Drugs for disorders of the adrenal cortex
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.
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
Carbohydrate metabolism.
Supplying the brain with glucose is essential for survival. Glucocorticoids help meet this need. Specifically, they promote glucose availability in four ways: (1) stimulation of gluconeogenesis, (2) reduction of peripheral glucose utilization, (3) inhibition of glucose uptake by muscle and adipose tissue, and (4) promotion of glucose storage (in the form of glycogen). All four actions increase glucose availability during fasting, and thereby help ensure the brain will not be deprived of its primary source of energy.
The effects of glucocorticoids on carbohydrate metabolism are opposite to those of insulin. That is, whereas insulin lowers plasma levels of glucose, glucocorticoids raise them. When present chronically in high concentrations, glucocorticoids produce symptoms much like those of diabetes.
Protein metabolism.
Glucocorticoids promote protein catabolism (breakdown). This action, which is opposite to that of insulin, provides amino acids for glucose synthesis. If present at high levels for a prolonged time, glucocorticoids will cause muscle wasting, thinning of the skin, and negative nitrogen balance.
Cardiovascular system.
Glucocorticoids are required to maintain the functional integrity of the vascular system. When levels of glucocorticoids are depressed, capillary permeability is increased, the ability of vessels to constrict is reduced, and blood pressure falls.
Glucocorticoids have multiple effects on blood cells. These hormones increase red blood cell counts and hemoglobin levels. Of the white blood cells, only counts of polymorphonuclear leukocytes increase. In contrast, counts of lymphocytes, eosinophils, basophils, and monocytes decrease.
Central nervous system.
Glucocorticoids affect mood, central nervous system (CNS) excitability, and the electroencephalogram. Glucocorticoid insufficiency is associated with depression, lethargy, and irritability. Rarely, outright psychosis occurs. In contrast, when present in excess, glucocorticoids can produce generalized excitation and euphoria.
Stress.
In response to stress (eg, anxiety, exercise, trauma, infection, surgery), the adrenal cortex secretes increased amounts of glucocorticoids, and the adrenal medulla secretes increased amounts of epinephrine. Working together, glucocorticoids and epinephrine serve to maintain blood pressure and blood glucose content. If glucocorticoid levels are inadequate, hypotension and hypoglycemia can occur. If the stress is extreme (eg, trauma, surgery, severe infection), glucocorticoid deficiency can result in circulatory collapse and death. Accordingly, it is imperative that patients with adrenal insufficiency receive glucocorticoid supplements when severe stress occurs.
Respiratory system in neonates.
During labor and delivery, the adrenals of the full-term fetus release a burst of glucocorticoids. Within hours, these steroids act on the lungs to accelerate their maturation. In the preterm infant, the adrenals produce only small amounts of glucocorticoids. As a result, preterm infants experience a high incidence of respiratory distress syndrome.
Regulation of synthesis and secretion
Adrenal storage of glucocorticoids is minimal. Accordingly, the amount of glucocorticoid released from the adrenals per unit time closely approximates the amount being made.
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.
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.
Mineralocorticoids
The mineralocorticoids influence renal processing of sodium, potassium, and hydrogen. In addition, they have direct effects on the heart and blood vessels. Of the mineralocorticoids made by the adrenal cortex, aldosterone is the most important.
Physiologic effects.
Aldosterone promotes sodium and potassium hemostasis, and helps maintain intravascular volume. Specifically, the hormone acts on the collecting ducts of the nephron to promote sodium reabsorption in exchange for secretion of potassium and hydrogen. The total amount of hydrogen and potassium lost equals the amount of sodium reabsorbed. You should note that, as sodium is reabsorbed, water is reabsorbed along with it. In the absence of aldosterone, renal excretion of sodium and water is greatly increased, whereas excretion of potassium and hydrogen is reduced. As a result, aldosterone insufficiency causes hyponatremia, hyperkalemia, acidosis, cellular dehydration, and reduction of extracellular fluid volume. Left uncorrected, the condition can lead to renal failure, circulatory collapse, and death.
In addition to its effects on the kidneys, aldosterone acts on the heart and blood vessels as well. When aldosterone levels are high, cardiovascular effects are harmful, increasing the risk of heart failure and hypertension. Specific cardiovascular effects include (1) promotion of myocardial remodeling (which can impair pumping); (2) promotion of myocardial fibrosis (which increases the risk of dysrhythmias); (3) activation of the sympathetic nervous system and suppression of norepinephrine uptake in the heart (both of which can promote dysrhythmias and ischemia); (4) promotion of vascular fibrosis (which decreases arterial compliance); and (5) disruption of the baroreceptor reflex.
Control of secretion.
Secretion of aldosterone is regulated by the renin-angiotensin-aldosterone system (RAAS), not by ACTH. The mechanisms by which the RAAS regulates aldosterone are discussed in Chapter 44. It is important to note that, because aldosterone is not regulated by ACTH, conditions that alter secretion of ACTH do not alter secretion of aldosterone.
Adrenal androgens
The adrenal cortex produces several steroids that have androgenic properties. Androstenedione is representative. Under normal conditions, physiologic effects of adrenal androgens are minimal. In adult males, the influence of adrenal androgens is overshadowed by the effects of testosterone produced by the testes. In adult females, a metabolite of the adrenal androgens—testosterone—contributes to development of sexual hair and maintenance of normal libido. Although adrenal androgens normally have very little effect, when production is excessive, as occurs in congenital adrenal hyperplasia, virilization can result.
Pathophysiology of the adrenocortical hormones
Adrenal hormone excess
Cushing’s syndrome
Causes.
Signs and symptoms of Cushing’s syndrome result from excess levels of circulating glucocorticoids. Principal causes are (1) hypersecretion of ACTH by pituitary adenomas (Cushing’s disease), (2) hypersecretion of glucocorticoids by adrenal adenomas and carcinomas, and (3) administering glucocorticoids in the large doses used to treat arthritis and other nonendocrine disorders (see Chapter 72).
Clinical presentation.
Cushing’s syndrome is characterized by obesity, hyperglycemia, glycosuria, hypertension, fluid and electrolyte disturbances, osteoporosis, muscle weakness, myopathy, hirsutism, menstrual irregularities, and decreased resistance to infection. The skin is weakened, resulting in striae (stretch marks) and increased susceptibility to injury. Fat undergoes redistribution to the abdomen, face, and upper back, giving the patient a characteristic potbelly, “moon face,” and “buffalo hump.” Psychiatric changes are common.
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