21-hydroxylase deficiency medical therapy

Congenital adrenal hyperplasia main page
Overview
Classification 21-hydroxylase deficiency
11β-hydroxylase deficiency
17 alpha-hydroxylase deficiency
3 beta-hydroxysteroid dehydrogenase deficiency
Cytochrome P450-oxidoreductase (POR) deficiency (ORD)
Lipoid congenital adrenal hyperplasia
Differential Diagnosis

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

Overview

Medical treatment of 21-hydroxylase deficiency disorder depends on age: neonatal treatment is hydrocortisone or fludrocortisone as early as possible. If treatment cannot be started by 9 weeks, it should not be given at all. Surgical correction of ambiguous genitalia is the best treatment. Adults management: Hydrocortisone and Fludrocortisone acetate are the treatment of choice. CAH  patients need oral contraceptive pills to regulate the menstrual cycle and induction of ovulation.

Medical Therapy

Neonatal management

Prenatal diagnosis

Virilization of female fetus begins early; Therefore, early diagnosis and treatment are required as following :

• If classic CYP21A2 gene mutations exist in parents, maternal administration of dexamethasone. Dexamethasone crosses the placenta into the fetal circulation and prevents ambiguous genitalia in female fetus.
• This treatment should be started before nine 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 detected, treatment should be discontinued.
• 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

• Hydrocortisone is 20 to 30 mg/m²/day divided in three doses 
• Fludrocortisone 100 mcg twice daily 
• One gram or 4 mEq/kg/day of sodium chloride divided in several doses 
• One first time high doses of hydrocortisone, 50 mg/m²/day, can be used in order to suppress adrenal hormones.  
• The minimization of steroid doses should be considered to avoid steroid complications. 

• Growth suppression and shorter height in adulthood are the complications of using high d occurs in neonates treated with high doses of hydrocortisone.

Ambiguous genitalia 

• Ambiguous genitalia should be managed immediately. Infants with ambiguous genitalia and nonpalpable 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
• Reconstructive surgery can be done in patients.

Adrenal crisis

• Normal saline 0.9 percent, 20 mL/kg should be administered.
• An intravenous bolus of 2 to 4 mL/kg of 10 percent dextrose should be considered if there is significant hypoglycemia.  
• Initial dose of hydrocortisone of 50 to 100 mg/m² should be administered as an IV bolus, then 50 to 100 mg/m² IV per day divided four times a day.  
• 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

Glucocorticoid replacement is necessary in all infants and children who have classic 21-hydroxylase deficiency. In infants and children, this is usually administered as hydrocortisone (cortisol) in a dose of 10 to 15 mg/m2 body surface area/day

Mineralocorticoid replacement is necessary in all pediatric patients who have classic 21-hydroxylase deficiency. Mineralocorticoid replacement can often be tapered after four to six months of age. Caution should be used, especially in the first 18 months of life, to avoid inducing hypertension as the neonatal kidney matures and becomes more sensitive to mineralocorticoids. Dosing should be guided by measurement of plasma renin activity and blood pressure

Response to therapy is monitored by measuring serum 17-hydroxyprogesterone, androstenedione, plasma renin activity or direct renin, as well as growth velocity (measured by serial measurements of height), blood pressure, and the rate of skeletal maturation. Laboratory and clinical monitoring should be performed every month in the neonate and infant, and every three to six months thereafter. Bone age should be measured at least annually after two years of age until skeletal maturity

Adults management

Goals of therapy — The two major goals of therapy for classic 21OHD in adults are to: ● Provide adequate glucocorticoid and mineralocorticoid replacement, as with any form of adrenal insufficiency

● Reduce the excessive secretion of both corticotropin-releasing hormone (CRH) and corticotropin (ACTH) and, thus, attenuate the production of adrenal-derived androgens

These goals can be difficult to achieve without overtreatment, with its attendant risk of bone loss, obesity, and other clinical manifestations of Cushing's syndrome

Glucocorticoids 

• Glucocorticoids reduce the excess production of adrenal androgens and reduce the excessive secretion of both corticotropin-releasing hormone and  ACTH.

Preferred Regimen Hydrocortisone 15-30 mg/d divided into three doses Alternative Regimen

hydrocortisone, a short-acting glucocorticoid, is the treatment of choice.

• Dexamethasone a very potent and long-acting glucocorticoid effectively suppresses ACTH secretion but almost always causes the development of Cushingoid features with chronic use.
• Combination therapy, with typical doses of hydrocortisone to replace the cortisol deficiency during the day and a very small dose of a long-acting glucocorticoid. We suggest this approach when standard hydrocortisone regimens are ineffective.
• Stress dosing: patients with classic 21OHD should be provided stress dosing.

Mineralocorticoid replacement 

• Fludrocortisone acetate, in a dose sufficient to restore normal serum potassium concentrations and plasma renin activity.
• The usual adult dose of fludrocortisone is 0.1 to 0.2 mg/day.
• Patients who are undertreated and in chronic poor control develop testicular adrenal rest tumors.

Infertility in men

• Sperm production is often impaired in untreated men due to defected spermatogenesis and Leydig cells suppression.
• Most of the patients have severe oligospermia. Moreover, Most of the untreated patients have testicular tumors that need surgical removal.
• An elevated FSH is a sensitive indicator for patients fertility condition but semen analysis is the specific test.

Infertility in women

• Lowering blood androgen levels helps women to control annoying cosmetic symptoms such as acne and hirsutism.
• Similar to polycystic ovary syndrome, CAH  patients need oral contraceptive pills to regulate the menstrual cycle and induction of ovulation.
• Women need pregnancy should consult a surgeon to repair previous genital malformations.
• hydrocortisone doesn’t pass placenta so, it can be used safely during pregnancy.
• Glucocorticoids doses need to increase at end of pregnancy with careful monitoring.