Adrenal gland function has provided great academic material for investigation and controversy. It was not until 1937 that 17-hydroxy-11-dehydrocorticosterone, or cortisone, was isolated by Reichstein from the adrenal cortex. By 1947, synthetic cortisone was developed. At the same time, in addition to the use of cortisone for Addison's disease, this compound was found to have a therapeutic effect in patients with rheumatoid pain through its ability to inhibit stress and inflammation.
Adrenal insufficiency presents as chronic primary (about 5 per million incidence) or secondary (about 200 per million incidence). Both of these entities are more common in women, and diagnosis peaks anywhere from the fourth to the sixth decade. Historically, the most common cause of adrenal insufficiency was tuberculous adrenalitis. In developed countries, autoimmune adrenalitis has become a much more common cause of adrenal insufficiency, as tuberculous adrenalitis still plays a major role in the disease in developing countries.1
The adrenal gland has two anatomic divisions. The medulla secretes the catecholamines epinephrine and norepinephrine, and the cortex produces mineralocorticoids (via the renin–angiotensin system) and glucocorticoids. Critical illness and stress activate the hypothalamic–pituitary–adrenal (HPA) axis and stimulate the release of hypothalamic corticotropin-releasing hormone (CRH) and pituitary adrenocorticotropic hormone (ACTH).2 ACTH secretion reaches its effector organ, the adrenal cortex, where it stimulates the synthesis and secretion of glucocorticoids, mineralocorticoids, and adrenal androgens. The mechanisms regulating ACTH secretion during stress are multifactorial, with the stimulatory effect of CRH and the inhibitory influence of cortisol. The “closed-loop” negative feedback of cortisol to the HPA axis acts to suppress the secretion of CRH, ACTH, and cortisol itself (Figure 33-1).
There are three types of “closed-loop” negative feedback systems in the hypothalamic-pituitary-adrenal (HPA) axis. Corticotropin-releasing hormone (CRH) acts directly on the hypothalamus to control its own secretion in the ultrashort-loop system. Adrenocorticotropic hormone (ACTH) feeds back on the hypothalamus in the short–loop system. Glucocorticoids exert a negative feedback on the anterior pituitary and hypothalamus in the long-loop system.
Physiologic ACTH and cortisol secretion have a diurnal pattern with nadirs at 10 pm and 2 am, and peak at 8 am. During infection and inflammatory states, cortisol levels are increased through stimulation of the hypothalamus and pituitary by cytokines and a reduction in the negative feedback loop. The diurnal variation of cortisol secretion is lost, and resources are shifted away from mineralocorticoid and androgen production toward corticosteroid production. ACTH release can also be increased by the influence of endorphinergic pathways and from the acute (but not chronic) administration of morphine. Even with the negative feedback loop in place, during periods of high stress (after major surgery, septic shock), the adrenal cortex is also influenced directly by paracrine pathways, endothelin, atrial natriuretic peptide, or cytokines.
The adrenocortical response to stress has several mechanisms. Cortisol is 90% bound to cortisol-binding globulin, ...