Medication Summary
Patients with classic salt-losing 3-beta–hydroxysteroid dehydrogenase require replacement of glucocorticoids, mineralocorticoids, and sex steroids.
For late-onset (nonclassic) 3-beta–hydroxysteroid dehydrogenase deficiency, the need for replacement therapy varies, depending on the severity of the defect. Hydrocortisone (or other glucocorticoid) replacement suppresses excess androgens in children with premature pubarche and may correct menstrual irregularities and decrease hirsutism and acne in pubertal and postpubertal females.
Approximately 15 mg/m2/d of oral hydrocortisone divided 3 times daily may be used as an initial dose. Hydrocortisone is the drug of choice in infants and children. Longer-acting preparations, such as prednisone and dexamethasone, are difficult to titrate and can lead to overtreatment and growth suppression. Fludrocortisone acetate, 50 mcg (newborns and infants) to 200 mcg (older children) per day, is also required in patients with salt-losing variants of 3-beta–hydroxysteroid dehydrogenase deficiency. Adjust long-term dosages on an individual basis.
Exogenous glucocorticoid therapy suppresses adrenocorticotropic hormone (ACTH) secretion and decreases pregnenolone, 17-hydroxypregnenolone, and DHEA levels. Exogenous mineralocorticoid therapy normalizes both renin and ACTH levels. Combination therapy of mineralocorticoid plus glucocorticoid replacement reduces total glucocorticoid dose required and improves statural growth.
Glucocorticoids
Class Summary
Exogenous glucocorticoid therapy suppresses adrenocorticotropic hormone (ACTH) secretion, decreasing pregnenolone, 17-hydroxypregnenolone, and dehydroepiandrosterone (DHEA) levels. Doses used are somewhat empirical and must be individualized based on clinical findings, growth and skeletal maturation, and hormonal data, including monitoring of pregnenolone, 17-hydroxypregnenolone, and DHEA levels.
Hydrocortisone (A-Hydrocort, Cortef, Hydrocort)
Longer-acting preparations, such as prednisone and dexamethasone, are difficult to titrate and can lead to overtreatment and growth suppression.
Mineralocorticoids
Class Summary
Exogenous mineralocorticoid therapy is required in patients with salt-losing variants of CAH (21-hydroxylase deficiency and 3-beta–hydroxysteroid dehydrogenase [3BHSD] deficiency). Plasma renin levels are elevated in patients with untreated salt-losing variants, and the addition of mineralocorticoid replacement normalizes both renin and ACTH levels. Combination therapy of mineralocorticoid plus glucocorticoid replacement reduces total glucocorticoid dose required and improves statural growth.
Fludrocortisone acetate (Florinef)
Only drug available in this category. Promotes increased reabsorption of sodium and loss of potassium renal distal tubules. Dosages are adjusted to achieve suppressed plasma renin levels.
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Normal adrenal steroid biosynthesis results in 3 products: mineralocorticoid (aldosterone), glucocorticoids (cortisol), and androgens (androstenedione). Cortisol production is regulated by feedback with adrenocorticotropic hormone (ACTH). ACTH stimulates the enzyme P-450scc (20,22 desmolase) with subsequent increased production of all adrenal steroids.
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Representation of typical congenital adrenal hyperplasia (CAH). In this example, both the mineralocorticoid and glucocorticoid pathways are deficient. Decreased serum cortisol levels stimulate adrenocorticotropic hormone (ACTH) release via negative feedback. Increased ACTH secretion results in overproduction of adrenal steroids preceding the missing enzyme as well as those not requiring the missing enzyme. In this example, a deficiency of 21-hydroxylase results in deficient mineralocorticoid and glucocorticoid production and excessive androgen production.
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3-beta-hydroxysteroid dehydrogenase (3BHSD) is required for the synthesis of all three groups of adrenal steroids: mineralocorticoids, glucocorticoids, and sex steroids. 3BHSD catalyzes the conversion of pregnenolone to progesterone (mineralocorticoid pathway), 17-alpha-hydroxypregnenolone to 17-alpha-hydroxyprogesterone (glucocorticoid pathway), and dehydroepiandrosterone to androstenedione (sex steroid pathway). Complete absence of this enzyme thus impairs all steroid production. 17OH Preg = 17-alpha-hydroxypregnenolone; DHEA = Dehydroepiandrosterone; 17OH Prog = 17-alpha-hydroxyprogesterone; Andros = Androstenedione; DOC = Deoxycorticosterone; Cmp S = Compound S.
