There is no doubt that controversy exists regarding surgery before the 1st year of life. The Intersex Society of North America (ISNA) initially proposed that even sex assignment should not be done in the newborn period. They have now modified their position stating that sex assignment should be done in the newborn period although surgery should be postponed. However, this does not apply to CAH, a condition in which 46, XX females are usually ambiguous but do not have complete virilization of the genitalia. The ambiguity of the genitalia often requires surgical correction because urine collects in the vagina or in the urogenital sinus and can cause repeated infections. As fertility is not impaired if control of adrenal androgens is maintained after genitoplasty, the 46, XX female is capable of having a child as she has all the organs necessary for becoming a mother (i.e. uterus, fallopian tubes, ovary and vagina). It is one of the few intersex conditions in which fertility is possible. We are in the midst of an evaluation of 200 patients born with genital ambiguity and who have reached adult life. Preliminary analysis suggests that assignment to the female sex is accepted by these women who maintain a female gender. These data were presented at the conference entitled, “Hormonal and Genetic Basis of Sexual Differentiation Disorders,” held in Tempe, AZ in May 2002.(59)

Lifelong glucocorticoid replacement therapy is the mainstay of treatment for classical and symptomatic nonclassical CAH patients. Glucocorticoids not only replace cortisol but also reduce the overstimulation of the adrenal cortex by reducing the release of ACTH, thereby suppressing the overproduction of adrenal androgens. Hydrocortisone is usually chosen for infants and children, as it is shorter acting than prednisone or dexamethasone, thus less likely to comprise growth. Excessive glucocorticoid administration should be avoided as it can cause cushingoid facies, growth retardation, and inhibition of epiphyseal maturation.

Oral hydrocortisone administration of 10-20 mg/m2 is conventionally given in daily divided doses, as it is believed divided doses better suppress the production of adrenal androgens. The dosage is increased 2 to 3 times that of the normal daily dosage during times of non life threatening illness or stress. Up to 5 to 10 times the daily dosage may be required during surgical procedures. Patients with salt wasting CAH may also require mineralocorticoid replacement. A cortisol analogue, fluorohydrocortisone (Florinef), is used for its potent mineralocorticoid activity. Patients with non-classical 21-OH deficiency are only treated with glucocorticoids if they manifest symptoms of androgen excess. In cases of excess ovarian androgen production, the use of progestational and estrogenic agents may be necessary for suppression of gonadotropin release. In the author’s clinic, serum concentrations of Δ5-17-hydroxypregnenolone, 17-OHP, Δ4-androstenedione, dehydroepiandrosterone (DHEA), testosterone, estradiol, deoxycorticosterone (DOC), corticosterone, cortisol, and aldosterone in all CAH patients, as well as levels of PRA in salt-wasting patients, are monitored every three months.

Successful treatment of CAH children hinges on the delicate balance of suppressing adrenal androgen secretion with glucocorticoid administration while maintaining normal growth. However, CAH causes short stature in adults even when good adrenal hormonal control is maintained throughout childhood and puberty. The adult height of CAH patients may be as low as 2 standard deviations (SD) below the mean. (7, 8, 60) Elevated adrenal androgens causing advanced epiphyseal maturation and premature epiphyseal fusion, as well as over treatment with glucocorticoids, are likely causes of short adult stature. One recent study found that growth hormone therapy alone or in combination with gonadotropin-releasing hormone analog (GnRHa) was effective in improving growth rate, height deficit, and height in children with CAH. (61) More recently, Lin-Su et al (2005) demonstrated that the combination of growth hormone and LHRH analogue improved final adult height by 8 cm when compared to CAH subjects treated only with glucocorticoid and mineralocorticoid therapy.(62)

Another new approach for management of CAH patients is the use of an antiandrogen (flutamide) and an aromatase inhibitor (testolactone) in combination with a reduced hydrocortisone dose. (63-65) This treatment regimen was successful in normalizing linear growth and bone maturation in children over two years of treatment. However, the use of flutamide is prohibited from use in any young patient outside of the NIH because of severe liver toxicity. Second, the use of antiandrogens in women of reproductive age carries the risk of causing incomplete virilization in affected males. Antiandrogens are not employed as treatment in many centers.

Bilateral adrenalectomy has been reported to improve symptoms in a few patients who were extremely difficult to control with medical therapy alone.(66-68) An adult female with CAH who had long-term amenorrhea resumed regular menses following bilateral adrenalectomy.(69) Because this approach induces complete adrenal insufficiency, however, it should be reserved for extreme cases and is not a good treatment option for patients who have a history of poor compliance with medication.

Congenital adrenal hyperplasia owing to 21-hydroxylase deficiency may prove to be an excellent candidate for gene therapy. The disorder is monogenic and 21-hydroxylase is only expressed in the adrenal glands. Indeed, a mouse model for steroid 21-hydroxylase deficiency is currently being used to develop gene therapy for congenital adrenal hyperplasia. (70, 71) An adeno-associated vector demonstrated a longer period of expression and much lower immune response than previously used adenovirus vector. (72) Gene therapy would eliminate the difficulties of adequate adrenal androgen suppression without hypercortisolism.