21-hydroxylase deficiency medical therapy

Congenital adrenal hyperplasia due to 21-hydroxylase deficiency Microchapters
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Ahmad Al Maradni, M.D. [2]

Overview

The mainstay of therapy for congenital adrenal hyperplasia due to 21-hydroxylase deficiency is glucocorticoid replacement.

Medical Therapy

Early-onset: Severe 21-hydroxylase deficient congenital adrenal hyperplasia

Salt-wasting crises in infancy

As ill as these infants can be, they respond rapidly to treatment with hydrocortisone and intravenous saline and dextrose quickly restores blood volume, blood pressure, and body sodium content, and reverses the hyperkalemia. With appropriate treatment, most infants are out of danger within 24 hours.

Long-term management of congenital adrenal hyperplasia

Management of infants and children with congenital adrenal hyperplasia is complex and warrants long term care in a pediatric endocrine clinic. After the diagnosis is confirmed, and any salt-wasting crisis averted or reversed, major management issues include

1. Initiating and monitoring hormone replacement
2. Stress coverage, crisis prevention, parental education
3. Reconstructive surgery
4. Optimizing growth
5. Optimizing androgen suppression and fertility in women with congenital adrenal hyperplasia

Hormone replacement

The primary goals of hormone replacement are:

• To protect from adrenal insufficiency
• To suppress the excessive adrenal androgen production.

Glucocorticoids are provided to all children and adults with all but the mildest and latest-onset forms of congenital adrenal hyperplasia. The glucocorticoids provide a reliable substitute for cortisol, thereby reducing ACTH levels. Reducing ACTH also reduces the stimulus for continued hyperplasia and overproduction of androgens. In other words, glucocorticoid replacement is the primary method of reducing the excessive adrenal androgen production in both sexes. A number of glucocorticoids are available for therapeutic use. Hydrocortisone or liquid prednisolone is preferred in infancy and childhood, and prednisone or dexamethasone are often more convenient for adults.

The glucocorticoid dose is typically started at the low end of physiologic replacement (6-12 mg/m² but is adjusted throughout childhood to prevent both growth suppression from too much glucocorticoid and androgen escape from too little. Serum levels of 17OHP, testosterone, androstenedione, and other adrenal steroids are followed for additional information, but may not be entirely normalized even with optimal treatment.

Mineralocorticoids are replaced in all infants with salt-wasting and in most patients with elevated renin levels. Fludrocortisone is the only pharmaceutically available mineralocorticoid and is usually used in doses of 0.05 to 2 mg daily. Electrolytes, renin, and blood pressure levels are followed to optimize the dose.

Optimizing growth in congenital adrenal hyperplasia

One of the challenging aspects of long-term management is optimizing growth so that a child with congenital adrenal hyperplasia achieves his or her height potential because both undertreatment and overtreatment can reduce growth or the remaining time for growth. While glucocorticoids are essential for health, dosing is always a matter of approximation. In even mildly excessive amounts, glucocorticoids slow growth. On the other hand, adrenal androgens are readily converted to estradiol, which accelerates bone maturation and can lead to early epiphyseal closure. This narrow target of optimal dose is made more difficult to obtain by the imperfect replication of normal diurnal plasma cortisol levels produced by 2 or 3 oral doses of hydrocortisone. As a consequence, average height losses of about 4 inches (10 cm) have been reported with traditional management.

Traditionally, pediatric endocrinologists have tried to optimize growth by measuring a child every few months to assess current rate of growth, by checking the bone age every year or two, by periodically measuring 17OHP and testosterone levels as indicators of adrenal suppression, and by using hydrocortisone for glucocorticoid replacement rather than longer-acting prednisone or dexamethasone.

The growth problem is even worse in the simple virilizing forms of congenital adrenal hyperplasia which are detected when premature pubic hair appears in childhood, because the bone age is often several years advanced at the age of diagnosis. Even with adrenal suppression, many children will have already had central precocious puberty triggered by the prolonged exposure of the hypothalamus to the adrenal androgens and estrogens. If this has begun, it may be advantageous to suppress puberty with a gonadotropin-releasing hormone agonist such as leuprolide to slow continuing bone maturation.

In recent years some newer approaches to optimizing growth have been researched and are beginning to be used. It is possible to reduce the effects of androgens on the body by blocking the receptors with an antiandrogen such as flutamide and by reducing the conversion of testosterone to estradiol. This conversion is mediated by aromatase and can be inhibited by aromatase blockers such as testolactone. Blocking the effects and conversions of estrogens will allow use of lower doses of glucocorticoids with less risk of acceleration of bone maturation. Other proposed interventions have included bilateral adrenalectomy to remove the androgen sources, or growth hormone treatment to enhance growth.

For a more extensive review of the difficulties of optimizing growth, see Migeon CJ, Wisneiewski AB. Congenital adrenal hyperplasia owing to 21-hydroxylase deficiency: growth, development, and therapeutic considerations. Endocrinol Metab Clin N Am 30:193-206, 2001.

Childhood onset (simple virilizing) congenital adrenal hyperplasia

The mainstay of treatment is:

• Suppression of adrenal testosterone production by a glucocorticoid such as hydrocortisone
• Mineralocorticoid in cases where the plasma renin activity is high.
• Suppression of central precocious puberty by leuprolide.
• Aromatase inhibitior to slow bone maturation by reducing the amount of testosterone converted to estradiol, estrogen blockers are also used for the same purpose.
• Stress steroid coverage for significant illness or injury.

Late onset (nonclassical) congenital adrenal hyperplasia

Treatment may involve a combination of very low dose of glucocorticoid to reduce adrenal androgen production and any of various agents to block the androgen effects and/or induce ovulation.