Congenital Adrenal Hyperplasia Treatment & Management

Infants with ambiguous genitalia should be closely observed for symptoms and signs of salt wasting while a diagnosis is being established. Clinical clues include abnormal weight loss or lack of expected weight gain. Electrolyte abnormalities generally take from a few days to 3 weeks to appear because the placenta maintains the fetal electrolytes in utero. In mild forms of salt-wasting adrenal hyperplasia, salt wasting may not become apparent until an illness stresses the child.

• Patients with dehydration, hyponatremia, or hyperkalemia and a possible salt-wasting form of adrenal hyperplasia should receive an intravenous (IV) bolus of isotonic sodium chloride solution (20 mL/kg or 450 mL/m²) over the first hour, as needed, to restore their intravascular volume and blood pressure.

  • This dosage may be repeated if the blood pressure remains low.

  • Dextrose must be administered if the patient is hypoglycemic and must be included in the rehydration fluid after the bolus dose to prevent hypoglycemia.

  • After samples are obtained to measure electrolyte, blood sugar, cortisol, aldosterone, and 17-hydroxyprogesterone concentrations, the patient should be treated with glucocorticoids based on suspected adrenal insufficiency. Treatment should not be withheld while confirmatory results are awaited because it may be life preserving (see Medication).

• After the patient's condition is stabilized, treat all patients who have adrenal hyperplasia with long-term glucocorticoid or aldosterone replacement (or both), depending on which enzyme is involved and on whether cortisol and/or aldosterone synthesis is affected.

• Another approach currently under investigation is the combined use of glucocorticoid (to suppress ACTH and adrenal androgen production), mineralocorticoid (to reduce angiotensin II concentrations), aromatase inhibitor (to slow skeletal maturation), and flutamide (an androgen blocker to reduce virilization).

• Some patients develop precocious puberty, which further compromises adult height. Suppression of puberty with long-acting gonadotropin-releasing hormone (GnRH) agonists while simultaneously stimulating growth with growth hormone may partially improve the patient's height. ^{[20, 21]}

The Endocrine Society's 2010 clinical practice guidelines note the following: ^[7]

• Prenatal treatment for CAH should be regarded as experimental.

• Glucocorticoid therapy should be carefully titrated to avoid Cushing syndrome.

• Mineralocorticoid replacement is encouraged. In infants, mineralocorticoid replacement and sodium supplementation are encouraged.

• Use of agents to delay puberty and promote growth are experimental.

• Psychiatric support should be encouraged for patients with adjustment problems.

• Medication should be used judiciously during pregnancy and in symptomatic patients with nonclassical CAH.

Infants with ambiguous genitalia require surgical evaluation and, if needed, plans for corrective surgery. The traditional approach to the female patient with ambiguous genitalia due to adrenal hyperplasia is clitoral recession early in life followed by vaginoplasty after puberty. ^[8]

Vocal groups of patients with disorders of sexual differentiation (eg, Intersex Society of North America) have recently challenged this approach.

Some female infants with adrenal hyperplasia have only mild virilization and may not require corrective surgery if they receive adequate medical therapy to prevent further virilization.

A study by Roth et al determined that between 2004 and 2014, 12% of girls in the Pediatric Health Information System database with congenital adrenal hyperplasia were treated with female genital restoration surgery. A vaginal procedure was performed in 92% of those who underwent the surgery, a clitoral procedure in 48%, and a perineal procedure (nonclitoral) in 85%. The initial operation was carried out at a median patient age of 9.9 months. Perioperative surgical complications occurred in 4% of the operative group. ^[22]

A retrospective study by Dangle et al on feminizing reconstructive surgery in 26 toddlers with congenital adrenal hyperplasia reported that the procedures are typically well tolerated and successful. Although complications were found in seven patients (27%), including dysuria, stitch dehiscence, wound separation, and urinary tract infection, revision surgery was needed in only two individuals (7.7%). The patients were followed up for an average of about 6 years. ^[23]

Bilateral adrenalectomies have been suggested in the management of virilizing forms of adrenal hyperplasia in order to prevent further virilization and advancement of skeletal maturation. ^[24] This approach is experimental and should be considered only in the context of a controlled study.

