Hormones - conducting the symphony of life

Hormones - conducting the symphony of life.

Have you ever googled “how many cells are in the human body” and found answers ranging from 40 trillion to 100 trillion? In truth, we have never known exactly the number of cells in the human body but according to a research article published in the Journal of Cell Biology in 2023, scientists have now calculated that males have on average 36 trillion cells and females on average 28 trillion cells in their body. This is quite a way from the 100 trillion suggested historically, but still a rather mind-blowing number of cells. Given life on this planet started out as single cells organisms it has taken quite some intelligent evolution to get here.

Our existence depends on our ability to coordinate the functioning of all these cells so they can work in synergy to maintain optimal conditions for life. Hormones are key players in this network of communication where they function as messenger molecules to deliver information from one part of the body to another (endocrine) or from one cell to another (paracrine) or even within the cell itself (autocrine). Hormones also influence each other and link together our psychology and physiology. They are the sole group of substances that provide adaptogenic capacity. Health equals our ability to adapt, in perfect time, to constant changes in our inner and outer environment. Hence, it is not difficult to imagine how things can quickly spiral out of control when there is a disruption in the production of, or the signalling of, hormones.

We secrete and circulate around 50 different hormones, primarily from eight major glands distributed throughout the body and still more hormones are being discovered, the most recent, called ‘fabkin’ in 2021. In this blog we will focus on just one of these many hormones, namely cortisol and the specific role cortisol plays in guiding the inflammatory response to resolution.
Cortisol – a key player in the resolution of inflammation
It is well accepted that low grade chronic inflammation lies at the root of most, if not all, chronic health conditions and the process of inflammation is therefore a central consideration in understanding the development and progression of disease. For complementary or functional medicine practitioners, much of our work revolves around inflammation; understanding how it is triggered, why it persists and how to resolve it.

Cortisol, a hormone produced by the adrenal glands (cortex), is secreted both in a diurnal rhythm and as part of our stress response. It plays a pivotal role in initiating the so-called eicosanoid switch directing the immune response from the initial pro-inflammatory phase to the wound healing or anti-inflammatory phase. Optimal function of cortisol is therefore central in preventing ongoing inflammation.
Let’s first recall that stress response activation and immune activation go hand in hand.
During the first phase of a stress response, noradrenalin (NA) produced by the locus coeruleus (LC) in the brainstem, leads to secretion of catecholamines by the adrenal medulla. This in turn increases the proliferation of existing innate immune cells and activates the NFkB pathway, resulting in the production of pro-inflammatory cytokines. We refer to this as the SAM (sympathetic-adrenal-medulla) axis activation.  In the 2nd phase of the stress response, NA from the LC triggers the activation of the HPA (hypothalamus-pituitary-adrenal) axis. The end product of the HPA axis activation is cortisol production. Cortisol not only helps to ensure that there is sufficient energy (glucose) in the bloodstream to meet the extra demands of a stress reaction, but it is also capable of inhibiting the innate immune system through its upstream regulation of inhibiting factor kappa B (IkB) and can guide the inflammation to the resolution phase. Termination is instigated when cortisol overrules the NA effect on NFkB signalling. The termination effect of cortisol is normally supported by a compensatory response through activation of the vagal anti-inflammatory loop using the alpha-7-nicotin-acetylcholinergic- receptor. The resulting production of Ach inhibits the innate immune system.

So, in summary NA from the sympathetic nervous system drives the pro-inflammatory immune response in the initiation phase, whereas delayed cortisol production by the HPA axis triggers the switch to resolution. Integrity of the SAM axis and hence the secretion of NA is necessary for an adequate initial inflammatory response. At the beginning of the initiation phase there is cortisol resistance to allow for the activation of the innate immune system. At the end of this phase, cortisol sensitivity should be recovered to facilitate the eicosanoid switch to enter the resolution phase. This switch can only take place when NA is equal to the level of cortisol and when cortisol sensitivity is recovered. The stop signal requires a low level of NA and normalised cortisol sensitivity.
Adrenal fatigue or cortisol resistance?

Let’s focus now on dysregulated cortisol. The term adrenal fatigue was coined in 1998 by chiropractor James Wilson, PhD and has become a popular concept over the past 25 years in the complementary healthcare world. Wilson’s work was based on the work of Dr Hans Selye, the ‘father of stress research’. Wilson argued that prolonged or chronic stress exhausts the adrenal glands resulting in their inability to produce adequate quantities of adrenal hormones, particularly cortisol, which can lead to a broad range of associated symptoms. Scientific understanding on this topic is now becoming more sophisticated, which may consign the concept of adrenal fatigue to historic textbooks. Rather more recent propositions of HPA dysfunction are zeroing in on glucocorticoid receptor (GR) resistance/down-regulation as key areas of interest.

