The adrenal glands are small (6–8 g) endocrine glands located bilaterally at the superior pole of each kidney. Each gland contains an outer cortex and an inner medulla. The adrenal medulla functions as a sympathetic ganglion and secretes catecholamines, primarily epinephrine. The adrenal cortex secretes several steroid hormones with multiple actions ( Fig. 15.1 ).
The adrenal cortex makes up about 90% of the gland and consists of three zones. The outer zone is the zona glomerulosa. The middle zone is the zona fasciculata, and the innermost zone is the zona reticularis. The cortex manufactures three classes of adrenal steroids: glucocorticoids, mineralocorticoids, and androgens. All are derived from cholesterol and share a common molecular nucleus. The predominant hormone of the zona glomerulosa is aldosterone, a mineralocorticoid that responds to hormones made by the kidneys (i.e., renin and angiotensin). Aldosterone regulates physiologic levels of sodium and potassium; these two electrolytes are important for control of intravascular volume and blood pressure. The zona fasciculata secretes glucocorticoids, and the zona reticularis secretes androgens, or sex hormones.
Cortisol, the primary glucocorticoid, has several important physiologic actions on digestion, metabolism, cardiovascular function, and the immune system and for maintaining homeostasis during periods of physical or emotional stress. Cortisol acts as an insulin antagonist ( Fig. 15.2 ), increasing blood levels and peripheral use of glucose by activating key enzymes involved in hepatic gluconeogenesis and inhibiting glucose uptake in peripheral tissues (i.e., skeletal muscles). In adipose tissue, cortisol activates lipolysis, resulting in the release of free fatty acids into circulation. Cortisol increases blood pressure by potentiating the vasoconstrictor action of catecholamines and angiotensin II on the kidney and vasculature. Its antiinflammatory action is modulated by its inhibitory action on (1) lysosome release, (2) prostaglandin production, (3) eicosanoid and cytokine release, (4) endothelial cell expression of intracellular and extracellular adhesion molecules (ICAMs and ECAMs, respectively) that attract neutrophils, and (5) leukocyte function. Cortisol also activates osteoclasts and inhibits osteoblasts.
Regulation of cortisol secretion occurs through activity of the hypothalamic–pituitary–adrenal (HPA) axis ( Fig. 15.3 ). Central nervous system afferents mediating circadian rhythm and responses to stress stimulate the hypothalamus to release corticotropin-releasing hormone (CRH), which stimulates the production and secretion of adrenocorticotropic hormone (ACTH) by the anterior pituitary. Corticotropin (ACTH) then stimulates the adrenal cortex to produce and secrete cortisol. Plasma cortisol levels are increased within a few minutes after stimulation. Circulating levels of cortisol inhibit the production of CRH and ACTH, thus completing a negative feedback loop.
Cortisol secretion is pulsatile and normally follows a circadian pattern. Peak levels of plasma cortisol occur around the time of waking in the morning and are lowest in the evening and night ( Fig. 15.4 ). This pattern is reversed in a person who habitually works nights and sleeps during the day. The normal secretion rate of cortisol over a 24-hour period is approximately 20 mg. During periods of stress, the HPA axis is stimulated, resulting in increased secretion of cortisol. Anticipation of surgery or an athletic event usually is accompanied by only minimal increases in cortisol secretion. However, surgery itself is one of the most potent activators of the HPA axis. Also, various stressors such as trauma, illness, burns, fever, hypoglycemia, and emotional upset (e.g., anxiety) can trigger this effect. The most pronounced response is noted in the immediate postoperative period after surgery. However, this can be reduced by morphine-like analgesics, benzodiazepines, or local anesthesia, suggesting that the pain response mechanism increases the requirement for cortisol.
