hpa AXIS

In an earlier post on the labs in Chronic Inflammatory Response Syndrome (CIRS), I wrote that CIRS is, first and foremost, an inflammatory condition. Consequently, the identification of inflammatory markers is an important aspect of objective bio-marker diagnosis. This article is about the second most important set of bio-markers which pertain to hormone levels of the hypothalamic-pituitary-adrenal axis, or the HPA axis for short.

One simple means of explaining this hormonal effect is the systemic inflammation of CIRS wreaks havoc on the delicate HPA axis. The HPA axis is a coordinated endocrine system with a movement of chemical signal information (hormones) that flows from the hypothalamus to the pituitary and then to the adrenal glands, a key hormonal organ that sits atop each of the kidneys. There are literally hundreds of hormones in the HPA axis, some of which are household names: cortisol, progesterone, estrogen, and testosterone are probably the most familiar.

Much of the harm from CIRS results from the devastation of hormonal health. Some of the hormonal abnormalities are used to characterize and diagnose CIRS. The hormones used to diagnose CIRS include adrenocorticotropic hormone (ACTH), cortisol, anti-diuretic hormone (ADH), dehydroepiandrosterone (DHEA), and melanocyte-stimulating hormone (MSH). Vasoactive intestinal peptide (VIP) used to be a diagnostic bio-marker, but its measurement has fallen out of favor because of the lack of reliability with plasma or serum levels, since VIP tends to be most concentrated in tissues.

The above hormones are certainly not the only hormones affected in CIRS, but rather the ones that Dr. Ritchie Shoemaker, the discoverer of CIRS, empirically found to be disrupted clinically and then published in the scientific literature and incorporated into the diagnostic criteria of CIRS. Clinically, other patterns of hormonal disruptions that I frequently observe in CIRS patients are low testosterone, high or low estrogen, low progesterone, and low pregnenolone. These other hormonal disruptions may be clinically significant, but are not part of the diagnostic criteria for CIRS at this time.


ACTH is a hormone released by a part of the brain called the pituitary gland. ACTH gets its name–adrenocorticotropic hormone–from its function of stimulating the adrenal gland to release cortisol. As cortisol production and release into the blood increased from ACTH stimulation, the pituitary gets a signal to reduce ACTH release. This type of signal is called a negative feedback signal.

Cortisol is a steroid hormone made by the adrenal gland and the range of its function is far in excess of its typical identity as a “stress hormone.” Cortisol is essential to life and its extreme absence, as occurs with a adrenal disease called Addison’s disease, is fatal without treatment with steroid supplementation. Cortisol’s key functions include controlling blood sugar levels and blood pressure, regulating metabolism, reducing inflammation, and brain health.

In CIRS, ACTH may rise excessively high in the early course of the disease. Cortisol may be too high or too low. The most important parameter is typically not an out-of-range ACTH or cortisol, but rather a relative imbalance in the ratio between them. As you may recall earlier in this article, I discussed how ACTH stimulates cortisol release, and increased cortisol signals to the pituitary to reduce ACTH release in a process called a negative-feedback loop.

With CIRS, the relative ratio of ACTH to cortisol can be abnormal, a type of imbalance called dysregulation. In dysregulation, a relatively low level of cortisol may be accompanied by an inappropriately low ACTH. Or a relatively high level of cortisol may be accompanied by a inappropriately high ACTH. Dysregulation, rather than an absolutely out-of-range ACTH or cortisol, is the disruption seen most commonly on this parameter.


Anti-diuretic hormone (ADH) is named for its function of reducing urine output at the kidneys. ADH is made by the hypothalamus, stored and secreted by the pituitary gland, and has its effect on the kidneys. It regulates the amount of water re-absorbed versus urinated at the kidney. In CIRS, the ADH is reduced which may result in excessive urination due to an inadequate amount of re-absorption at the kidney.

Symptomatically, the effect of low ADH is frequent urination. The urine will be found to be excessively dilute (a low specific gravity). This excessive water excretion will result in dehydration. To maintain salt balance, the body may start shifting sodium chloride out through the skin. This alteration in solute may create a electro-chemical charge that results in greater frequency of static shocks, a bizarre symptom that many CIRS patients are relieved to find is a consequence of a physiologic process.

The osmolality is a biomarker that measures the concentration of all chemical particles within a liter of blood including sodium, potassium, glucose, and a protein called blood urea nitrogen. The normal rage of osmolality is 280-300 mosmol and many CIRS patients will be on the higher end of the distribution, above 290 mosmol. The sodium levels will also tend to be on the high-end of normal for CIRS patients impacted by low ADH.


Alpha-melanocyte stimulating hormone has the distinction of being the single most sensitive biomarker for CIRS. Over 95% of patients with CIRS will have a low MSH defined as less than 35pg/mL. Made by the pituitary gland, MSH is named after its effect of stimulating melanin, a chemical involved in the darkening of skin and hair. An increase in melanin causes darker skin in humans. As a regulator hormone, MSH has a broad number of functions including regulation of inflammation, energy, pain perception, other hormones, and mood. Symptomatically, the effect of low MSH may include increased inflammatory illnesses such as rheumatoid arthritis, fatigue, pain, mood swings, and chronic sleep disorders.


Like MSH, Vasoactive Intestinal Polypeptide (VIP) is a regulatory hormone. It also has some overlap in function and can regulate inflammation and other hormones. VIP also affects lung pressures (pulmonary artery pressures). Consequently, low VIP is associated with unusual shortness of breath. Low VIP plays a role in the extreme and generalized intolerance to chemicals known as multiple chemical sensitivity.

VIP gets its name in reference to its effects on the digestive system. VIP causes the smooth muscle of the digestive system to relax, for example, at the esophagus, stomach, and gallbladder. It also stimulates the pancreas and reduces re-absorption of fluid from the intestine, which may result in watery diarrhea. The measurement of VIP is not typically done due to the lack of precision in serum or plasma levels as a reflection of the body’s stores.


Vascular Endothelial Growth Factor (VEGF) is a hormone that regulates blood vessel production and the leakiness, or permeability, of blood vessels. Made by different cells in the body, VEGF is not technically as part of the HPA-axis like the other hormones in this list. In CIRS, there may be a VEGF deficiency which results in blood flow to the small blood vessels called the capillaries (capillary perfusion). This reduction in blood flow will cause functional abnormalities due to the reduced oxygen and nutrient availability. Low VEGF is defined as less than 31pg/mL.


ACTH >15 and CORTISOL >15
ACTH <40 and CORTISOL >8
ADH <4 and OSM >292
ADH >2 and OSM <278
VEGF<31pg/mL or >86pg/mL