Stress has become a synonymous, integral even, accompaniment of life in our fast-paced world. Generally regarded as "distress," our bodies struggle to re-establish physiological integrity at certain times, such as after working long hours, or when we have insufficient exercise, sleep and nutrition. Driven by persistent exposure to stressors, the body begins to lose its dynamic resilience and fails to return the system to a normal baseline healthy state. Derailed and overwhelmed, our susceptibility to stress-related diseases is greatly increased [1].

The Building Blocks of the Stress Response

Helping us react to a perceived threat, stress is a sophisticated defense mechanism that prepares the body for action. At the most fundamental level are the HPA axis and the sympathetic neurons that originate in the brainstem and project to the adrenal glands [2]. Regulating the "fight or flight" response under conditions of acute stress, the sympathetic nervous system signals the adrenals to release epinephrine and norepinephrine. 

Circulating epinephrine is derived 100% from the adrenal glands. Approximately 20% of circulating norepinephrine is produced by adrenals and the rest (80%) by sympathetic nerves [3]. When produced by the adrenal glands, the epinephrine/norepinephrine response is hormonal in nature as opposed to a neural one, which is why these neurotransmitters are sometimes called hormones. 

The Inverted "U" Response

Together with cortisol, the catecholamines norepinephrine and epinephrine help the body respond to internal and external stressors in an adequate manner. Rhythmic secretions of cortisol, norepinephrine and epinephrine help tune our internal clocks to the immediate environment. In general, the levels of these stress hormones are low at night when we sleep and rise during the day to adjust the body’s response to stressors accordingly. Specifically, the fluctuations throughout the day observed with norepinephrine and epinephrine show a distinct fingerprint compared to cortisol’s diurnal pattern. Under basal conditions of little to no stress, norepinephrine and epinephrine levels are low, increase towards mid-morning, peak in the afternoon, and decrease by bedtime with low levels during the night – taking the shape of an inverted "U." This diurnal rhythmicity is critical when evaluating the performance of the stress system in a clinical setting.  Any alterations in the typical diurnal pattern may indicate a dysregulation of the HPA axis.

"Fight or Flight"

Sympathetic activation is synonymous with the "fight or flight" response. Think of the "butterflies in the stomach" sensation when giving a speech in front a large audience. It’s the exact same system that allowed our predecessors to escape the saber-toothed tiger that is now helping us cope with the stressors of the modern world. Norepinephrine and epinephrine are at the heart of this response. The release of these molecules into the bloodstream as part of sympathetic activation is immediate, short-term and reflexive. Rising heart rate, escalating blood pressure, increasing respiration rate and activation of sweat secretion are sure signs that the body is bathed with enough norepinephrine and epinephrine to prepare us for action.

This system, however, is only intended for acute situations of immediate threat. If the stressors persist, for example when providing care for a chronically ill family member, this results in sustained and prolonged activation over time, which keeps the body in constant long-term distress.  

Normally, norepinephrine and epinephrine signal for increased cortisol production – the "second responder" or long-term stress modulator. Cortisol (the “second responder”) secreted from the adrenal cortex as a product of HPA axis activation, in turn modulates the activity and expression of genes that code for the enzymes involved in the synthesis of norepinephrine and epinephrine (the "first responders") [4]. So over time, if norepinephrine and epinephrine levels are chronically high, cortisol levels will be consistently elevated as well, establishing a stress loop with diminished capacity to self-regulate. And with that, these stress hormones will suppress the actions of estrogens, androgens, thyroid, insulin hormones and their receptors – all the necessary components to health and wellbeing. In other words, with a dysregulated stress system, the ability to regain homeostasis plummets and increased susceptibility to disease arises, including cardiovascular disease, senile dementia, diabetes, osteoporosis, etc. [5].   

Variation from the Inverted “U”

Abnormal patterns in diurnal norepinephrine and epinephrine are reported in conditions that affect sleep [6], blood sugar regulation [7], and high blood pressure [8]. A number of patients tested at ZRT Laboratory with dysregulated norepinephrine and epinephrine rhythms report symptoms of anxiety, mood swings, morning and/or evening fatigue, and irritability.

The Ease of Collection in Dried Urine

The diurnal norepinephrine and epinephrine test at ZRT is a simple and convenient way to analyze circadian fluctuations of the stress response system. Four separate urine samples dried on filter cards at specific time points during the day (first void of the morning, second void about 2 hours after waking, early evening, and bedtime) are used to circumvent the inconvenience of handling liquid urine. This collection method ensures ease of sample collection and stability of the sample during shipping and handling.

Final Thoughts

Evaluating the diurnal rhythms of epinephrine and norepinephrine, along with the circadian rhythm of cortisol, may help identify specific imbalances in an individual’s response to stress, and how the body adjusts sympathetic nervous system parameters accordingly. Across a lifespan, the continued ability to respond to stress appropriately is a critical component to maintaining optimal health.

Related Content

• Blog: The Cortisol Awakening Response in Assessing Adrenal Function
• Blog: Is it Adrenal Fatigue? Reassessing the Nomenclature of HPA Axis Dysfunction.
• Blog: How Stress Caused My Cancer 

References

[1] Chrousos GP: Stress and disorders of the stress system. Nat Rev Endocrinol 2009;5:374-381.

[2] Thomas G.Guilliams PhD: The Role of Stress and the HPA Axis in Chronic Disease Management. The Standard Road Map Series, 2015.

[3] Fitzgerald PA, Goldfiend A: Adrenal Medulla; in Greenspan FS, Gardner DG, (eds): Basic and Clinical Endocrinology. Lange Medical Books/McGraw-Hill Medical Publishing Division, 2004.

[4] Tank AW, Lee WD: Peripheral and central effects of circulating catecholamines. Compr Physiol 2015;5:1-15.

[5] Bale TL, Epperson CN: Sex differences and stress across the lifespan. Nat Neurosci 2015;18:1413-1420.

[6] Stephen C.Gangemi DD: Identifying and Correcting Sleep Disturbances Related to Nocturnal Glucose Regulation.; 2011.

[7] Rao R: Hypothalamic-Pituitary-Adrenal Axis Programming after Recurrent Hypoglycemia during Development. J Clin Med 2015;4:1729-1740.

[8] James GD, Alfarano AS, van Berge-Landry HM: Differential circadian catecholamine and cortisol responses between healthy women with and without a parental history of hypertension. Am J Hum Biol 2014;26:753-759.