Diagnosis and Treatment of Adrenal Insufficiency in the Critically Ill Patient

Kwame Asare, Pharm.D.


Pharmacotherapy. 2007;27(11):1512-1528. 

In This Article


The two adrenal glands, each weighing about 4 g, lie at the superior poles of the two kidneys. Each gland is made of two distinct parts, the adrenal medulla and adrenal cortex. The adrenal medulla acts in concert with the central nervous system to secrete the hormones epinephrine and norepinephrine in response to sympathetic stimulation.

The adrenal cortex is anatomically separated into three zones: zona glomerulosa, zona fasciculata, and zona reticularis. However, functionally it can be seen as two independent units: the outer zona glomerulosa, which is responsible for secreting the mineralocorticoid aldosterone, and the inner zonae fasciculate and reticularis, responsible for secreting glucocorticoids (e.g., cortisol) as well as androgens. An adrenocorticotropic hormone (ACTH), also called corticotropin or adrenocorticotropin, stimulates the adrenal cortex to synthesize and secrete the two principal adrenocortical hormones: cortisol, which regulates carbohydrate, protein, and lipid metabolism,[2] and aldosterone, which regulates fluid and electrolyte balance through sodium and potassium homeostasis. In addition to cortisol and aldosterone, the adrenal cortex also secretes other steroids with glucocorticoid, mineralo-corticoid, or both activities, but in much smaller quantities.

Cortisol levels respond within minutes to stressful stimuli, protecting the organism from the damaging effects of the stressor. Without this response, humans could not resist physical or mental stress, and thus, any minor illness could result in death. The reasons why elevated glucocorticoid levels protect the organism under stress are not completely understood. The detailed process, known as steroidogenesis, is rather complex and beyond the scope of this review, but Figure 1 (which depicts a rather simplified version) will suffice for the purposes of this discussion.

A simplified version of the process of steroidogenesis. Stress stimulates the hypothalamus, which releases corticotropin-releasing hormone (CRH), which in turn stimulates the release of adrenocorticotropic hormone (ACTH) from the pituitary. Then ACTH stimulates the adrenal cortex to release cortisol. Cortisol then initiates a series of metabolic effects that relieves the stressful state. A direct negative feedback mechanism of cortisol inhibits both the hypothalamus and anterior pituitary gland, decreasing the release and concentration of cortisol.

Three organs-hypothalamus, anterior pituitary, and adrenal cortex, collectively known as the hypothalamic-pituitary-adrenal (HPA) axis-maintain appropriate levels of glucocorticoids. There are three distinct modes of regulation of the HPA axis: diurnal rhythm in basal cortisol secretion, marked increases in steroidogenesis in response to stress, and the negative feedback regulation by adrenal cortisol.[12] Typically, cortisol is released in episodic bursts in a diurnal pattern. This diurnal rhythm is such that ACTH secretion rises during the late hours and peaks in early morning, around 8 A.M., after which the negative feedback regulation by the HPA axis modulates the glucocorticoid levels in the appropriate range (Figure 1).[9,12] When daily sleeping habits are changed, the cycle changes correspondingly. Thus, measurements of blood cortisol levels are meaningful when expressed in terms of the time of a person's sleep cycle at which they were measured.[13] It must be kept in mind that stressful circumstances as well as chronic disease may override these normal negative feedback mechanisms, resulting in marked increases in plasma levels of corticosteroids. Almost any type of physical or mental stress can result in enhanced secretion of ACTH, and consequently cortisol secretion, by as much as 20-fold,[13] a factor that is proportional and positively correlated to the severity of the condition. Examples of stressful stimuli include trauma of almost any type, major surgery, severe infection, pain, hypoglycemia, hypovolemia, hypotension, hypoxemia, bleeding, fear, and intense heat or cold.

Adrenocorticotropic hormone is necessary for aldosterone secretion but has little effect in controlling its rate of secretion.[13] Aldosterone secretion is not regulated by the HPA axis but primarily by the renin-angiotensin system in response to a decrease in blood volume, and by elevated extracellular potassium. In the setting of persistently elevated ACTH levels, mineralocorticoid levels initially increase and then return to normal. This phenomenon is sometimes called the ACTH escape.


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