Adrenal Disorders

The adrenal gland makes glucocorticoids, mineralocorticoids, and androgens. Deficiency of glucocorticoid and/or mineralocorticoid production presents as adrenal insufficiency, whereas excess production of glucocorticoids, mineralocorticoids, and/or androgens may result in various signs and symptoms as described below.

• Congenital adrenal hyperplasia (CAH) is the most common cause of visible genital abnormalities in female infants.

• The most common cause of primary adrenal insufficiency is autoimmune.

• Adrenoleukodystrophy (ALD) is another important cause of primary adrenal insufficiency; all boys with ALD should be screened for adrenal function beginning in infancy.

• The hypercortisolism in Cushing syndrome causes obesity and decreased growth velocity, and patients may also present with moon facies, dorsocervical fat pad (“buffalo hump”), striae, acne, hirsutism, and decreased strength.

• Adrenal steroid synthesis is responsible for mineralocorticoid production in the zona glomerulosa, glucocorticoid production in the zona fasciculata, and androgen production in the zona reticularis.

(Source: Congenital Adrenal Hyperplasia. N Engl J Med 2003.)

Physiologic Production of Glucocorticoids

The physiologic production of glucocorticoids is thought to be about 8-10 mg of cortisol (hydrocortisone) per square meter of body surface area per day for infants and 6-10 mg/m²/day for children and adults. During times of stress, there is a physiologic increase in glucocorticoids. Glucocorticoid needs are estimated as 2 to 3 times the baseline requirements during minor stressors (e.g., viral infections) and 5 to 10 times the baseline requirements during major stressors (e.g., trauma or surgery).

Medications for Adrenal Hormone Replacement

Glucocorticoids: Glucocorticoid medications (previously often referred to as steroids) include hydrocortisone, prednisone, and dexamethasone. Therapeutic doses of prednisone and dexamethasone used for inflammatory conditions such as asthma or inflammatory bowel disease are much higher than those needed for physiologic adrenal replacement. Most glucocorticoids also have some mineralocorticoid effect.

Endocrinologists generally dose glucocorticoids based on hydrocortisone equivalents. (The dose of the specific glucocorticoid prescribed is converted to “hydrocortisone equivalents” based on potency and compared to the amount of physiologic hydrocortisone production.) In general, 1 mg of prednisone is equivalent to about 4-5 mgs of hydrocortisone, and 1 mg of dexamethasone is equivalent to about 40-50 mg of hydrocortisone. The relative potency of glucocorticoids is shown in the table below.

Mineralocorticoids: Oral fludrocortisone is the only available pure mineralocorticoid. High (“stress”) doses of glucocorticoids (except dexamethasone) often have enough mineralocorticoid effect to cover mineralocorticoid needs so that fludrocortisone is not required during stress dosing of glucocorticoids. Note that dexamethasone has no mineralocorticoid effect.

Adrenal Exam

• For congenital adrenal hyperplasia (CAH):

  • In infants, overall impression is important. If a child is ill-appearing, steroids should be administered immediately before further evaluation.

  • Perform a careful genital exam (see Differences in Sexual Development).

  • Assess for hyperpigmentation. In males, the scrotum is often more rugated and pigmented than normal.

• For suspected primary adrenal insufficiency:

  • Hyperpigmentation may be widespread. When it is not, it is most often seen in the creases of the hands, along the gums, or at areas of increased friction.

  • Weight loss or failure to gain weight will often be apparent on the growth chart. (Height is usually not affected unless growth slows from poor nutrition.)

• For patients with possible pituitary involvement or a CNS cause of adrenal insufficiency:

  • Perform visual field exam via confrontation. Visual field cuts may indicate a lesion abutting the optic chiasm.

• For suspected Cushing syndrome (excess glucocorticoid from any cause) or Cushing disease (excess glucocorticoid due to an adrenocorticotropic hormone (ACTH)-producing pituitary adenoma):

  • Assess fat distribution: Central and truncal fat accumulation or dorsocervical fat (“buffalo hump”) are common, as is increased fat in the supraclavicular space. Extremities are typically thinner in comparison to the trunk.

  • Assess for decreased strength of major muscle groups (quadriceps and biceps): Ask the patient to stand from squatting, which may be hard for people with Cushing syndrome.

  • Assess growth charts in children who are still growing: Cushing syndrome in children is almost always accompanied by decreased growth velocity.

  • Check for hirsutism and acne.