Synthetic glucocorticoids (cortisol-like drugs) used in the treatment of autoimmune and inflammatory diseases (e.g., rheumatoid arthritis, systemic lupus erythematosus, asthma, hepatitis, inflammatory bowel disease, dermatoses, mucositis) can affect adrenal function. Glucocorticoids are used on a long-term basis in patients during immunosuppressive therapy for organ transplantation and joint replacement. In dentistry, corticosteroids may be used during the perioperative period for the reduction of pain, edema, and trismus after oral surgical and endodontic procedures. Many synthetic glucocorticoids are available, and they differ in potency relative to cortisol and in their duration of action ( Table 15.1 ).
| Compound | Antiinflammatory Potency | Mineralocorticoid Potency | Equivalent Dose * (mg) |
|---|---|---|---|
| SHORT ACTING (<12 HOURS) | |||
| Cortisol | 1 | 2 | 20 |
| Hydrocortisone | 0.8 | 2 | 20 |
| INTERMEDIATE ACTING (12–36 HOURS) | |||
| Prednisone | 4 | 1 | 5 |
| Prednisolone | 4 | 1 | 5 |
| Triamcinolone | 5 | 0 | 4 |
| Methylprednisolone | 5 | 0.5 | 4 |
| Fludrocortisone | 15 | 200 | 1.4 |
| LONG ACTING (>36 HOURS) | |||
| Betamethasone | 25 | 0 | 0.75 |
| Dexamethasone | 25 | 0 | 0.75 |
| INHALED | |||
| Beclometasone dipropionate † | 8 puffs 4 times a day equals 14 mg oral prednisone once a day | — | — |
† Fluticasone propionate is roughly twice as potent as beclometasone dipropionate and budesonide.
Mineralocorticoids
Aldosterone is the primary mineralocorticoid secreted by the adrenal cortex. It is essential to sodium and potassium balance and to the maintenance of extracellular fluid (i.e., intravascular volume) and blood pressure. Its actions occur primarily on the distal tubule and the collecting duct of the kidney, where it promotes sodium and water retention and potassium excretion. Aldosterone secretion is predominantly regulated by the renin–angiotensin system and extracellular potassium levels and less so by plasma sodium levels. Aldosterone secretion is stimulated by a fall in renal blood pressure, which results from decreased intravascular volume or a sodium imbalance. The drop in volume or pressure causes renin release from the kidney, which activates angiotensinogen to form angiotensin I and II. Angiotensin II, in turn, stimulates secretion of aldosterone from the adrenal cortex. When blood pressure rises, renin–angiotensin release diminishes, serving as a negative feedback loop that inhibits additional production of aldosterone ( Fig. 15.5 ).
Adrenal Androgens
Dehydroepiandrosterone (DHEA) is the principal androgen secreted by the adrenal cortex. The effects of adrenal androgens are the same as those of testicular androgens (i.e., masculinization and the promotion of protein anabolism and growth). The activity of the adrenal androgens, however, is only about 20% that of the testicular androgens and is of relatively minor physiologic importance. Estrogen precursors are secreted from the zona reticularis of the adrenal cortex.
Adrenal Androgens
Dehydroepiandrosterone (DHEA) is the principal androgen secreted by the adrenal cortex. The effects of adrenal androgens are the same as those of testicular androgens (i.e., masculinization and the promotion of protein anabolism and growth). The activity of the adrenal androgens, however, is only about 20% that of the testicular androgens and is of relatively minor physiologic importance. Estrogen precursors are secreted from the zona reticularis of the adrenal cortex.
Definition
Disorders of the adrenal glands can result in overproduction (hyperadrenalism) or underproduction (hypoadrenalism or adrenal insufficiency) of adrenal products.
Hyperadrenalism is characterized by excessive secretion of adrenal cortisol, mineralocorticoids, androgens, or estrogen in isolation or combination. The most common type of overproduction is due to glucocorticoid excess. When this is caused by pathophysiologic processes, the condition is known as Cushing disease. The term Cushing syndrome is a generalized state caused by excessive cortisol in the body, regardless of the cause.
Adrenal insufficiency is divided into three categories: primary, secondary, and tertiary. Primary adrenocortical insufficiency, also known as Addison disease, occurs when the adrenal cortex is destroyed or the gland is removed. Secondary adrenocortical insufficiency is the consequence of pituitary disease or a lack of responsiveness of the adrenal glands to ACTH (corticotrophin) or caused by critical illness. Tertiary adrenal insufficiency results from processes that impair function of the hypothalamus, which is most commonly caused by chronic use of corticosteroids. Because abnormal adrenal function can be life threatening, these conditions are of significant concern in clinical practice.
