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];
Overview
Medical Therapy
Early-onset: Severe 21-hydroxylase deficient CAH
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 CAH
Management of infants and children with CAH 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 CAH
Hormone replacement
The primary goals of hormone replacement are to protect from adrenal insufficiency and 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 CAH. 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
Even after diagnosis and initiation of treatment, a small percentage of children and adults with infancy or childhood onset CAH die of adrenal crisis. Deaths from this are entirely avoidable if the child and his family understand that the daily glucocorticoids cannot be allowed to be interrupted by an illness. When a person is well, missing a dose, or even several doses, may produce little in the way of immediate symptoms. However, our glucocorticoid needs are increased during illness and stress, and missed doses during an illness such as the "flu" (or viral gastroenteritis) can lead within hours to reduced blood pressure, shock, and death.
To prevent this, 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 CAH, see the booklet prepared by the Johns Hopkins Pediatric Endocrine Service.
Optimizing growth in CAH
One of the challenging aspects of long-term management is optimizing growth so that a child with CAH 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 CAH 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 CAH 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.
Psychosexual development and issues
Nearly all mammals display sex-dimorphic reproductive and sexual behavior (e.g., lordosis and mounting in rodents). Much research has made it clear that prenatal and early postnatal androgens play a role in the differentiation of most mammalian brains. Experimental manipulation of androgen levels in utero or shortly after birth can alter adult reproductive behavior.
Girls and women with CAH constitute the majority of genetic females with normal internal reproductive hormones who have been exposed to male levels of testosterone throughout their prenatal lives. Milder degrees of continuing androgen exposure continue throughout childhood and adolescence due to the imperfections of current glucocorticoid treatment for CAH. The psychosexual development of these girls and women has been analyzed as evidence of the role of androgens in human sex-dimorphic behaviors.
Girls with CAH have repeatedly been reported to spend more time with "sex-atypical" toys and "rough-and-tumble" play than unaffected sisters. These differences continue into adolescent, as expressed in social behaviors, leisure activities, and career interests. Interest in babies and becoming mothers is significantly lower by most measures.
Cognitive effects are less clear and reports have been contradictory. Two studies reported spatial abilities above the average for sisters and for girls in general. Other evidence in males with and without androgen deficiencies suggest that androgens may play a role in these aptitudes.
However, gender identity of girls and women with CAH is nearly always unequivocally female. Sexual orientation is more mixed, though the majority are heterosexual. In one study, 27% of women with CAH were rated as bisexual in their orientations. Abnormalities of body image due to the effects of the disease likely play a role in the sexual development of these women, and one cannot conclude that the androgens are the major determinant of their erotic interests.
Prenatal diagnosis and treatment
Since CAH is an autosomal recessive disease, most children with CAH are born to parents unaware of the risk and with no family history. However, once a first child has CAH, it can be predicted that each successive child will have a 25% chance of being born with the disease (12.5% chance of an affected girl, 12.5% chance of an affected boy). Few families would choose not to continue with a pregnancy of a second child with CAH but all would wish to minimize the degree of virilization of a girl. There is no known prenatal harm to a male fetus from CAH, so treatment can begin at birth.
Adrenal glands of female fetuses with CAH begin producing excess testosterone by the 9th week of gestation. The most important aspects of virilization (urogenital closure and phallic urethra) occur between 8 and 12 weeks. Theoretically, if enough glucocorticoid could be supplied to the fetus to reduce adrenal testosterone production by the 9th week, virilization could be prevented and the difficult decision about timing of surgery avoided.
The challenge of preventing severe virilization of girls is twofold: detection of CAH at the beginning of the pregnancy, and delivery of an effective amount of glucocorticoid to the fetus without causing harm to the mother.
The first problem has not yet been entirely solved, but it has been shown that if dexamethasone is taken by a pregnant woman enough can cross the placenta to suppress fetal adrenal function.
At present no program screens for risk in families who have not yet had a child with CAH. For families desiring to avoid virilization of a second child, the current strategy is to start dexamethasone as soon as a pregnancy has been confirmed even though at that point the chance that the pregnancy is a girl with CAH is only 12.5%. Dexamethasone is taken by the mother each day until it can be safely determined whether she is carrying an affected girl.
Whether the fetus is an affected girl can be determined by chorionic villus sampling at 9-11 weeks of gestation, or by amniocentesis at 15-18 weeks gestation. In each case the fetal sex can be determined quickly, and if the fetus is a male the dexamethasone can be discontinued. If female, fetal DNA is analyzed to see if she carries one of the known abnormal alleles of the CYP21 gene. If so, dexamethasone is continued for the remainder of the pregnancy at a dose of about 1 mg daily.
Most mothers who have followed this treatment plan have experienced at least mild cushingoid effects from the glucocorticoid, but have borne daughters whose genitalia are much less virilized.
Childhood onset (simple virilizing) CAH
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) CAH
Diagnosis of late-onset CAH may be suspected from a high 17-hydroxyprogesterone level, but some cases are so mild that the elevation is only demonstrable after cosyntropin stimulation. 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.