21-hydroxylase deficiency medical therapy

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

Medical therapy for classic type of 21-hydroxylase deficiency includes maternal administration of dexamethasone for genetically diagnosed intranatal patients. Hydrocortisone and fludrocortisone is given in children and adults. Treatment for non-classic type of 21 hydroxylase deficiency in children includes hydrocortisone up to puberty and in women in reproductive age, oral contraceptive pills are given for regulation of menstrual cycle. Men with non-classic type of 21 hydroxylase deficiency are asymptomatic and do not need any treatment.

Medical therapy for 21-hydroxylase deficiency in prenatal period, neonates, children and adults, is as below:^{[1][2][3][4][5]}

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

• If classic CYP21A2 gene mutations exist in parents, maternal administration of dexamethasone should be prescribed.
  • Preferred regimen: Dexamethasone 20 micrograms/kg q24h 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 cell-free fetal DNA testing reveals the gender to be male, treatment should be discontinued.
    • Approximately 85% of managed cases appear quite normal after delivery.
    • Side effects of prenatal dexamethasone are:^{[6][7][8][9][10]}
      • Postnatal failure to thrive
      • Psychomotor developmental delay
      • Increased risk of cleft lip and palate
      • Increased risk for psychiatric disturbances and ADHD

2.1 Medical therapy for 21-hydroxylase deficiency in the neonates is as follows:^[4]

• Preferred regimen: Hydrocortisone 20 to 30 mg/m² q24h divided in three doses PO AND Fludrocortisone 100 mcg q12h PO AND sodium chloride one gram or 4 mEq/kg q24h 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.

2.2 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 q24h divided in three doses PO AND Fludrocortisone 100 mcg q12h PO AND sodium chloride one gram or 4 mEq/kg q24h divided in several doses PO.

2.3 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.

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

3.1 Response to therapy can be monitored by checking the following parameters:

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

21 hydroxylase deficiency should be managed as follows:^{[4][11][12][13][3][14][15]}

4.1 Treatment goals

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

4.2 Glucocorticoids and mineralocorticoid replacement 

• Preferred regimen: Hydrocortisone 15-30 mg q24h divided into three doses PO AND 9-alpha-fludrocortisone acetate 0.1 to 0.2 mg q24h PO.
• Alternative regimen (1): Dexamethasone 0.75 mg q24h PO AND 9-alpha-fludrocortisone acetate 0.1 to 0.2 mg q24h PO.
• Alternative regimen (2): Prednisone 5mg q24h PO AND 9-alpha-fludrocortisone acetate 0.1 to 0.2 mg q24h PO.

4.3 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.

4.4 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 is as following:^{[16][4][17][18]}

• Preferred regimen: Hydrocortisone 10 to 15 mg/m² divided into three doses q24h.
  • Treatment should be continued until puberty.
  • In symptomatic girls after puberty, other treatment options such as oral contraceptive pills may be used in order to avoid glucocorticoids.

• Female patients may need oral contraceptive pills for regulation of 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.

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