Figure 29.20 Gonadal and adrenal steroid pathways and the enzymes required for steroid conversion. DOC, deoxycorticosterone; 17α-OH Preg, 17α-hydroxypregnenolone; 17α-OH Prog, 17α-hydroxyprogesterone; DHEA, dehydroepiandrosterone sulfate. (From Rebar RW, Kenigsberg D, Hodgen GD. The normal menstrual cycle and the control of ovulation. In: Becker KL, ed. Principles and practice of endocrinology and metabolism. 2nd ed. Philadelphia, A: JB Lippincott, 1995:868–880, with permission.) nonclassic form of 11-hydroxylase deficiency was reported but apparently is very uncommon (84).
Treatment of Congenital Adrenal Hyperplasia The treatment of CAH involves providing replacement doses of the deficient steroid hormones. Hydrocortisone (10 to 20 mg/m2 body surface area) or its equivalent is given daily in divided doses to suppress the elevated levels of pituitary corticotropin present and thus suppress the elevated androgen levels. With such treatment, signs of androgen excess should regress. In children, growth velocity, bone age, and hormone levels should be monitored carefully because both overreplacement and underreplacement can result in premature closure of the epiphyses and short stature. Data now indicate that early diagnosis and compliance with therapy lead to adult height within 1 standard deviation of the anticipated target height in girls with 21-hydroxylase deficiency (86).
Mineralocorticoid replacement is generally required in individuals with 21-hydroxylase deficiency whether or not they are salt losing. The intent of glucocorticoid therapy should be to suppress morning 17α-hydroxyprogesterone levels to between 300 and 900 ng/dL. Sufficient ﬂudrocortisone should be given daily to suppress plasma renin activity to less than 5 mg/mL per hour.
It is possible to diagnose 21-hydroxylase deficiency prenatally in patients known to be at risk (84). The diagnosis is established by documenting elevated levels of 17α-hydroxyprogesterone or 21-deoxycortisol in amniotic ﬂuid. Genetic diagnosis using specific probes and cells obtained by chorionic villus sampling or amniocentesis is possible. Dexamethasone (20 μg/kg/day in three divided doses) can be administered to the pregnant women beginning before the ninth week of gestation because the urogenital sinus begins to form at nine weeks of gestation. If the fetus is determined to be a male or an unaffected female upon DNA analysis, treatment is discontinued. Otherwise, treatment is continued to term. Human studies found that this treatment regimen is effective in reducing virilization in the genetic female so that genitoplasty was not needed in the majority of cases (87,88). The majority of studies proved that this management scheme is effective for both mother and the child. Maternal complications, including hypertension, massive weight gain, and overt Cushing syndrome, were noted in about 1% of pregnancies in which the mothers are given low doses of dexamethasone. All maternal complications disappear after delivery. The long-term effects of this treatment strategy on the physical and neurodevelopmental health of the offspring remains unclear. A recent systematic review concluded that dexamethasone seems to reduce virilization without significant adverse maternal or fetal effects, though the available data allow merely weak inferences to be made (89). Despite the risks and the nonuniformity of beneficial outcome to affected female fetuses, many parents may choose prenatal medical treatment because of the psychological impact of ambiguous genitalia.
Girls with ambiguous genitalia may require reconstructive surgery, including clitoral recession and vaginoplasty. Timing of such surgery is debated, but the girl must be of appropriate size to ensure the surgery is as simple as possible.