21-hydroxylase deficiency medical therapy

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Mehrian Jafarizade, M.D [2]

Overview

Medical therapy for classic type of 21-hydroxylase deficiency includes maternal administration of dexamethasone for genetically recognized patients. Hydrocortisone and fludrocortisone is given in children and adults. Treatment for non-classic type of 21 hydroxylase deficiency in children includes hydrocortisone until puberty and in women oral contraceptive pills are given for regulating menstrual cycle. Men with non-classic type of 21 hydroxylase deficiency are asymptomatic and they do not need treatment.

Medical Therapy for classic type of 21 hydroxylase deficiency

Neonatal management

Medical therapy for 21-hydroxylase deficiency in prenatal period, neonates, children and adults, is as below:

Prenatal treatment

In the prenatal period virilization of female fetus begins early; therefore, early diagnosis and treatment are required as follows:

• If classic CYP21A2 gene mutations exist in parents, maternal administration of dexamethasone should be prescribed
  • Preferred regimen: Dexamethasone 20 micrograms/kg/day in 2 or 3 fractioned doses orally
  • Dexamethasone crosses the placenta into the fetal circulation and prevents ambiguous genitalia in female fetus
  • This treatment should be started before 9 weeks of pregnancy age; if treatment cannot be started by 9 weeks, it should not be given at all
  • If in cell-free fetal DNA testing male fetus is detected, treatment should be discontinued
  • Approximately 85% of managed cases appear quite normal after delivery
  • Side effects of prenatal dexamethasone are:   
    • Postnatal failure to thrive
    • Psychomotor developmental delay
    • Increased risk of cleft lip and palate
    • Increased risk for psychiatric disturbances and ADHD

Neonatal treatment

Medical therapy for 21-hydroxylase deficiency in the neonates is as follows:

• Preferred regimen: Hydrocortisone 20 to 30 mg/m²/day divided in three doses PO AND Fludrocortisone 100 mcg twice daily PO AND sodium chloride one gram or 4 mEq/kg/day divided in several doses PO
  • The minimization of steroid doses should be considered to avoid steroid complications in infants 
  • Growth suppression and shorter height in adulthood are the complications of using high dose steroids which occurs in neonates

Ambiguous genitalia 

• Ambiguous genitalia should be managed immediately
• Infants with ambiguous genitalia and non palpable gonads should be considered to have congenital adrenal hyperplasia and empirical treatment should be start early after obtaining blood sample for 17-hydroxyprogesterone
• Initial empiric therapy should contains doses of glucocorticoid and mineralocorticoid and sodium chloride supplementation
  • Preferred regimen: Hydrocortisone is 20 to 30 mg/m²/day divided in three doses PO AND Fludrocortisone 100 mcg twice daily PO AND sodium chloride one gram or 4 mEq/kg/day divided in several doses PO

Adrenal crisis

• Preferred regimen: Normal saline 0.9 percent, 20 mL/kg intravenous bolus AND dextrose 10 percent 2 to 4 mL/kg intravenous bolus (if there is significant hypoglycemia) AND hydrocortisone 50 to 100 mg/m² intravenous bolus, THEN continue hydrocortisone alone 50 to 100 mg/m² IV per day divided into four times per 24 hours
• The blood sample should be obtained for steroid hormone levels before giving hydrocortisone  
• Hyperkalemia should be corrected on the base of its level and complications

Children management

• Preferred regimen: Hydrocortisone (cortisol) in a dose of 10 to 15 mg/m2 body surface area/day orally AND fludrocortisone in a dose of 50 to 200 mcg per day (0.05 to 0.20 mg/day) orally
  • Mineralocorticoid replacement should be started in all 21-hydroxylase deficient patients, and often may be tapered after six months of age

Response to therapy can be monitored by below items:

• • Serum 17-hydroxyprogesterone
  • Androstenedione
  • Plasma renin activity or direct renin
  • Height measurements

Adults management

21 hydroxylase deficiency should be managed as follows:

Treatment goals

• Provide proper dosing of glucocorticoid and mineralocorticoid.
• Decrease secretion of cosyntropin; therefore decrease adrenal overstimulation and androgen production.

Glucocorticoids and mineralocorticoid replacement: 

• Preferred regimen: Hydrocortisone 15-30 mg per day divided into three doses orally AND 9-alpha-fludrocortisone acetate 0.1 to 0.2 mg/day PO
• Alternative regimen (1): Dexamethasone 0.75 mg per day orally AND 9-alpha-fludrocortisone acetate 0.1 to 0.2 mg/day PO
• Alternative regimen (2): Prednisone 5mg pe day orally AND 9-alpha-fludrocortisone acetate 0.1 to 0.2 mg per day PO

Considerations:

• Glucocorticoids reduce the excess production of adrenal androgens and reduce the excessive secretion of both corticotropin-releasing hormone and ACTH
• Stress dosing: In patients with 21-hydroxylase deficiency and serious illness, glucocorticoids stress dosing is necessary
• Dexamethasone is very potent and long-acting glucocorticoid that effectively suppresses ACTH secretion but almost always causes the development of cushingoid appearance with chronic use
• The proper dose of fludrocortisone acetate should be used to restore normal serum potassium concentrations and plasma renin activity

Therapy consideration in women

• Lowering blood androgen levels with glucocorticoids, can helps women to control annoying cosmetic symptoms such as acne and hirsutism.
• In  21 hydroxylase deficient patients oral contraceptive pills in combination with glucocorticoids can be used to regulate the menstrual cycle and induction of ovulation.

Medical Therapy for non-classic type of 21 hydroxylase deficiency

Medical Therapy for non-classic type of 21 hydroxylase deficiency is as following:

Children

• Preferred regimen: Hydrocortisone 10 to 15 mg/m² divided into three doses per day.
  • Treatment should be continued until puberty.

• • In symptomatic girls after puberty, other treatment options such as oral contraceptive pills can be used in order to avoid glucocorticoids.

Adults

• Female patients may need oral contraceptive pills in order to regulate menstrual cycle; oral contraceptive pills are preferred other than glucocorticoids in this condition.
• Female patients with infertility and anovulatory cycles who desire conceive, glucocorticoids with above dosage are the initial choice for ovulation induction.

• Male patient with non-classic 21 hydroxylase deficiency are asymptomatic and they do not need treatment.