].  MTP is enhanced by increased Ca2+, oxidative stress, and low membrane potential, while Mg2+, ADP, high membrane potential [38, 39], CoQ10, vitamin E, reduced glutathione, melatonin and nicotine oppose that effect [41, 42].

Diabetes decreases the capacity of mitochondria to accumulate Ca2+ thus leading to MPT opening [31, 32]

Type 2 Diabetes & Alzheimer's



Insulin has been shown to support mitochondrial function in skeletal muscles [43]. It seems to impact the function of neuronal mitochondria in multiple ways [40]:

1. prevents the depolarization of mitochondrial inner membrane [44]

2. increases CoQ9 antioxidant  [44]

3. modulates glutathione redox cycle [127]

4. increases the capacity of mitochondria to accumulate Ca2+ [40]

5. promotes clearance of Aβ [13]

Type 2 Diabetes & Alzheimer's

“ Although insulin does not affect basal mitochondria function, in the presence of Aβ  insulin prevents a drastic decline in mitochondrial OXPHOS efficiency and avoids an increase in the oxidative stress, improving and/or preserving the function of neurons under adverse conditions.” [40]



While genetics indisputably play a role in the development of AD; with 50% of patients being carriers of the APOE4 gene [1], there is enough research showing the link between T2D and AD. Non-APOE4 carriers have 535% (1.4 -> 7.5%) more chances of developing AD if their fasting blood insulin is > 89.4 pmol/l [54, 55].

The relationship between T2D and AD is intricate though if you consider the following:

1. One of the hallmarks of T2D is insulin resistance causing elevated insulin levels.

2. One of the hallmarks of AD is elevated Αβ peptides.

3. Insulin counteracts many of the toxic effects of the Aβ peptides in the brain of patients with AD.

3. Aβ peptides appear to contribute to the development of insulin resistance independent of insulin’s action, by binding on insulin receptors.

AD -> high Aβ peptides -> Insulin Resistance / T2D -> elevated insulin -> Protect from Aβ toxicity

Could T2D be a defense mechanism against the brain’s degeneration in AD?

Type 2 Diabetes & Alzheimer's


* IDE is a zinc-metallopeptidase. It is also known as insulysin.

** It is not clear if insulin is produced in the brain or transferred there through the bloodstream [48]

*** Sporadic AD are the patients without a genetic predisposition to develop AD

**** The mitochondrial permeability transition (MPT) is the sudden increase of inner mitochondrial membrane permeability to solutes with a molecular mass less than 1500 Da [29,30]



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27. Davis RE, Miller S, Hermstadt C, Ghosh SS, Fahy E, Shinobu LA, et al. Mutations in mitochondrial cytochrome c oxidase genes segregate with late-onset Alzheimer’s disease. Proc Natl Acad Sci U S A 1997;94:4526–31

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43. Stump CS, Short KR, Bigelow ML, Schimke JM, Nair KS. Effect of insulin on human skeletal muscle mitochondrial ATP production, protein synthesis, and mRNA transcripts. Proc Natl Acad Sci U S A 2003;100:7996–8001.

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50. Steen, E., B.M. Terry, E.J. Rivera, J.L. Cannon, T.R. Neely, R. Tavares, X.J. Xu, J.R. Wands, and S.M. de la Monte. 2005. Impaired insulin and insulin-like growth factor expression and signaling mechanisms in Alzheimer’s disease–is this type 3 diabetes? J. Alzheimers Dis. 7:63–80.

51. Moloney, A.M., R.J. Griffin, S. Timmons, R. O’Connor, R. Ravid, and C. O’Neill. 2010. Defects in IGF-1 receptor, insulin receptor and IRS-1/2 in Alzheimer’s disease indicate possible resistance to IGF-1 and insulin signalling. Neurobiol. Aging. 31:224–243. doi:10.1016/j.neurobiolaging.2008.04.002

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55. Kuusisto, J., Koivisto, K., Mykkänen, L., Helkala, E.L., Vanhanen, M., Hänninen, T., Kervinen, K., Kesäniemi, Y.A., Riekkinen, P.J. and Laakso, M., 1997. Association between features of the insulin resistance syndrome and Alzheimer’s disease independently of apolipoprotein E4 phenotype: cross sectional population based study. Bmj, 315(7115), pp.1045-1049.


Is my erectile dysfunction linked to stress?

Updated: 17 April 2017

“ Is my erectile dysfunction linked to stress ?” is a question most men would intuitively answer yes. To understand how chronic stress interferes with the reproductive system let’s look at the 4 stages of erection:

Non-excitable stage: Adrenaline (a stress neurotransmitter) is keeping the arteries in the penis constricted preventing blood from flowing.



Excitement-stimulation: The activation of the parasympathetic nervous system (NS) allows the flow of blood into the veins. Nitric Oxide accommodates the dilation of the arteries in the area. Viagra promotes the production of NO.