Staying with the idea of GR resistance/down regulation, chronic stress and consequent persistent demand for cortisol production is thought to lead to cortisol resistance in much the same way as persistent insulin secretion can lead to insulin resistance, and with that an inability to reach the resolution phase since this switch requires recovered cortisol sensitivity. When we lose cortisol function, we lose adaptogenic capacity and metabolic resilience increasing vulnerability for disease. It may therefore be important to also start to consider GR resistance/down-regulation when working with clients suffering low grade chronic inflammatory problems.

Some risk factors for cortisol resistance:
● Perceived chronic stress.
● Chronic infections, dysbiosis, heavy metals, environmental toxins, inflammatory diet etc.
● Excessive blood sugar fluctuations
● Loss of circadian rhythm
● Adverse childhood experiences
● Trauma
● Polymorphisms

Testing cortisol
When engaging in testing cortisol it is important to understand how to interpret the results in the context of cortisol sensitivity.
Saliva testing measures unbound cortisol or free cortisol. This is the most potent form of cortisol, but it only makes up around three to five percent of total body cortisol at any given time, so this is not necessarily representative of the total levels of cortisol in the body. The remaining cortisol is metabolised through various pathways before it is excreted in the urine. Adding urinary cortisol metabolites may therefore help to get a more accurate measure of total body cortisol. Choosing a saliva test with a marker for CAR or cortisol awakening response, which is measured in saliva within the first fifteen to thirty minutes of waking, can also help in the overall assessment of cortisol levels since fifty percent of the total cortisol production for that day takes place in the first 30 minutes after waking so this gives a good idea of overall cortisol secretion.
A measure of high or low cortisol on a four point saliva test (without CAR) does not equal to high or low total cortisol but is an excellent way to gain insights into the oscillation or rhythmical cortisol secretion which in a healthy person should follow a curve depicting the highest levels upon waking in the morning and lowest levels at night. A near flat curve is most certainly a sign of loss of rhythm and may also indicate cortisol resistance.
As always, the context is the most critical part of test interpretation so using adrenal testing alongside a detailed history taking accounting for symptoms of cortisol resistance, which include obesity, fatigue, depression, low grade chronic inflammatory disease and autoimmune disease, is the only way to make informed decisions about cortisol function in the individual client.
When considering testing options, it is important to remember that nothing exists in isolation. Thus, cortisol also influences other hormones such as thyroid hormones and insulin and can affect many body systems including the cardiovascular system. We always recommend contextualising markers like cortisol with other pertinent markers that may be relevant in a
particular case, to build a body of evidence. Checking heart rate and blood pressure may also be important in the context of cortisol dysregulation.

Colabs’ cortisol test options:
Just Cortisol
1. Serum Cortisol - values can vary across laboratory settings, so if you are doing follow up testing, we recommend repeat testing with the same lab under similar conditions e.g. fasted, at 8am, in order to track results over a period of time. Please note that serum testing cannot be used to assess cortisol resistance.
2. Saliva testing can be measured as a 4 point test through the day, or with CAR, a cortisol awakening response measurement to add a 15-30 minute waking sample. Cortisone is typically added to contextualise the cortisol level. It is important to note that medications and other substances can impact results. Saliva and urinary testing may give a better representation of cell concentration levels.
3. Urinary testing - this can be done very simply at home, and like saliva testing no draw is required. Again, we would recommend testing at a similar time of day and under similar conditions using 2-3 tests to get a clearer picture of trending levels. Urinary levels may also not be fully representative as excretion capacity needs to be sufficient.
Medically significant results to consider would be a very high result which may be indicative of Cushing’s Syndrome, or a very low result could be associated with adrenal insufficiency (Addison’s Disease).

Our preferred testing options are those which measure cortisol alongside other markers:
1. Cortisol as part of a wider hormone panel such as Z721 Advanced Metabolites testing- this test includes sex hormone metabolites and a 4 point melatonin.
2. The Z721 test can also be run in conjunction with the Urinary Neurotransmitter test which includes noradrenalin (this test can also be run on its own)
3. Inflammatory testing such as for CIRS where other inflammatory markers are measured e.g. TGFb1, with cortisol measured alongside ACTH. Insulin/Insulin resistance markers can also be added to these panels, and bespoke options curated.