The Endocrine Society's 2010 clinical practice guidelines note the following: ^[7]

• Adrenalectomy should be avoided.

• While surgical reconstruction may not be necessary during the newborn period in mildly virilized girls, it may be appropriate in severely virilized girls. It should be a single stage genital repair, performed by experienced surgeons.

An endocrinologist should be consulted when adrenal insufficiency is suspected.

An experienced surgeon is required if genitalia are ambiguous or inconsistent with genetic sex and corrective surgery is contemplated.

A consultation with a geneticist is useful in establishing the genetic defect causing the disorder. In parents contemplating a subsequent pregnancy, genetic counseling for prenatal diagnosis and treatment of this disorder is important.

Patients with congenital adrenal hyperplasia should be on an unrestricted diet.

Patients should have ample access to salt because salt wasting is common in some forms of the disease.

Infants who have salt wasting generally benefit from supplementation with NaCl (2-4 g/d) added to their formula.

Caloric intake may need to be monitored and restricted if excess weight gain occurs because glucocorticoids stimulate appetite.

Activity restriction is not necessary if appropriate glucocorticoid and mineralocorticoid therapy is provided.

Complications of congenital adrenal hyperplasia are common. Too little glucocorticoid results in adrenal insufficiency and further virilization in the virilizing forms. Complications of excessive administration of glucocorticoids include growth failure, obesity, striae, hypertension, hyperglycemia, and cataracts. The complications of excess mineralocorticoid administration include hypertension and hypokalemia.

A study by Maccabee-Ryaboy et al of 180 pediatric patients indicated that children with CAH are more likely to experience hypertension than are children in the general population, with the incidence of hypertension varying according to sex and the type of CAH. In children with classic CAH, 55% of those who received fludrocortisone had hypertension, compared with 31% of those who did not.  Moreover, 58% of children with salt-wasting CAH had hypertension, compared with 35% of those with simple virilizing CAH. In 91% of salt-wasting males and 50% of salt-wasting females, hypertension developed prior to age 5 years, while hypertension usually occurred between the ages of 10 and 18 years in children with simple virilizing CAH. Higher hypertension rates were seen in children in whom at least three measurements of 17-hydroxyprogesterone were below 400 ng/dL, with the difference being significant in salt-wasting males. ^[25]

Short stature is a frequent complication of virilizing forms of congenital adrenal hyperplasia (see the image below). In general, patients have final heights 1-2 standard deviations below their estimated genetic potential. ^[26] This difference results from exposure to excessive concentrations of adrenal androgens that cause rapid skeletal maturation or from excessive exposure to glucocorticoids that limit growth. Early central puberty is often observed in children with advanced skeletal maturation and can contribute to the limitation in growth.

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.

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Growth hormone in combination with GnRH agonist therapy may improve adult height. ^{[20, 21]}

A study by Riehl et al indicated that in patients with congenital adrenal hyperplasia, especially women with the simple-virilizing form, higher-dose glucocorticoid treatment may result in lower bone mineral density. This effect appeared to be more pronounced with prednisolone than with hydrocortisone. The investigators also found evidence that adolescents who undergo higher-dose glucocorticoid treatment (as indicated by a lower androstenedione/testosterone ratio) may display lower bone mineral density as adults. ^[27]

Female patients with virilizing forms of adrenal hyperplasia have a decreased fertility rate. ^[28] The reasons are believed to be multifactorial and include abnormal genital anatomy, vaginal stenosis, and poor control of adrenal androgen production that results in diminished ovulation. When pregnancy does occur, the baby is generally born by means of caesarian delivery because of vaginal stenosis or an android pelvis. Virilization of female infants born to mothers with congenital adrenal hyperplasia has not been reported but is potentially possible if the condition is uncontrolled.

Males with uncontrolled congenital adrenal hyperplasia may develop masses in the testes (adrenal rests or adrenal tissue) because the gonads and adrenal glands are derived from the same embryologic anlage. Because the adrenal rests are under ACTH control, the adrenal rests enlarge when ACTH concentrations are elevated. The adrenal rests may cause discomfort and may be mistaken for testicular tumors, resulting in unnecessary surgery. Furthermore, these rests may cause oligospermia or azoospermia and infertility.