Ejaculation/orgasm: A shift of the NS into sympathetic causes the release of adrenaline -> the constriction of the arteries in the penis -> the ejaculation.



Loss of erection/refractory phase: The adrenaline keeps the arteries constricted and smooth muscle contracted while endorphins produce a feeling of well being! This stage can last from minutes to days.




Chronic stress causes the adrenals to be constantly switched on. The body’s inability to swift to a relaxed (parasympathetic) state, can cause lack of arousal and inability to maintain an erection. While the body’s inability to shift to an alert (sympathetic) state, such as when someone is drunk, can cause inability to ejaculate. Erectile Dysfunction ED is linked with Cardio Vascular Disease and exhausted adrenals are one of the links.


How can you tell if one suffers from erectile dysfunction?

There are no standards on how quickly one should ejaculate or how long his refractory phase last.

“ It is like athletics, there are sprinters and marathon runners!” ~ Dr Ronald Virag


How can you support an Erectile Function?

  1. Support your adrenals with a diet low in Glycemic Load.
  2. Supplements that support adrenal function are: Pantothenic acid (vitamin B5), Ascorbic acid (vitamin C), Niacin (vitamin B3), Zinc, and Magnesium.
  3. Use adaptogens wisely (i.e. Ashwagandha & Licorice root)
  4. Off-load stress-inducing activities.



Erectile Dysfunction is very often linked with a compromised cardiovascular function. Doing a comprehensive cardiovascular tests (such as the one offered by Genova Diagnostics) can be life-saving.

5 ways to heal ulcers caused by stress.

Those of you that have visited a GP for stomach pain might be familiar with the following diagnosis: “Stomach ulcers caused by stress.”


Ulcer & Stress might not be a love at first sight but definitely have a strong friendship.


How many of you are not familiar with stomach aches in periods of stress? Despite how common the disease is, it’s only partially understood and the common treatments not a guarantee for relief from symptoms.


Based on the current theories (on what causes ulcer) below I am suggesting a series of approaches to alleviate the symptoms:


1 Acid rebound

Healthy digestion depends on the normal transport of food, through the digestive tract. Acid rebound occurs when hydrochloric acid is produced in the stomach, while food is not there. To support hydrochloric acid’s function you can drink a glass of water with apple cider or lemon prior to eating, especially if the meal includes animal protein. This way you can help your digestion.


Supporting acid rebound is most relevant for: Vegetarians & vegans are more likely to have issues with hydrochloric acid production, thus apple cider and lemon might be a useful strategy for those following this diet.


2 Decreased blood flow

Circulation of blood in the stomach muscles is restricted when stressed, making the formation of micro ulcers more likely to occur. Give yourself some time to calm down before eating. Try to avoid eating soon after or while feeling stressed.


Supporting decreased blood flow is most relevant for: Those with poor circulation (ie. cold feet/ hands, athlete’s foot) are more likely to experience restriction of blood supply to their stomach when stressed. Become aware of when you are stressed by following your breath or checking your Heart Rate.


3 Immune suppression

When the pH of the stomach is higher than the naturally low levels, it gives the opportunity to bacteria Helicobacter pylori to multiply. If you test positive for H. pylori and have symptoms of acid reflux you can supplement with antibacterial supplements alongside nutrients that support the immune system (incl. Zinc, Pantothenic Acid, and vitamin C, D) to fight the pathogen.


Supporting immune suppression is most relevant for: Those that get often sick are more likely to have a suppressed immune system which will allow the development of H. Pylori. You can support your immune system in multiple ways, including supplementation & cold exposure.


4 Insufficient amount of Prostaglandins

Prostaglandins are hormones helping the repair of wounds like ulcer. Testing for your levels of Prostaglandins is possible but unfortunately not widely available or cheap. Minimize the use of NSAIDs & aspirin while, consume a diet with an adequate amount of Essential Fatty Acids.


Supporting the function of prostaglandins is most relevant for: Those that demonstrate deficiency of Essential Fatty Acids are likely to have poor hair, skin health & hormone imbalances. Evening primrose oil and Omega 3s are important for “healthy” Prostaglandins.


5 Stomach muscle contractions

Calming exercises and balanced thoughts can activate your parasympathetic system and allow the stomach muscles to regain their regular function.


Supporting the function of stomach muscle contractions is most relevant for: those with poor abdominal muscle tone. Yoga offers many abdominal exercises to support abdominal muscle peristalisis.



Whether ulcers manifest in the stomach or the intestines in most cases the trouble started in the stomach! Stress is synonymous with life and to assume it will disappear together with your symptoms of ulcer is highly unlikely. Adopting the 5 above steps is likely to resolve the problem if you haven’t been dealing with ulcer caused from stress for a long period. If you are on proton pump inhibitors or chronically suffering with stomach pain here are 3 more areas to address :

• food allergens

• food timing

• weight management



For an entertaining read on the topic you can read: Why Zebras don’t get ulcers by Robert M. Sapolsky