INTRODUCTION — Defective conversion of 17-hydroxyprogesterone to 11-deoxycortisol accounts for more than 90 percent of cases of congenital adrenal hyperplasia [1-3]. This conversion is mediated by 21-hydroxylase, or in current terminology, CYP21A2.

The most severely affected individuals with classic congenital adrenal hyperplasia due to CYP21A2 deficiency present during the neonatal period and early infancy with adrenal insufficiency with or without salt wasting, or later, with virilization. Females have genital ambiguity.

"Nonclassic," or late-onset CYP21A2 deficiency, does not manifest with neonatal genital ambiguity; rather, it presents later in life with signs of androgen excess. Clinical features in late childhood include premature pubarche, acne and accelerated bone age; adolescent and adult females present with acne, hirsutism and menstrual irregularity [4-10].

The diagnosis and treatment of late-onset congenital adrenal hyperplasia due to CYP21A2 deficiency are reviewed here. The genetics and clinical manifestations of the nonclassic form of CYP21A2 deficiency, and the classic form of CYP21A2 deficiency are reviewed separately. (See "Genetics and clinical presentation of nonclassic (late-onset) congenital adrenal hyperplasia due to 21-hydroxylase deficiency" and "Genetics and clinical presentation of classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency" and "Diagnosis of classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency" and "Treatment of classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency in adults".)

DIAGNOSIS

Classic CYP21A2 deficiency — The characteristic biochemical abnormality in patients with CYP21A2 deficiency is a high serum concentration of 17-hydroxyprogesterone, the normal substrate for CYP21A2. Most affected neonates (with the classic form) have concentrations greater than 3500 ng/dL (105 nmol/L) [1], with most exceeding 10,000 ng/dL (300 nmol/L), whereas the levels in normal newborns are below 100 ng/dL (3 nmol/L) [2]. Patients with this disorder also have an exaggerated serum 17-hydroxyprogesterone response to ACTH stimulation with values more than 10,000 ng/dL (300 nmol/L), providing good diagnostic separation from patients with nonclassic CYP21A2 deficiency (graph 1) [3,4].

Nonclassic CYP21A2 deficiency — The biochemical findings are less severe in patients with the late-onset form of the disorder. Basal serum 17-hydroxyprogesterone concentrations (during the follicular phase of the menstrual cycle) may be only slightly high, especially late in the day, but are always greater than 200 ng/dL (6 nmol/L) in adult women and greater than 82 ng/dL (2.5 nmol/L) in children. A morning value greater than 200 ng/dL (6 nmol/L) in the early follicular phase or greater than 82 ng/dL in children strongly suggests the diagnosis, which may be confirmed by a high dose (250 mcg) ACTH stimulation test. The response to ACTH is exaggerated, and most patients have values exceeding 1500 ng/dL (43 nmol/L) after ACTH stimulation [5,6]. Stimulated values of serum 17-hydroxyprogesterone concentrations at 60 minutes range between 1000 ng/dL (30 nmol/L) and 10,000 ng/dl (300 nmol/L) [4].

Other abnormalities that may be present include high serum concentrations of 17-hydroxypregnenolone, dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEA-S), androstenedione, 3-alpha-androstanediol glucuronide, testosterone, 21-deoxycortisol, and progesterone, and increased urinary excretion of metabolites of cortisol precursors, particularly pregnanetriol, pregnanetriol glucuronide, and 17-ketosteroids (pregnanetriol and its glucuronide are the major metabolites of 17-hydroxyprogesterone, and 17-ketosteroids are metabolites of androgens, especially DHEA and DHEA-S). (See "Measurement of adrenal androgens".)

• In one study of 161 unrelated women, 20 had a plasma testosterone level greater than 1.4 ng/mL, while values were normal in 56 (38.3 percent). By contrast, androstenedione was elevated in most, being normal in only 11 patients (8 percent) [11].

Heterozygote carriers — Heterozygote carriers have the same pattern of abnormalities.

• They have smaller responses to ACTH that may overlap the responses of normal subjects [7]. In one study of 31 heterozygote carriers, only 16.1 percent had a serum 17-hydroxyprogesterone value after ACTH stimulation greater than the maximum value seen in 90 healthy control subjects (580 ng/dL [17.55 nmol/L]) [8].
• The amplitude of the response to ACTH was not correlated with the specific gene mutation in one study of unselected carriers [9]. In another study, the carriers of the V281L mutation had a slightly but significantly higher serum 17-hydroxyprogesterone value after ACTH stimulation [10].
• A third study included 242 family members who had a single abnormal allele and 51 with two abnormal alleles. The 17-hydroxyprogesterone value after ACTH was significantly higher in the latter group, but responses did not differ between heterozygous individuals with or without a severe mutation [11].

There is no clear consensus as to whether heterozygote carriers are at increased risk of developing hyperandrogenic symptoms. In one study of 83 women with hirsutism, 11 carriers were identified [12]; in another study of 252 hirsute women, 8.6 percent of women were carriers compared to 6.3 percent in 252 non-hirsute women [13]. In another report, the rate of hirsutism in 38 obligate carriers (11 percent) was similar to that calculated for the general population [14]. However, no relative with a single mutation was clinically symptomatic in another study of 242 subjects [11].

