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). 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 regulated by the renin-angiotensin system, ACTH, and plasma sodium and potassium levels. Aldosterone secretion is stimulated by a fall in renal blood pressure, which results from decreased intravascular volume or a sodium imbalance.² The drop in volume and/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 (Figure 15-5).

FIGURE 15-5 Regulation of aldosterone secretion.

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.² Estrogen precursors are secreted from the zona reticularis of the adrenal cortex.

Incidence and Prevalence

Adrenal insufficiency occurs in 90 to 110 per 1 million persons of all ages, and diagnosis peaks in the fourth decade of life.¹³ Secondary adrenocortical insufficiency is about 2 to 3 times more common than primary adrenal insufficiency, and diagnosis peaks in the sixth decade.¹⁴ Both conditions are more common in women. Approximately 5% of adults in the United States use corticosteroids on a chronic basis and thus are at risk for secondary adrenocortical insufficiency. A dental practice serving 2000 adults can expect to encounter 100 patients who use corticosteroids or who have potential adrenal abnormalities.

Etiology

Primary adrenocortical insufficiency is caused by progressive destruction of the adrenal cortex, usually because of autoimmune disease, chronic infectious disease (tuberculosis, human immunodeficiency virus [HIV] infection, cytomegalovirus infection, and fungal infection) or malignancy. The condition also may result from hemorrhage, sepsis, adrenalectomy, drugs, or genetic mutations (e.g., familial glucocorticoid deficiency).^14–16

Secondary adrenocortical insufficiency is a far more common problem and may be caused by structural lesions of the hypothalamus or pituitary gland (e.g., tumor), administration of exogenous corticosteroids, or less commonly, administration of specific drugs (e.g., desferrioxamine in the treatment of thalassemia) or a critical illness (burns, trauma, systemic infection).¹⁷ Suppression of the HPA axis by exogenous or endogenous glucocorticoids is the most common cause of secondary adrenal insufficiency. The secretion of cortisol is directly dependent on the level of circulating ACTH. As plasma cortisol level increases, the production of ACTH decreases by virtue of negative feedback to the pituitary and the hypothalamus. With the administration of corticosteroids, the feedback system senses the elevated plasma steroid levels and inhibits ACTH production, which in turn suppresses adrenal production of cortisol (see Figure 15-3). The result is partial adrenal insufficiency. The production of aldosterone, because it is ACTH-independent, is not appreciably affected.

Pathophysiology and Complications

The major hormones of the adrenal cortex are cortisol and aldosterone. Addison’s disease is caused by the lack of these compounds. 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.^1,2

Chronic excessive use of glucocorticoids can result in clinical features mimicking those of Cushing’s disease. This collection of clinical features of glucocorticoid excess is known as Cushing’s syndrome. This condition results from high levels of cortisol altering the proteins, carbohydrate and fat metabolism, the effects of insulin and vasculature homeostasis.

Corticosteroids that are topically applied or repeatedly locally injected or inhaled are rare inducers of adrenal suppression by absorption through the skin, subjacent tissues, or pulmonary alveoli.¹⁸ 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.^19–21 Similar comments may be made regarding the use of inhaled corticosteroids, if they are given in frequent and high doses.^22,23 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.^23–25

Once corticosteroid administration has ceased, the HPA axis regains its responsiveness, and normal ACTH and cortisol secretion eventually resumes. The time required to regain normal adrenal responsiveness is thought to range from days to months. However, studies from a large review²⁶ demonstrated a return to stress stimulation of HPA function within 14 days, despite the fact that supraphysiologic doses were given for a month or longer.

Signs and Symptoms

Hypoadrenalism

Signs and symptoms of the adrenal insufficiency are the result of deficiencies of adrenocortical hormones and often are nonspecific, leading to delays in diagnosis. Clinical evidence of deficiency generally appears only after 90% of the adrenal cortices have been destroyed.

Primary adrenal insufficiency (Addison’s disease) produces signs and symptoms that relate to a deficiency of aldosterone and cortisol. The most common complaints are weakness, fatigue, abdominal pain, and hyperpigmentation of the skin and mucous membranes (Figure 15-6). Hypotension, anorexia, salt craving, myalgia, hypoglycemia, and weight loss are additional commonly associated features. If a patient with Addison’s disease is challenged by stress (e.g., illness, infection, surgery), an adrenal crisis may be precipitated.²⁷ 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.^1,2

FIGURE 15-6 Patient with Addison’s disease. Note bronzing of the skin with pigmentation of the lip (A) and the oral mucosa (B).

Secondary adrenal insufficiency caused by long-term corticosteroid administration may cause a partial insufficiency that is limited to glucocorticoids. The condition usually does not produce 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 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.²

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 due to glucocorticoid excess (endogenous or exogenous), and it leads to a syndrome known as Cushing’s syndrome. This syndrome classically produces weight gain, a broad and round face (“moon facies”) (Figure 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).²¹ Long-term steroid use also may increase risks for insomnia, peptic ulceration, cataract formation, glaucoma, growth suppression, and delayed wound healing.

FIGURE 15-7 “Moon-shaped face”: A clinical manifestation of Cushing’s disease.

Laboratory Findings

Laboratory assessment for adrenal insufficiency generally is initiated with a provocative stimulation test of the HPA axis. These tests include the synthetic ACTH (cosyntropin) stimulation test, the CRH test, and the dexamethasone suppression test. The ACTH stimulation test is the most reliable and most commonly used test of the three. It is carried out by injecting a synthetic ACTH hormone, such/>