21-hydroxylase deficiency medical therapy
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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
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
- Initiating and monitoring hormone replacement
- Stress coverage, crisis prevention, parental education
- Reconstructive surgery
- Optimizing growth
- 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. (See Glucocorticoid for more on this topic.)
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.
Stress coverage, crisis prevention, parental education
To prevent adrenal crisis, all persons taking replacement glucocorticoids are taught to increase their doses in the event of illness, surgery, severe injury, or severe exhaustion. More importantly, they are taught that vomiting warrants an injection within hours of hydrocortisone (e.g., SoluCortef) or other glucocorticoid. This recommendation applies to both children and adults. Because young children are more susceptible to vomiting illnesses than adults, pediatric endocrinologists usually teach parents how to give hydrocortisone injections.
As an additional precaution, persons with adrenal insufficiency are advised to wear a medical identification tag or carry a wallet card to alert those who may be providing emergency medical care of the urgent need for glucocorticoids.
For an excellent example of parent education materials for congenital adrenal hyperplasia, see the booklet prepared by the Johns Hopkins Pediatric Endocrine Service.
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. While a boy (or girl) with simple virilizing congenital adrenal hyperplasia is taller than peers at that point, he will have far fewer years remaining to grow, and may go from being a very tall 7-year-old to a 62-inch 13-year-old who has completed growth. Even with adrenal suppression, many of these 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 is only added in cases where the plasma renin activity is high.
A third key aspect of management is suppression of central precocious puberty if it has begun. The usual clues to central puberty in boys are that the testes are pubertal in size, or that testosterone remains elevated even when the 17OHP has been reduced toward normal. In girls central puberty is less often a problem, but breast development would be the main clue. Central precocious puberty is suppressed when appropriate by leuprolide.
As outlined above, recent additions to treatment to preserve growth include aromatase inhibition to slow bone maturation by reducing the amount of testosterone converted to estradiol, and use of blockers of estrogen for the same purpose.
Once adrenal suppression has been achieved, the patient needs stress steroid coverage as described above for significant illness of injury.
Late onset (nonclassical) congenital adrenal hyperplasia
Treatment may involve a combination of very low dose glucocorticoid to reduce adrenal androgen production and any of various agents to block the androgen effects and/or induce ovulation.