Main Hormones involved in stress and homeostasis regulation:

• Cortisol

• Serotonin, also known as 5-HT

• Corticotropin-releasing hormone (CRH)

• Adrenocorticotrophic hormone (ACTH)

• Erythropoietin (EPO)

• Hypoxia-inducible factor (HIF) including HIF-1α, HIF-2α and ARNT

• Epinephrine and Norepinephrine

 

EXPLAINED:

Activation to stressful stimuli is controlled by a small collection of parvocellular neurons located in the PVN of the hypothalamus. Upon such stimulation, “these neurons release neural factors, such as CRH and AVP, into the hypophyseal portal circulation”v, which is a group of blood vessels connecting the hypothalamus to the anterior pituitary. When this occurs, the factors can pass into the anterior pituitary causing a release of ACTH into the systemic circulation, triggering the adrenal cortex to synthesize and secrete glucocorticoids. Simultaneously, with glucocorticoids and serotonin regulating the HPA-axis via the PVN, the CRH and LC/NE systems stimulate arousal and attention, noting that CRH, via somatostatin, suppresses reproductive, growth, and thyroid functions via inhibiting GH, TRH and TSH, and 5' deiodinase.

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• FIGHT RESPONSE: Feeling confident that you can overcome the trigger by facing it and fighting it.

• FLIGHT RESPONSE: Perceiving the trigger as too difficult to fight but feeling confident that you can safely escape it.

• FREEZE RESPONSE: The stimulus can neither be defeated, or safely escaped from, leaving you paralyzed in fear[i]. Can be described as being “overwhelmed” by the trigger.

 

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ALTERED BREATHING PATTERNS:

PICTURE: more related to breathing patterns to change the one above

Enterochromaffin Cells (ECs) monitor low circulating levels of oxygen, initiating aspects of the SWI/SNF (SWItch/Sucrose Non-Fermentable) to be recruited to a HIF-1α (Hypoxia-Inducible Factor-1 alpha) target, increasing the number of REPC (Renal EPO-Producing Cells), and thus, increasing EPO (Erythropoietin) levels.

Circa 90% of EPO is produced in the kidney, with circa 10% produced in the liver (vice versa during fetal gestation)[ii], and is the leading regulator of red cell production, promoting their development and initiating the synthesis of haemoglobin[iii]. So, there is a reason why the Adrenal Cortex can be found on the kidney and not the brain!) REPC are predominantly found in the renal cortex, particularly the juxtamedullary region, and outer medulla[iv].

 

Successfully Overcoming the Trigger

Homeostasis returns to normal, noting the bigger perception of threat and duration of stress can impact future responses.

 

Unsuccessfully Overcoming the Trigger/Chronic Stress

PICTURE

Chiang et al. (2013)[v] found that the pathogenetic alteration of hypoxia depends on the interactive signals of both the HIF and the endoplasmic reticulum (ER) in the liver and kidneys via the unfolded protein response (UPR). The UPR being the ERs response to cellular stress, activating a surge of signals to maintain homeostasis, of which “failure to regain homeostasis causes the UPR to activate cell death pathways”[vi].

Increased circulatory cortisol levels influences Glucocorticoid Recepter (GR) binding and relatively recently it has been found that glucocorticoids produce feed-forward mechanisms at the amygdala during the stress responsev[vii], providing the potential for a ‘fast nongenomic feedback system’. Serotonin can also take a hit with stress induced serotonin dysfunction being linked to conditions such as PTSD, Depression, and Fibromyalgia.

 

Furthermore, Tank and Lee Wong (2015)[viii] explain Epinephrine and Norepinephrine’s roles perfectly:

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“Physical challenges, emotional arousal, increased physical activity, or changes in the environment can evoke stress, requiring altered activity of visceral organs, glands, and smooth muscles. These alterations are necessary for the organism to function appropriately under these abnormal conditions and to restore homeostasis. These changes in activity comprise the "fight-or-flight" response and must occur rapidly or the organism may not survive. The rapid responses [include the] catecholamines, epinephrine, and norepinephrine, secreted from the adrenal medulla. The catecholamine neurohormones interact with adrenergic receptors present on cell membranes of all visceral organs and smooth muscles, leading to activation of signalling pathways and consequent alterations in organ function and smooth muscle tone.

During the "fight-or-flight response," the rise in circulating epinephrine and norepinephrine from the adrenal medulla and norepinephrine secreted from sympathetic nerve terminals cause increased blood pressure and cardiac output, relaxation of bronchial, intestinal and many other smooth muscles, mydriasis, and metabolic changes that increase levels of blood glucose and free fatty acids. Circulating catecholamines can also alter memory via effects on afferent sensory nerves impacting central nervous system function.

While these rapid responses may be necessary for survival, sustained elevation of circulating catecholamines for prolonged periods of time can also produce pathological conditions, such as cardiac hypertrophy and heart failure, hypertension, and posttraumatic stress disorder. In this review, we discuss the present knowledge of the effects of circulating catecholamines on peripheral organs and tissues, as well as on memory in the brain.”ii

FLOW CHARD OF EP AND NOREP ROLES

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Absorbing all of this information may take some time, but there is one thing it makes clear, you should address any chronic stress and that there are a plethora of ways to do this, with research constantly discovering more as mental health becomes increasingly more important. Section 5 which covers ‘Breathing Patterns’ will offer you a simple and easily accessible way in which to hack your stress and symptoms of oxidative stress – and whilst this platform may involve some cost, this hack involves tools you already have in your body meaning you can do it anywhere at any time!!! A hint: it’s your diaphragm! There is a lot more to it than that though… if it were that simple, everyone would know and be doing it already.

 

For anyone interested, here is a paper published in 2012 which has been cited over 1800 times, so I highly recommend the read:

Semenza, G. L. (2012). Hypoxia-inducible factors in physiology and medicine. Cell, 148(3), 399-408.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3437543/

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[i] Seltzer, “Trauma and the Freeze Response: Good, Bad, or Both” [online]

[ii] Noguchi, C. T. (2008). Where the Epo cells are. Blood, The Journal of the American Society of Hematology, 111(10), 4836-4837.

[iii] Siamak N Nabili. Erythropoietin (EPO, The EPO Test), https://www.medicinenet.com/erythropoietin/article.htm

[iv] Haase, V. H. (2013). Mechanisms of hypoxia responses in renal tissue. Journal of the american society of nephrology, 24(4), 537-541.

[v] Chiang, C. K., Nangaku, M., Tanaka, T., Iwawaki, T., & Inagi, R. (2013). Endoplasmic reticulum stress signal impairs erythropoietin production: a role for ATF4. American Journal of Physiology-Cell Physiology, 304(4), C342-C353.

[vi] Bravo, R., Parra, V., Gatica, D., Rodriguez, A. E., Torrealba, N., Paredes, F., ... & Quest, A. F. (2013). Endoplasmic reticulum and the unfolded protein response: dynamics and metabolic integration. In International review of cell and molecular biology (Vol. 301, pp. 215-290). Academic Press.

[vii] Geuze, E., van Wingen, G. A., van Zuiden, M., Rademaker, A. R., Vermetten, E., Kavelaars, A., ... & Heijnen, C. J. (2012). Glucocorticoid receptor number predicts increase in amygdala activity after severe stress. Psychoneuroendocrinology, 37(11), 1837-1844.

[viii] William Tank, A., & Lee Wong, D. (2011). Peripheral and central effects of circulating catecholamines. Comprehensive Physiology, 5(1), 1-15. https://www.ncbi.nlm.nih.gov/pubmed/25589262