  • Check for striae: Wide (approximately 1 cm), violaceous striae are typical of Cushing syndrome and are due to skin thinning from glucocorticoid excess.

Congenital Adrenal Hyperplasia

Congenital adrenal hyperplasia (CAH) is an autosomal recessive condition caused by mutations in both alleles encoding one of the five enzymes necessary for cortisol synthesis. The most frequent defect is in 21-hydroxylase, which is required for both cortisol and aldosterone synthesis and is the focus of this section. The phenotype of CAH depends on the severity of the mutation:

• Simple virilizing CAH: Mutations in which some enzyme function is preserved lead to deficiency of cortisol but allow for enough mineralocorticoid production.

• Salt-wasting CAH: Mutations in which all or nearly all enzyme function is lost lead to deficiency of both cortisol and aldosterone.

• Nonclassic CAH: Very mild mutations lead to a milder form of CAH in which adequate cortisol can be produced at the expense of producing higher levels of adrenal androgens. Nonclassic CAH can present with more-subtle virilization or irregular menses later in life, and probably goes undiagnosed in males.

• Other forms of CAH: Other rare types of CAH cause different patterns of change in the adrenal steroids and different types of symptoms, depending on which steroids increase and decrease.

CAH Due to 21-Hydroxylase Deficiency

Key to understanding CAH is that cortisol usually exerts feedback at the pituitary to decrease secretion of adrenocorticotropic hormone (ACTH). Lack of cortisol feedback in CAH leads to high amounts of ACTH in circulation. These high levels of ACTH put the adrenal steroid synthesis pathway in overdrive:

• Because of dysfunction of the enzyme 21-hydroxylase, a “block” in the pathway is created and all steroid precursors are shunted over into the androgen synthesis pathway. This is what causes the virilization.

• Additionally, the “block” at 21-hydroxylase leads to an accumulation of 17-hydroxyprogesterone (17OHP), the steroid right above the dysfunctional enzyme in the pathway. An elevated 17OHP is used to screen for and diagnose CAH.

Presentation

• In the salt-wasting form, hyperkalemia and hyponatremia start around days 5-14 of life. Dehydration and shock-like presentation develop if diagnosis is delayed. Although females with salt-wasting CAH usually receive a timely diagnosis due to external virilization of the genitalia, diagnosis in males was often delayed before CAH was added to the newborn screen.

• In salt-wasting and simple virilizing forms, female infants have varying degrees of virilization, often with an enlarged clitoris/phallic structure and a single urogenital sinus (see image below). Male infants may have increased penile size and scrotal hyperpigmentation. In females, the uterus, fallopian tubes, and ovaries are normally formed.

• In the simple virilizing form, children who are not diagnosed until later in childhood are likely to have growth acceleration and advanced bone age (due to increased androgens). They may present with early development of pubic hair and axillary hair, body odor, and acne (i.e., premature adrenarche).

• In both salt-wasting and simple virilizing forms, long-term exposure to adrenal androgens can activate the hypothalamic-pituitary-gonadal axis early and lead to central precocious puberty.

• Nonclassic CAH often manifests with premature adrenarche, precocious puberty, irregular menses, or, in older girls, a polycystic ovary-like phenotype with hirsutism, oligomenorrhea, and acne.

(Source: Congenital Adrenal Hyperplasia. N Engl J Med 2015.)

Diagnosis

• The newborn screen assesses levels of 17OHP for diagnosis of CAH before salt-wasting crisis develops. Endocrinology should be contacted for infants with elevated 17OHP on newborn screen. (Reasons for false positives include prematurity or significant stress around delivery.)

• Infants with elevated 17OHP should have expedited in-person assessment that includes physical exam and assessment of electrolytes, repeat 17OHP, and cortisol levels. Plasma renin activity may also be helpful in establishing whether the infant has salt wasting.

• The gold standard for diagnosing CAH due to 21-hydroxylase deficiency is an ACTH stimulation test, measuring 17OHP, cortisol, and other adrenal steroid precursors before and 60 minutes after administration of synthetic ACTH. This test may not be required in infants with such elevated baseline levels of 17OHP that the diagnosis is not in question.

• An infant with suspected CAH and normal initial electrolyte levels should be followed closely because abnormalities may not develop for 1 to 2 weeks.

Management

• Hydrocortisone should be given immediately in infants with suspected CAH who appear clinically unwell. If an infant appears well, measurement of electrolytes, cortisol, 17-hydroxyprogesterone, and plasma renin activity before administering hydrocortisone can aid diagnosis.