Epidemiology
Adrenal insufficiency occurs in 100 to 140 per 1 million persons of all ages, with about 5 new cases per million diagnosed each year. The diagnosis peaks in the fourth decade of life. Secondary adrenocortical insufficiency is about two times more common than primary adrenal insufficiency, and diagnosis peaks in the sixth decade. Both conditions are more common in women, and both conditions are associated with premature death. Approximately 2% of adults in the United States use corticosteroids on a chronic basis and thus are at risk for tertiary adrenocortical insufficiency. A dental practice serving 2000 adults can expect to encounter 50 patients who use corticosteroids or who have potential adrenal abnormalities.
Etiology
Primary adrenocortical insufficiency is caused by progressive destruction of the adrenal cortex, primarily because of autoimmune disease in adults and less frequently from chronic infectious disease (tuberculosis, human immunodeficiency virus [HIV] infection, cytomegalovirus infection, and fungal infection) or malignancy. The condition also may result from hemorrhage (e.g., heparin or low-molecular-weight heparin use), sepsis, adrenalectomy, genetic mutations (e.g., adrenoleukodystrophy, familial glucocorticoid deficiency), or drugs (e.g., that increase cortisol metabolism, inhibit gene transcription, or alter tissue resistance to glucocorticoids).
Secondary adrenocortical insufficiency is caused by structural lesions of the pituitary gland (e.g., tumor), removal of the pituitary gland, cranial irradiation of the pituitary gland, head trauma, and lack of responsiveness of the adrenal glands to ACTH (corticotrophin) or due to critical illness (e.g., sepsis, liver cirrhosis).
Tertiary adrenal insufficiency results from defective hypothalamus function or, more commonly, as a result of chronic administration of exogenous corticosteroids. Prolonged corticosteroid use suppresses the hypothalamic–pituitary axis, which in turn inhibits ACTH production and adrenocortical production of cortisol (see Fig. 15.3 ). Less common causes include administration of specific drugs ( Table 15.2 ) or a critical illness (burns, trauma, systemic infection).
| Drug Class | Generic Drug Examples |
|---|---|
| Antidepressant | Imipramine |
| Antifungal | Ketoconazole, fluconazole |
| Antipsychotic | Chlorpromazine |
| Antisteroid | Aminoglutethimide |
| Antiseizure | Phenytoin, topiramate |
| Antituberculosis | Rifampin |
| Barbiturate | Phenobarbital |
| Benzodiazepine | Midazolam |
| Diagnostic | Metyrapone |
| General anesthetic | Etomidate |
| Iron reducer (thalassemic drug) | Desferrioxamine |
Pathophysiology and Complications
Primary adrenal insufficiency (Addison disease) is caused by the lack of the major hormones of the adrenal cortex: cortisol and aldosterone and to a lesser degree the androgens. Lack of cortisol results in impaired metabolism of glucose, fat, and protein, as well as hypotension, increased ACTH secretion, impaired fluid excretion, excessive pigmentation, and an inability to tolerate stress. The relationship between corticosteroids and response to stress involves the maintenance of vascular reactivity to vasoactive agents and the maintenance of normal blood pressure and cardiac output. Aldosterone deficiency results in an inability to conserve sodium and eliminate potassium and hydrogen ions, leading to hypovolemia, hyperkalemia, and acidosis.
Secondary and tertiary adrenal insufficiency are associated with low levels of cortisol. Unlike primary adrenal insufficiency, aldosterone is not impaired with secondary or tertiary adrenal insufficiency. This is because aldosterone secretion is ACTH independent.
Cushing syndrome refers to a condition caused by excessive cortisol in the body. When Cushing syndrome is caused by a pathophysiologic process (e.g., tumor of the pituitary gland or tumor of the adrenal gland), it is called Cushing disease. In Cushing disease, the endocrine tumor stimulates excessive circulating levels of glucocorticoids. Both Cushing disease and syndrome produce similar clinical features that result from high levels of cortisol that alters protein, carbohydrate, and fat metabolism, the effects of altered insulin and vasculature homeostasis. The most common cause of elevated cortisol levels in Cushing syndrome is the medical administration of corticosteroids (e.g., prednisone).
