Drugs for disorders of the adrenal cortex

The hormones of the adrenal cortex affect multiple physiologic processes, including maintenance of glucose availability, regulation of water and electrolyte balance, development of sexual characteristics, and life-preserving responses to stress. As you might guess, when production of adrenal hormones goes awry, the consequences can be profound. The two most familiar forms of adrenocortical dysfunction are Cushing’s syndrome, caused by adrenal hormone excess, and Addison’s disease, caused by adrenal hormone deficiency.

In approaching the drugs for treating disorders of the adrenal cortex, we begin by reviewing adrenocortical endocrinology. After that, we discuss the disease states associated with adrenal hormone excess and adrenal hormone insufficiency. Having established this background, we discuss the agents used for diagnosis and treatment of adrenocortical disorders.

Physiology of the adrenocortical hormones

The adrenal cortex produces three classes of steroid hormones: glucocorticoids, mineralocorticoids, and androgens. Glucocorticoids influence carbohydrate metabolism and other processes; mineralocorticoids modulate salt and water balance; and adrenal androgens contribute to expression of sexual characteristics. When referring to either the glucocorticoids or the mineralocorticoids, three terms may be used: corticosteroids, adrenocorticoids, or simply corticoids. These terms are not used in reference to adrenal androgens.

Glucocorticoids

Glucocorticoids are so named because they increase the availability of glucose. Of the several glucocorticoids produced by the adrenal cortex, cortisol is the most important. The structural formula of cortisol is shown in Figure 60–1.

Figure 60–1 Structural formulas of representative adrenocortical hormones.

When considering the glucocorticoids, we need to distinguish between physiologic effects and pharmacologic effects. Physiologic effects occur at low levels of glucocorticoids (ie, the levels produced by release of glucocorticoids from healthy adrenals, or by administering glucocorticoids in low doses). Pharmacologic effects occur at high levels of glucocorticoids. These levels are achieved when glucocorticoids are administered in the large doses required to treat disorders unrelated to adrenocortical function (eg, allergic reactions, asthma, inflammation, cancer). Pharmacologic levels can also be reached when production of endogenous glucocorticoids is excessive, as occurs in Cushing’s disease. In this chapter, we focus on the physiologic role of glucocorticoids. The use of high-dose glucocorticoids for nonendocrine purposes is discussed in Chapter 72.

Physiologic effects

Glucocorticoid synthesis and release are regulated by a negative feedback loop (Fig. 60–2). The loop begins with release of corticotropin-releasing hormone (CRH) from the hypothalamus. CRH acts on the anterior pituitary to promote release of adrenocorticotropic hormone (ACTH), which stimulates the zona fasciculata of the adrenal cortex, causing synthesis and release of cortisol and other glucocorticoids. Following release, cortisol acts in two ways: (1) it promotes its designated biologic effects and (2) it acts on the hypothalamus and pituitary to suppress further release of CRH and ACTH. Hence, as cortisol levels rise, they act to suppress further stimulation of glucocorticoid production, thereby keeping glucocorticoid levels within an appropriate range.

Figure 60–2 Negative feedback regulation of glucocorticoid synthesis and secretion.
(ACTH = adrenocorticotropic hormone, CRH = corticotropin-releasing hormone.)

The hypothalamic-pituitary-adrenal system is activated by signals from the CNS. These signals turn the system on by causing the hypothalamus to release CRH. As indicated in Figure 60–2, two modes of activation are involved. One provides a basal level of stimulation; the other increases stimulation at times of stress. Basal stimulation follows a circadian rhythm: Cortisol levels are lowest near bedtime, rise during sleep, reach a peak just before waking, and then decline through the day. (Note that this cycle is linked to one’s sleep pattern, and not to the clock. Hence, for some people, cortisol may peak in the morning, and for others it may peak in the afternoon or evening, depending on when they normally sleep.) When stress occurs, glucocorticoid production goes up. Stressful events that can activate the loop include injury, infection, and surgery. The signals generated by stress produce intense stimulation of the hypothalamus. The resultant release of CRH and ACTH can cause plasma levels of cortisol to increase 10-fold. Because stress is such a powerful stimulus, it overrides feedback inhibition by cortisol.