Prenatal testing using amniocentesis or chorionic villus sampling has been successful in diagnosing congenital adrenal hyperplasia secondary to 21-hydroxylase deficiency and 11-beta-hydroxylase deficiency if a sibling had a known mutation or deletion in a previous pregnancy.

Prenatal treatment of congenital adrenal hyperplasia appears to be somewhat successful in preventing the virilization due to 21-hydroxylase deficiency in a female fetus. ^[29]  According to the protocol Carlson et al proposed, the mother is treated with 20 mcg/kg/d of dexamethasone divided into 3 doses as soon as the pregnancy is recognized to suppress fetal ACTH secretion and to prevent the fetal adrenal gland from overproducing adrenal androgens. ^[30]

Dexamethasone treatment is discontinued if chorionic villus sampling (done at 8-12 weeks' gestation) or amniocentesis (done at 18-20 weeks' gestation) indicates that the fetus is male or if genetic analysis indicates that the fetus is unaffected.

• Because only the female fetus is at risk of disfigurement from virilization, this strategy results in unnecessary treatment in 7 of 8 fetuses. However, because virilization occurs within the first 12 weeks' gestation, the virilization of an affected female fetus will have already occurred if one waits until the sex and diagnosis of the fetus are known.

• So far, this strategy has not resulted in an increase in fetal wastage or congenital malformations in treated pregnancies. ^[31]  However, it is associated with considerable maternal adverse effects during the pregnancy.

• Long-term follow-up studies are ongoing and required to determine whether dexamethasone treatment in early pregnancy results in any long-term adverse effects. ^{[32, 33]}  This issue remains highly controversial. Therefore, it is recommended that prenatal treatment be done within the confines of clinical research. ^[7]

Methods have been developed to screen neonates for congenital virilizing adrenal hyperplasia secondary to 21-hydroxylase deficiency and 11-hydroxylase deficiency by measuring 17-hydroxyprogesterone and 11-deoxycortisol, respectively, from heel blood samples collected on filter paper. ^{[34, 35]}

• This approach has permitted early identification of newborns with this disorder. This strategy has prevented salt-wasting crises in males whose condition is unrecognized at birth and resulted in the identification of both completely virilized females who may be mistaken for males with cryptorchidism and patients of both sexes with simple virilizing adrenal hyperplasia, enabling early treatment before undue advancement in skeletal maturation.

• Whether these benefits are deemed to be worth the economic cost of screening to justify more global screening remains to be determined. ^[34]

Closely monitor patients with adrenal hyperplasia for adequacy of dosing of glucocorticoids, mineralocorticoids, or both.

• Too little glucocorticoid results in symptoms of adrenal insufficiency (eg, anorexia, nausea, vomiting, abdominal pain, asthenia) and progressive virilization and advancement of skeletal maturation in virilizing forms.

• Too much glucocorticoid results in excess weight gain, Cushingoid features, hypertension, hyperglycemia, cataracts, and growth failure.

Growth failure is one of the more sensitive indicators of excess exposure to glucocorticoids. Short stature in adulthood is frequently the outcome in virilizing forms of adrenal hyperplasia because of the effect of uncontrolled adrenal androgens on skeletal maturation or the effects of excess glucocorticoid administration on growth.

Some patients develop precocious puberty, perhaps secondary to the advanced growth and skeletal maturation that occurs with androgen exposure. This may be treated with GnRH analogue therapy.

As puberty progresses, monitor for adrenal rests within the gonads. If ACTH is inadequately suppressed, these maybe mistaken for gonadal tumors and may cause gonadal pain. Adrenal rests are more commonly found in the testes than in the ovaries.

As adulthood approaches, vaginal adequacy should be assessed because many females with adrenal hyperplasia suffer from dyspareunia due to vaginal stenosis.

The Endocrine Society's 2010 clinical practice guidelines recommend that when patients with CAH reach adulthood, they should be assessed for known complications of CAH. ^[7]