Corticosteroids can be administered by a variety of routes, and most medical regimens attempt to limit the dose so elevated cortisol levels, and thus adrenal suppression, do not occur. Corticosteroids that are topically applied or repeatedly locally injected or inhaled rarely induce adrenal suppression by absorption through the skin, subjacent tissues, or pulmonary alveoli. Although the amount of topical steroid required to treat small, noninflamed areas probably does not cause significant suppression, prolonged treatment of large inflamed areas may be a cause for concern, especially if occlusive dressings are used with highly potent steroids. Similarly, the use of inhaled corticosteroids rarely causes adrenal suppression unless they are given in frequent and high doses. Doses above 400 to 500 µg/day in children or 800 to 1000 µg/day of beclomethasone dipropionate equivalent in adults (depending on body mass) generally are considered to represent the cutoff point, indicating that adrenal suppression is probable.
In patients treated with corticosteroids, after administration ceases, the HPA axis begins to regain its responsiveness, and normal ACTH and cortisol secretion eventually resume. The time required to regain normal adrenal responsiveness is thought to range from days to months. However, studies from a large review demonstrated a return of HPA function to stress stimulation within 14 days even when supraphysiologic doses were given for 1 month or longer.
Adrenal Crisis
Adrenal crisis is a potentially life-threatening complication resulting from adrenal insufficiency triggered by emotional and physical stress (e.g., infection, fever, sepsis, surgery). It manifests as hypotensive collapse, abdominal pain, myalgia, and fever. The condition occurs at a rate of 5 to 6 events per 100 patient-years among those with primary adrenal insufficiency, with older affected adults at higher risk.
Clinical Presentation
Signs and Symptoms
Hypoadrenalism.
Deficiencies of adrenocortical hormones produce signs and symptoms that are often nonspecific, leading to delays in diagnosis. Clinical evidence of adrenal deficiency generally appears only after 90% of the adrenal cortices have been destroyed.
Primary adrenal insufficiency (Addison disease) produces signs and symptoms associated with a deficiency of all adrenocortical hormones (aldosterone, cortisol, androgens). The most common complaints are weakness, fatigue, abdominal pain, and hyperpigmentation of the skin (i.e., skin areas subjected to pressure: elbows, knuckles, palmar creases) and mucous membranes ( Fig. 15.6 ). Hypotension, anorexia, salt craving, myalgia, hypoglycemia, and weight loss are additional commonly associated features. If a patient with Addison disease is challenged by emotional or physical stress (e.g., illness, infection, surgery), an adrenal crisis may be precipitated. This medical emergency evolves over a few hours and manifests as severe exacerbation of the patient’s condition, including sunken eyes, profuse sweating, hypotension, weak pulse, cyanosis, nausea, vomiting, weakness, headache, dehydration, fever, dyspnea, myalgias, arthralgia, hyponatremia, and eosinophilia. If not treated rapidly, the patient may develop hypothermia, severe hypotension, hypoglycemia, confusion, and circulatory collapse that can result in death.
Secondary and tertiary adrenal insufficiency may cause a partial insufficiency that is limited to glucocorticoids. The condition usually does not produce hyperpigmentation or any symptoms unless the patient is significantly stressed and does not have adequate circulating cortisol during times surrounding stress. In this event, an adrenal crisis is possible. However, an adrenal crisis in a patient with secondary or tertiary adrenal suppression is rare and tends not to be as severe as that seen with primary adrenal insufficiency because aldosterone secretion is normal. Thus, hypotension, dehydration, and shock are seldom encountered.
Hyperadrenalism.
Adrenal hyperfunction can produce four syndromes that are dependent on the adrenal product that is in excess—androgen, estrogen, mineralocorticoid, and cortisol. Androgen-related disorders are rare and primarily affect the reproductive organs. Mineralocorticoid excess (primary aldosteronism) is associated with hypertension, hypokalemia, and dependent edema (see Chapter 3 ). The most common form of hyperadrenalism is caused by glucocorticoid excess (endogenous or exogenous), and it leads to a syndrome known as Cushing syndrome. This syndrome classically produces weight gain, a broad and round face (“moon facies”) ( Fig. 15.7 ), a “buffalo hump” on the upper back, abdominal striae, hypertension, hirsutism, and acne. Other findings may include glucose intolerance (e.g., diabetes mellitus), heart failure, osteoporosis and bone fractures, impaired healing, and psychiatric disorders (mental depression, mania, anxiety disorders, cognitive dysfunction, and psychosis). Long-term steroid use also may increase risks for insomnia, peptic ulceration, cataract formation, glaucoma, growth suppression, and delayed wound healing.
