HPA Syndrome – The 3 Stages of HPA Exhaustion


Colorado Natural Medicine provides salivary hormone testing services to patients worldwide, with the most popular test panels involving four saliva samples performed over the course of one day, looking at cortisol levels as well as DHEA and DHEA(S). This convenient, simple and inexpensive process results in data that can provide a clinician with a window into your ability to tolerate stress. The 3 stages of HPA exhaustion (a variation of Selye’s General Adaptation Syndrome concept) are explained below in the context of this “functional HPA stress profiling”.

The 3 Stages of Hypothalamic-Pituitary-Adrenal Exhaustion/Dysfunction
Stage I HPA Exhaustion is defined as a prolonged, increased excitatory stimulus to the HPAs having resulted in a prolonged, increased cortisol output, usually with a corresponding prolonged decrease in DHEA. In the hypothalamic-pituitary-HPA control loop (HPA axis), an increase in ACTH output from the pituitary gland stimulates the HPA glands. The level of cortisol is regulated through the HPA negative feedback. Continued demand for increased cortisol production necessitates ongoing ACTH release by the pituitary, but the HPAs can eventually experience difficulty in meeting the demand. This difficulty begins the first stage of HPA exhaustion.

This diagram illustrates the common pattern of the hormone cortisol through the stages of HPA exhaustion. The total cortisol sum as measured in nanomoles (nM) is shown to rise then fall as the stages of exhaustion progress left to right.

Cortisol Saliva Test | Colorado Natural Medicine

Cortisol Saliva Test | Colorado Natural Medicine

Eventually, other pathways must compensate to facilitate the production of sufficient cortisol. One such compensation is often a shunt or “steal” of pregnenolone from the DHEA/sex hormone pathway to the progesterone/cortisol pathway. In this steal, the pathway from progesterone to cortisol becomes preferential over the pathway from DHEA to the sex hormones. There is consequently a decrease in DHEA and its metabolites, which include testosterone and the estrogens. Progesterone either remains normal or decreases, and cortisol increases. The overall cortisol increase in Stage I, therefore, is due to a combination of increased cortisol output by the HPAs, and pregnenolone steal.

Stage II HPA Exhaustion is a transitional phase. It signifies a continuing decline in cortisol output from levels above normal to those below normal, although ACTH stimulation remains high or even increases. There is a gradual change from increased to decreased cortisol output due to a decreasing response of the HPA glands to protracted ACTH stimulation. Any one or more of the morning, noon, or afternoon cortisol values can be low or borderline-low, but the nighttime cortisol level is usually normal. The decreasing cortisol output is a marker of mid-stage HPA exhaustion. In this transitory stage, the sum of the four cortisol levels is nevertheless normal. Pregnenolone steal from the DHEA/sex hormone pathway to the progesterone/cortisol pathway can assist in maintaining normal overall cortisol levels at the continued expense of DHEA. DHEA usually remains low or borderline-low.

Stage III is the terminal stage of HPA exhaustion. It is marked by the failure of the HPAs to produce enough cortisol to reach even normal levels in response to continued, increased ACTH stimulation. The sum of the four cortisol levels is below normal, and DHEA is usually low or borderline-low. Endocrine and autonomic pathways, through endogenous and/or exogenous stress, have been conditioned by a complex of stimuli to respond beyond normal physiological ranges. This conditioning ultimately results in HPA inability to produce the amount of cortisol demanded by the degree of stimulation. The result is a hypothalamic-pituitary-HPA axis “crash,” in which essential neuroendocrine feedback loops are unable to return the system to homeostasis. In such a case there is often a decreased nighttime cortisol, which is a marker of late Stage III HPA exhaustion.

A wide variety of seemingly unrelated symptoms usually appears; a situation which reflects the global nature of the dysfunction. Severe imbalances in other hormone systems are to be expected. Subclinical disorders are common, indicating the insidiousness of advanced HPA exhaustion. HPA failure, known as Addison’s Disease, is a natural outcome, and cardiovascular failure is a high probability.

I know this may sound complicated! The science in the above text may appear daunting, but here at Colorado Natural Medicine, we can sort out the complexities and provide interpretation and recommendations based on lab tests; then it is your responsibility to be compliant with any necessary supplementation protocols and lifestyle modification when the diagnosis made. Further lab testing may be necessary to root out underlying sources of chronic stress. For more information or to schedule your saliva hormone test, call us at (303) 995-5812.


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