Medication Summary
Short-term medical therapy
In patients with hypotension, 0.9% (isotonic) sodium chloride solution (450 mL/m2 or 20 mL/kg IV) must be rapidly administered over the first hour. This is followed by a continuous IV infusion of 3200 mL/m2/d or 200 mL/kg per 100 cal/d of estimated resting energy expenditure as isotonic or half-isotonic sodium chloride solution to restore intravascular volume. Dextrose must also be provided.
If the patient is hypoglycemic, 2-4 mL of dextrose 10% in water (D10W) should be administered to increase the blood sugar, followed by a continuous infusion of dextrose 5% in water (D5W). If the patient is not hypoglycemic, D5W should be administered to prevent hypoglycemia. Patients with salt-wasting forms of adrenal hyperplasia do not need potassium supplementation because they are usually hyperkalemic. However, patients with 11-hydroxylase and 17-alpha-hydroxylase deficiency may be hypokalemic and may require potassium. After appropriate diagnostic studies are performed or after the results are known, glucocorticoid therapy, mineralocorticoid therapy, or both may be started.
In patients who are sick and who have signs of adrenal insufficiency, therapy should consist of stress dosages of hydrocortisone (50-100 mg/m2 or 1-2 mg/kg IV administered as an initial dose), followed by 50-100 mg/m2/d IV divided every 6 hours. Comparable stress dosages include 10-20 mg/m2 of methylprednisolone administered IV or intramuscularly (IM) and 1-2 mg/m2 of dexamethasone. Methylprednisolone and dexamethasone have negligible mineralocorticoid effects. Therefore, if the patient is hypovolemic, hyponatremic, or hyperkalemic, large dosages of hydrocortisone (double or triple the stress dosages mentioned above) are preferred because of its mineralocorticoid effect.
No parenteral form of mineralocorticoid is currently available in the United States; however, if the patient has good GI function, administer 0.05-0.2 mg of fludrocortisone by mouth (PO).
Long-term medical therapy
The goal of therapy for adrenal hyperplasia is the replacement of glucocorticoid and mineralocorticoid to prevent signs of adrenal insufficiency and to prevent the accumulation of precursor hormones that cause virilization. Adequate glucocorticoid replacement should prevent excessive concentrations of ACTH from stimulating the adrenal glands to produce abnormal concentrations of adrenal androgens that result in further virilization. In the growing child with adrenal insufficiency, long-term glucocorticoid replacement must be balanced to prevent symptoms of adrenal insufficiency while still allowing the child to grow at a normal rate and prevent symptoms of glucocorticoid excess. The dosage must be tailored to each patient. The recommended hydrocortisone starting dose is 8-10 mg/m2/day divided in 2-3 doses, but the general average maintenance dosage is 10-25 mg/m2/day of hydrocortisone PO divided in 2-3 doses.
Hydrocortisone is available in 5-mg, 10-mg, and 20-mg tablets. Also, an immediate-release oral granule product (Alkindi Sprinkle) is available in 0.5-mg, 1-mg, 2-mg, and 5-mg dosage sizes to assist with dosing in young children. Hydrocortisone is recommended in the pediatric population because of its lower potency, which permits easier titration of appropriate doses. Unfortunately, hydrocortisone suspension (Cortef solution) is no longer available in the United States.
Prednisone, prednisolone, or even dexamethasone suspensions may be used. Prednisone is available in a suspension of 1 mg/mL, and prednisolone is available in a solution of 5 or 15 mg/5 mL. The estimated equivalencies are as follows: [36]
-
One mg of prednisone is equal to 4 mg of hydrocortisone.
-
One mg of prednisolone is equal to 5 mg of hydrocortisone.
-
One mg of dexamethasone is equal to 50 mg of hydrocortisone.
These forms of glucocorticoid have the advantage of half-lives longer than those of hydrocortisone, permitting twice-daily or even once-daily dosing (dexamethasone), which often aids compliance. However, because of their increased potency, growth suppression and other signs of glucocorticoid excess are common.
Administer fludrocortisone (0.05-0.2 mg/d PO) to patients with mineralocorticoid deficiency. Administer NaCl (2-5 g/d) to infants to counteract salt wasting. Older children can usually scavenge adequate salt to provide for their needs and may lose their salt-wasting tendencies as they mature. The dose of glucocorticoid is adjusted by clinically evaluating the patient (for an absence of symptoms of glucocorticoid deficiency and normal growth) and by periodically measuring the concentrations of precursor hormones. For example, in 21-hydroxylase deficiency, keeping plasma concentrations of 17-hydroxyprogesterone in the 200- to 500-ng/dL range and keeping androstenedione in the normal physiologic range is desirable.
