Stress, like inflammation, is a natural response. We need stress to function on a normal basis.  So, when the question arises, “Are you stressed?” the answer is yes, but what is happening is complex. Indeed, this physical adaptation is modulated by the HPA- axis, and even if the physical response is an orchestrated cascade reaction, the triggers can be varied.

Stress is defined as a state of a real or perceived threat to homeostasis. Indeed, when the balance of our body is threatened, and activation of several responses occur. This response is the combination of complex reactions modulated by the endocrine, nervous and immune systems. Nevertheless, the stress response has the only purpose of maintaining the stressed individual alive.

Stress response:
§  increased awareness.

§  improved condition.

§  euphoria.

§  enhanced analgesia.

Physiological adaptations:
§  increased cardiovascular tone.

§  high respiratory rate.

§  inhibition of feeding and digesting.

§  growth.

§  reproduction.

§  immunity.

HPA-axis and stress response:

The hypothalamic-pituitary-adrenal axis (HPA-axis) is how we commonly call the interaction between the paraventricular nucleus (PVN) located in the hypothalamus, the anterior lobe of the pituitary gland, and finally, the adrenal glands located over the kidneys. Besides, other structures like the brain stem noradrenergic neurons, sympathetic adrenomedullary circuits, and parasympathetic systems.

Nevertheless, the stress cascade’s first trigger is a corticotropin-releasing factor (CRF), secreted by the PVN’s hypophysiotropic neurons. Afterward, CFR travels through the hypophysial portal vessels that lead to the anterior pituitary gland. In this site, CFR binds to its receptor on the pituitary corticotropes and releases adrenocorticotropic hormone (ACTH) and then gets released into the systemic circulation.

Once ACTH reaches the adrenal cortex, the synthesis and release of glucocorticoids these glucocorticoids are the starters of the downstream effects controlled by the HPA-axis. Finally, the homeostasis returns with a negative feedback loop of cortisol that inhibits CFR release. Nevertheless, the unbalanced regulation of HPA effects is linked to the development of physiopathology.


When we talk about glucocorticoids, we refer to cortisol in humans and corticosterone in rodents. As estrogen, cortisol is considered a hormone, and cortisol receptor is widely distributed in our body. Therefore, cortisol regulates metabolism, cardiovascular processes, as well as the immune system and behavioral processes.

General adaptation syndrome:


First described by Hans Selye in 1930, the general adaptation syndrome is described as the manifestation of stress in the whole body, as developed over time. Once a stressor, considered either good or bad, starts the stress cascade, the body initiates an alarm reaction.

Alarm reaction: Selye
§  gluconeogenesis.

§  decreased insulin sensitivity.

§  amino acid mobilization.

§  protein catabolism.

§  mobilization of free fatty acids from the adipose tissue.

§  decreased phagocytosis.

§  decreased white blood cell migration.

§  decreased lymphocyte production.

§  increased red blood-cell production.

 Levels of resistance:

Alarm reaction: body’s defenses are low.

Stage of resistance: on a chronic state of alarm, defenses are elevated.

Stage of exhaustion: the cortisol feedback receptors in the hippocampus become desensitized and damaged. Afterward, the defenses get depleted and reduced.

Symptoms of adrenal dysfunction:
Afternoon low between 3-4 PM

Cognitive dysfunction Confusion

Decreased libido Decreased memory recall Decreased productivity

Decreased tolerance

Depressed mood

Difficulty concentrating

Fatigue not relieved by rest

Feeling better after eating.

Increased effort to do every day


Craving salt or sugar
Dark circles under eyes Decreased ability to handle stress.Difficulty getting up in the morning tasks.Increased fears
Elevated recovery timeExacerbated symptoms with skipped meals

Orthostatic hypotension

Pre-menstrual tension

How to treat adrenal dysfunction:


Test don’t guess. Indeed, that is the rule; what we are looking for are high cortisol levels at times where they should be low. For example, we want cortisol to be released in the morning, to feel awake, and go on with our morning routine. On the other hand, cortisol levels should remain low when we get prepared to sleep and have a relaxing night sleep.

Ironically, blood tests for CRH, ACTH stimulation can induce a cortisol upregulation. Nevertheless, salivary cortisol tests are available and have similar results compared to plasma-cortisol levels. A cortisol salivary test can be sufficient to assess HPA-axis status.

Lifestyle modifications:


Cortisol can influence glucose levels the same way hypoglycemia can induce cortisol release. Indeed, the alarm reaction caused by cortisol release induces gluconeogenesis, protein catabolism, and amino acid mobilization. On the other hand, we skip a meal and present a hypoglycemia state. Our body responds to it as a “stress” signal. This induces the release of cortisol, which in chronic stress condition will raise blood glucose levels.


Also, caffeine should be avoided in patients who are under chronic stress. Caffeine is a stimulant of the central nervous system, and additionally, it amplifies cortisol production that could last several hours after drinking it.

Stress-relieving techniques can lower cortisol levels, as well as exercise. In fact, exercise is considered a stressor and releases cortisol, but constant exercise has been shown to induce a cortisol receptor sensitivity factor. Also, the stress signal induced by exercise is less-inflammatory than the immune-stress response.

Nutraceutics and adrenal dysfunction:


Eleutherococcus senticosus: (Siberian ginseng) antistress, antifatigue, and immunomodulatory properties.

Ginkgo biloba: used in the Chinese culture to aid short-term memory loss and vertigo. It is linked to have anti-stress properties and a potent antioxidant.

Ocimum sanctum: Borrowed from Ayurvedic medicine, it reduces the levels of cortisol.

Panax ginseng: It contains polysaccharides, flavonoids, and it is the most antistress adaptogen.

Nutrigenomics and SNP Care Plan Dynamics

A sound mind in a sound body

As part of your care plans with our office, we offer DNA testing to better aid in your treatment protocols.

According to our research, neuropsychiatric disorders account for up to 25% of all disability-adjusted life years. Whilst the heritability of these mental disorders is significant, environmental factors also factor in their development. To that point, genetic variations involved in key biological processes that contribute toward the risk of development of mental health disorders may give insights into the prevention, diagnosis, and treatment of the disease.


Anderson, D. “Assessment and nutraceutical management of stress-induced adrenal dysfunction.” Integrative Medicine 7.5 (2008): 18-25.

Smith, Sean M., and Wylie W. Vale. “The role of the hypothalamic-pituitary-adrenal axis in neuroendocrine responses to stress.” Dialogues Clin Neurosci 8 (2006): 383-395.

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