Definition and Epidemiology

Adrenal gland disorders are conditions marked by inadequate or excessive amounts of glucocorticoid, mineralocorticoid, or androgen hormones as a consequence of changes in the adrenal gland itself, from hypothalamic or pituitary gland dysfunction, or through exogenous administration. The three most common types of adrenal gland disorders are discussed: Addison disease, Cushing syndrome, and pheochromocytoma.

Pathophysiology

Hypothalamus-synthesized corticotropin-releasing hormone regulates the secretion of ACTH, which in turn regulates the production of glucocorticoids (cortisol). Cortisol adjusts the metabolic responses in the body to both physical and psychological stressors. These responses range from hepatic glucose production to inflammatory vascular reactions. Proinflammatory cytokines also increase cortisol secretion.³ Normal circadian ACTH secretion is highest on waking and lowest at night. Men average 18 pulses of ACTH daily, but women have only 10.¹ Disrupted sleep-wake cycles of shift workers or travelers crossing time zones interrupt the pulses, which may result in changes in performance and behavior.

Primary underproduction disorders (Addison disease) stem from the destruction or dysfunction of the adrenal gland. Secondary disorders involve interruption of the hypothalamic-pituitary-adrenal (HPA) axis, pituitary tumors, or traumatic brain injury. Tertiary disorders are the sudden consequences of withdrawal of exogenous corticosteroids after high-dose use. Typically 90% of both adrenal glands is malfunctioning before clinically recognized insufficiency is present. Destruction by TB, adrenal hemorrhage (e.g., anticoagulant therapy or trauma), medications (rifampin, ketoconazole), and infections (meningococcemia, histoplasmosis) are rare causes. Inadequate production of cortisol in the context of severe sudden illness or trauma, particularly in chronic users of corticosteroids, is a more common manifestation.¹ Individuals with other pituitary dysfunction as well as septic shock, patients with critical illness,⁵ childhood brain cancer survivors,⁶ and patients sustaining traumatic brain injury⁷ should be monitored long term for insufficiency symptoms.

Most cases of Cushing syndrome come from the suppression of pituitary ACTH production when steroids are administered in high doses for long periods. When use is for more than 10 to 14 days as part of the management of asthma, difficult dermatitis problems, malignant neoplasms, rheumatic diseases, and other disorders, careful monitoring is mandatory to detect early, persistent endogenous corticosteroid suppression. When long-term exogenous glucocorticoid therapy (>15 mg/day) is indicated, HPA axis suppression occurs. Alternate-day therapies have been suggested to alleviate symptoms but are not evidence based.¹ Steroid use for less than 3 weeks typically does not generate concern. The exception is frequent “burst” therapy in asthma and chronic obstructive pulmonary disease exacerbations, when natural return of adrenal function can be impaired. Timing of steroid doses is critical to reduce impact. Most of the administration should occur in the morning, as heavier doses at night suppress the morning pulse of ACTH more significantly. Recovery from iatrogenic suppression of cortisol production can take 6 to 9 months.¹

Secondary Cushing syndrome results from ACTH-secreting tumors of the pituitary and occasionally (0.05%) from ectopic hormone secretion such as small cell lung carcinomas. Cortisol and ACTH levels are both elevated. Rarely, Cushing syndrome results from primary overproduction of cortisol by the adrenal gland (low levels of serum ACTH and high levels of serum cortisol).

Abnormal production of epinephrine and norepinephrine by a pheochromocytoma produces multisystem effects. Renal effects include sodium retention, increased renin secretion, and reduction of hydrostatic pressure. Cardiovascular effects involve peripheral vasoconstriction and increased cardiac contraction and workload from significant hypertension. Tissue oxygen consumption and gluconeogenesis are also increased.⁴

Clinical Presentation

Addisonian presentations are nonspecific with chronic malaise, dizziness, nausea, chronic abdominal pain, muscle cramps, hyperpigmentation, decreased libido, weight loss, and salt craving. Decreased axilla and pubic hair with altered menses is linked to the disorder in women because of lowered androgens. Men produce most of their androgens in the testes, so they avoid most of this hair loss.¹ Depression, impaired memory, and agitation to include outright psychosis may occur in 20% to 40% of individuals. A patient with known Addison disease can exhibit an abrupt onset of vomiting, hypotension, and acute shock during a period of severe trauma, illness, or physical exertion when mineralocorticoid levels drop. Adrenal crisis can occur in patients normally well controlled with glucocorticoids.¹

Cushing syndrome almost always manifests with chronic changes. Rapid weight gain, loss of menses, decreased libido, weakness, and bruising are all possible presenting symptoms. Many patients have hypertension, glucose intolerance, and insomnia. Memory and mental health disturbances occur in 50% of patients.¹ Depressed linear growth and excess weight gain are the most common presentations in pediatrics.⁶

Most adrenal tumors are incidentalomas, or the unexpected finding of a mass on computed tomography (CT) or magnetic resonance imaging (MRI) done for other reasons. Most (85%) of these masses are nonfunctional adrenal adenomas; the remainder are pheochromocytoma or metastasis from other organ cancers.⁸ Symptoms of pheochromocytoma are episodic and include headache, diaphoresis, and palpitations, which may occur several times daily or only a few times a month. The symptomatic episodes last 15 to 30 minutes and may be precipitated by specific activities, such as position change, Valsalva maneuver, exercise, anxiety, or medications (e.g., anesthesia or metoclopramide).⁴

Physical Examination

Patients with Addison disease appear chronically ill. They exhibit weight loss, dehydration, and increased skin pig­mentation on light-exposed skinfolds, a result of melanocyte stimulation by pituitary hormones. Darkened creases on the palms, elbows, knees, and lips commonly occur. Persons of color have darkened mucous membranes. Most discolorations resolve with adequate glucocorticoid therapy. Patients with secondary ACTH deficiency do not develop these skin changes.¹

Patients with Cushing syndrome have a characteristic habitus similar to but subtly and importantly different from that of many patients with exogenous obesity. Central obesity, a moon face appearance caused by thickening of facial fat, the classically described buffalo hump dorsocervical fat pad (very common with all obesity), increased supraclavicular fat pads, hypertension, muscle weakness and wasting, hirsutism, red-purple abdominal skin striae of more than 1 cm in size, and acne can be associated signs. Emotional lability or depression, “senile” purpura on the hands, and other bruising can occur in all age groups.¹

The hallmark of pheochromocytoma is a new onset of moderate to severe hypertension, with systolic pressures above 170 mm Hg. Arrhythmias, sinus tachycardia, or bradycardia may be present. The course is characterized by substantial variations in blood pressure measurements, palpitations, orthostasis, glucose intolerance, and diaphoresis, making “catching” it on a scheduled examination difficult. One third of patients have consistently normal blood pressure.⁴ Cushing syndrome can be considered as a differential diagnosis for refractory hypertension.