Plasma ACTH concentrations are of little help in adjusting doses of glucocorticoid in patients with primary adrenal insufficiency. Monitoring symptoms of salt craving and blood pressure, PRA, and electrolyte levels are helpful in adjusting the dose of fludrocortisone. High blood pressure with suppressed PRA should prompt a reduction in fludrocortisone dose.
Stress or illness
One of the important physiologic responses to stress is an increase in the cortisol production that ACTH mediates. Patients with adrenal insufficiency of any etiology cannot mount this response and must be given stress doses of glucocorticoid. In the patient with a minor illness (temperature of < 38°C), the dosage of hydrocortisone should be at least doubled. For patients with relatively severe illness (temperature of >38°C), the dosage of glucocorticoid should be tripled. If the patient is vomiting or listless, administer parenteral glucocorticoid (50-75 mg/m2 of hydrocortisone IM or IV or an equivalent dosage of methylprednisolone or dexamethasone). Because hydrocortisone succinate has a short duration of action, the dose must be repeated every 6-8 hours at a dosage of 50-100 mg/m2/d until the patient is well.
All patients with adrenal insufficiency must have injectable glucocorticoid available, and the caretaker must be instructed in its use and importance. Glucocorticoid or mineralocorticoid replacement has no contraindications when it is needed, and it has few drug-drug interactions.
Glucocorticoids
Class Summary
The purpose of glucocorticoid therapy in congenital adrenal hyperplasia is (1) to replace the body's requirement for glucocorticoids under normal conditions and during stress and (2) to suppress ACTH secretion, thereby reducing the stimulus for the adrenal glands to overproduce adrenal androgens in virilizing forms of congenital adrenal hyperplasia. Unfortunately, no currently available preparation is able to mimic the diurnal rhythm of physiologic cortisol secretion. Thus, in an attempt to suppress androgen secretion from the adrenal glands in response to early morning rises in ACTH, overtreatment often occurs, resulting in inhibition of linear growth and Cushingoid features.
Hydrocortisone (Alkindi Sprinkle, Cortef)
Mimics actions of cortisol, which is the primary steroid hormone secreted by adrenal zona fasciculata and reticularis. DOC in children owing to short half-life and decreased potential for growth suppression. Mineralocorticoid effect occurs with large doses.
Mineralocorticoids
Class Summary
Replacement of mineralocorticoids is required in patients who have salt-wasting congenital adrenal hyperplasia. This treatment is necessary to replace the aldosterone that is insufficiently produced by the adrenal cortex.
Fludrocortisone acetate (Florinef)
Synthetic steroid with predominantly mineralocorticoid activity. Acts on renal tubule to promote sodium retention in exchange for potassium or hydrogen ion and thus maintain intravascular and extracellular volume. For patients who require parenteral mineralocorticoid therapy, high-dose hydrocortisone must be used. Available only as tab; may be crushed for infants and children.
-
Enzymes and genes involved in adrenal steroidogenesis.
-
Steroidogenic pathway for cortisol, aldosterone, and sex steroid synthesis. A mutation or deletion of any of the genes that code for enzymes involved in cortisol or aldosterone synthesis results in congenital adrenal hyperplasia. The particular phenotype that results depends on the sex of the individual, the location of the block in synthesis, and the severity of the genetic deletion or mutation.
-
A female patient with the 46,XX karyotype with mild virilization due to congenital virilizing adrenal hyperplasia secondary to 21-hydroxylase deficiency. Despite the mild clitoromegaly, this patient has fusion of the labial-scrotal folds and salt wasting.
-
Severe virilization in a female patient with the 46,XX karyotype with congenital adrenal hyperplasia secondary to 21-hydroxylase deficiency. This patient also has salt wasting.
-
Short stature in a male patient with congenital adrenal hyperplasia secondary to 21-hydroxylase deficiency. His compliance with medical therapy was poor, and early growth and skeletal maturation was advanced, resulting in early puberty and completion of growth. This 12-year-old boy has reached final adult height, which is well below that of his mother.