• Hydrocortisone is the preferred glucocorticoid replacement for infants and children with CAH who are still growing. (Prednisone and dexamethasone have more growth-suppressive effects, likely due to longer half-life.) Dosing of hydrocortisone is a balancing act whereby the lowest possible dose that adequately suppresses androgens should be used to minimize adverse effects on growth.

• Infants with salt wasting also require treatment with fludrocortisone and often supplemental salt during infancy. The mineralocorticoid axis matures with age, and salt supplementation can usually be discontinued after several months.

• Patients with nonclassic CAH may not require glucocorticoid therapy unless significant virilization (e.g., development of pubic hair) occurs at an early age. Girls with signs and symptoms resembling polycystic ovary syndrome (PCOS) can be treated with standard PCOS treatments or a small dose of glucocorticoid. Glucocorticoid therapy may be helpful in achieving fertility when it is desired.

• For female infants with CAH who have virilization of external genitalia, parents should be informed that surgery may be delayed until children can express their gender preferences and help decide if surgery is appropriate.

Adrenal Insufficiency

Primary adrenal insufficiency, resulting from hypofunction of the adrenal glands, leads to deficiency of both mineralocorticoid and glucocorticoid. Primary adrenal insufficiency is often referred to as Addison disease.

Secondary (or tertiary) adrenal insufficiency, resulting from hypofunction of the pituitary (or hypothalamus), leads only to glucocorticoid deficiency, whereas mineralocorticoid function remains intact.

Signs and Symptoms

• fatigue, malaise, weakness

• failure to gain weight

• nausea, abdominal pain

• hyponatremia (primary adrenal insufficiency)

• hyperkalemia (primary adrenal insufficiency)

• hypoglycemia

• salt craving (primary adrenal insufficiency)

• hyperpigmentation (primary adrenal insufficiency)

• hypotension, shock, fever, confusion (in adrenal crisis)

Diagnosis

Adrenal insufficiency should be suspected in an ill-appearing child with any of the signs or symptoms listed above. Timely recognition and administration of hydrocortisone may be lifesaving.

• If a patient is in extremis, hydrocortisone (50-100 mg/m² IM or IV) should be given without delay, followed by laboratory evaluation of electrolytes, plasma renin activity, and ACTH. When safe and feasible, however, it is optimal to delay hydrocortisone until a cortisol level can be checked along with electrolytes, plasma renin activity, and ACTH. Cortisol should be high in the setting of acute illness.

• Fluid management of suspected adrenal crisis should include IV hydration with an isotonic fluid (e.g., normal saline) that also contains glucose (D5 or D10).

ACTH stimulation testing is the standard approach for diagnosis of adrenal insufficiency.

• In high-dose and low-dose versions of the test, either 250 mcg or 1 mcg (or in some practices, 250 mcg/m² or 1 mcg/m²), respectively, of synthetic ACTH is administered. In both versions, ACTH and cortisol are checked at baseline.

• In the high-dose test, synthetic ACTH can be given by IV or IM, and cortisol is checked again 60 minutes after administration.

• In the low-dose test, synthetic ACTH should be given by IV, and cortisol is typically checked at 30 and 60 minutes.

• Endocrinologists disagree, but many advocate that the low-dose test is more sensitive when secondary adrenal insufficiency is suspected.

• A peak cortisol level of at least 18 mcg/dL is traditionally considered an adequate response to stimulation. However, many newer cortisol assays are more specific, resulting in slightly lower readings. In these assays, peak cortisol slightly below 18 mcg/dL may also be normal.

In acute secondary adrenal insufficiency, the adrenal glands still respond to ACTH, and cortisol levels following ACTH stimulation may be normal. If the diagnosis is highly suspected, the patient should be treated, and the test repeated several weeks later.

Causes

Iatrogenic adrenal insufficiency, resulting from adrenal hypofunction following exogenous steroid use, is the most common form of adrenal insufficiency. Systemic administration of glucocorticoids for ≥2 weeks may result in iatrogenic adrenal insufficiency, whereas administration of even very high doses for ≤7 days is unlikely to cause adrenal insufficiency. Steroid creams or inhaled corticosteroids are unlikely to cause adrenal hypofunction unless they are used inappropriately (i.e., excessive dose and duration) or are used concomitantly with medications that reduce steroid metabolism, resulting in increased systemic concentrations.

Patients prescribed long-term systemic glucocorticoids should be cautioned about the possibility of adrenal insufficiency and, when applicable, should be provided instructions for glucocorticoid dosing in cases of severe illness or medical emergency.

Adrenoleukodystrophy (ALD): Boys with ALD are at very high risk of developing adrenal dysfunction. ALD is a peroxisomal disorder caused by mutation in the ABCD1 gene on the X chromosome. Accumulation of very-long-chain fatty acids (VLCFA) causes tissue damage and dysfunction, particularly in the brain and adrenal glands. Manifestations are varied, with the most severe disease including cerebral inflammatory demyelination and adrenal insufficiency in early childhood. Newborn screening for ALD is currently being added in many states, and male infants found to have ALD should be referred to endocrinology for routine screening of adrenal function. Likewise, adrenal insufficiency may be the first presenting sign of ALD in boys who were born prior to newborn screening, and VLCFA should be measured in boys with new presentations of primary AI unless another cause is already known. The first adrenal deficit in boys with ALD is typically glucocorticoid deficiency that can progress to include mineralocorticoid deficiency.

(Source: Predisposing Factors for Adrenal Insufficiency. N Engl J Med 2009.)

Management

Glucocorticoid replacement is necessary in both primary and secondary adrenal insufficiency, and under normal circumstances it is accomplished with oral medication. Until growth is complete, hydrocortisone is preferred because its shorter half-life seems to result in less suppressive effect on growth. After completion of growth, prednisone, prednisolone, or other forms of glucocorticoid can be used. Baseline physiologic dosing of hydrocortisone is usually 8-10 mg/m²/day.

Stress dosing for mild stress usually involves doubling or tripling the usual dose of glucocorticoid. Generally, it is best to err on the side of giving more glucocorticoid rather than less. For prolonged hospitalization or surgery, following the initial stress dose, children should receive 50-100 mg/m² hydrocortisone per day by IV, divided every 6 hours.

Mineralocorticoid replacement is accomplished with fludrocortisone, usually 0.05-0.2 mg daily.

Cushing Syndrome

The term Cushing syndrome refers to any state of cortisol excess, whereas Cushing disease refers specifically to cortisol excess from an ACTH producing pituitary adenoma. Causes of cortisol excess include:

• iatrogenic, from excess glucocorticoid administration (the most common type)

• excess ACTH secretion from the pituitary gland (very rare)

• abnormal endogenous production of cortisol (e.g., due to an adrenal tumor; very rare)

• abnormal/ectopic source of corticotropin-releasing hormone (CRH) or ACTH (e.g., carcinoid tumor, often referred to as ectopic Cushing syndrome and very rare)

Signs and Symptoms

• weight gain that is refractory to dieting and increased exercise

• reduced growth velocity in children who are still growing

• abnormal fat accumulation in the abdomen, dorsocervical area, and supraclavicular area

• wide, violaceous striae and easy bruising due to glucocorticoid effect to weaken skin

• moon facies (rounded facial appearance or facial plethora)

• irregular menses

• hirsutism, acne, female balding

• reduced proximal muscle strength, fatigue, depression

Moon facies, dorsocervical fat accumulation, hirsutism, and overall obesity in a child with Cushing syndrome. Please note that this is a particularly extreme presentation. (Source: Mutation in PDE8B, a Cyclic AMP-Specific Phosphodiesterase in Adrenal Hyperplasia. N Engl J Med 2008.)

(Source: Ectopic Cushing’s Syndrome. N Engl J Med 2011.)

Diagnosis and Management

The Endocrine Society provides guidelines for the diagnosis and management of Cushing syndrome. In children, the first diagnostic step is usually to order either late-night salivary cortisol levels or a 24-hour urine collection for urinary free cortisol measurement.

• For late-night salivary cortisol levels, patients are sent home with a cotton swab to chew before bed, and free cortisol is measured from the collected saliva. Because patients with Cushing syndrome lack diurnal variation in cortisol, late-night levels of cortisol that are normally very low are not low.

• A dexamethasone suppression test is also an appropriate initial test for Cushing syndrome. In the most commonly used version of this test, 1 mg of dexamethasone is given around 11 p.m. with a measurement of serum cortisol at 8 a.m. the next morning. Dexamethasone should exert negative feedback on ACTH to decrease endogenous cortisol production, such that low cortisol (<1.8 mcg/dL) is a normal response.