If it is important to document the presence of a carrier state, CYP21A2 genotyping should be performed in patients with borderline responses to ACTH stimulation to avoid a false diagnosis of late-onset CYP21A2 deficiency.

When to test — Testing for CYP21A2 deficiency should be considered in women with an early onset of hirsutism (including those with premature adrenarche), a family history of congenital adrenal hyperplasia, or a strong desire to know a specific etiologic diagnosis. In addition, testing should be considered for women who are Hispanic, Yugoslav, or Eastern European Jewish, because the prevalence of the disorder is higher in these women than in other ethnic groups.

Additionally, one study found a high prevalence of severe mutations in patients with late-onset CYP21A2 deficiency, which suggests that known patients desiring fertility should consider genotyping [11]. However, the overall risk of severe CYP21A2 deficiency in a child of a patient with the nonclassic form has been estimated at 2.5 percent, while the risk of nonclassic deficiency is about 15 percent [15].

TREATMENT

Indications — Indications for treatment of nonclassic CYP21A2 deficiency include:

Children

• Children with precocious pubarche or severe acne. (See "Treatment of classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency in infants and children".) Asymptomatic children do not require treatment [16].

Women

• Hirsutism and acne in women — Antiandrogen therapy, including cyproterone acetate may be superior to glucocorticoids for the treatment of hirsutism [17].

Oral contraceptives, which suppress ovarian androgens, also suppress ACTH and adrenal androgens [18-21]. Given the potential risks and side effects of glucocorticoids, and the fact that hirsutism typically requires long-term therapy, oral contraceptives and/or antiandrogens are reasonable options for first-line therapy. (See "Use of combination estrogen-progestin contraceptives in the treatment of hyperandrogenism and hirsutism" and "Treatment of hirsutism".)

• Oligomenorrhea – If fertility is not desired, we suggest oral contraceptive agents rather than glucocorticoid therapy for menstrual cycle management. Although glucocorticoids may restore ovulation and regular cycles, they do not provide contraception, and are associated with important risks and side effects.
• Anovulatory infertility – Dexamethasone is generally the initial treatment for ovulation induction [22]; clomiphene citrate and other assisted reproduction techniques may be added if glucocorticoid therapy alone is ineffective [23]. The management of the anovulatory infertility in these women is reviewed elsewhere. (See "Overview of ovulation induction".)

Treatment may be discontinued when an adult woman no longer seeks fertility. Hyperandrogenic symptoms persist, and require ongoing therapy, although not necessarily with glucocorticoids.

Men — Treatment is not necessary for men unless there are testicular masses (testicular adrenal rest tumors) or oligospermia (in a man desiring fertility). The few studies reporting treatment of testicular rest tumors or infertility in men initially used dexamethasone (0.75 mg/day), a dose which was often reduced later because of the development of Cushingoid features [24-26]. Surgical extirpation of the masses in eight men with classic CAH did not normalize sperm count in one study [27]. Further studies are needed to evaluate the optimal timing of surgery in men with classic and nonclassic CAH and the timing of initiation of glucocorticoid treatment in men with non-classic CAH.

Treatment may be discontinued when the symptoms resolve, eg, when a boy with precocious pubarche becomes an adult or an adult male no longer seeks fertility.

Choice of glucocorticoid — Dexamethasone, given as a bedtime dose of 0.25 to 0.75 mg, is the preferred treatment for older adolescents and adults after epiphyseal closure is complete. The lowest dose that ameliorates the sign or symptom being treated should be used.

• Prednisone (5 to 7.5 mg) also may be given at bedtime [5].

Monitoring treatment in adults — Standards have not been established for monitoring glucocorticoid therapy in adults with CYP21A2 deficiency. In general, the same principles apply as in treating children. Serum concentrations of 17-hydroxyprogesterone, DHEA sulfate, androstenedione, and testosterone should be measured in women, with the goal of normalizing testosterone levels. In men, reduction of serum 17-hydroxyprogesterone levels to slightly above normal provides a good index of therapeutic efficacy. However, the primary endpoint is normalization of symptoms (eg, acne, hirsutism).

• One should be alert to symptoms and signs of Cushing's syndrome. Patients should have measurements of bone mineral density periodically to look for bone loss [28]. The lowest dose that ameliorates symptoms should be used.

Patients with nonclassic CYP21A2 deficiency do not require higher glucocorticoid doses during stress [2], unless they are receiving glucocorticoids that might suppress the hypothalamic-pituitary axis [29].

SUMMARY AND RECOMMENDATIONS

Nonclassic CYP21A2 deficiency is one of the most common autosomal recessive diseases, and the frequency is ethnic-specific.

Diagnosis

• A basal, morning serum 17-hydroxyprogesterone value (drawn in the early follicular phase) greater than 200 ng/dL (6 nmol/L) strongly suggests the diagnosis.
• The diagnosis is confirmed by an exaggerated serum 17-hydroxyprogesterone response to high dose ACTH (250 mcg). Stimulated values 60 minutes after stimulation are typically ≥1500 ng/dL (≥43 nmol/L), and range between 1000 and 10,000 ng/dl (30 and 300 nmol/L) [4]. (See 'Diagnosis' above.)

Treatment

• For adolescent girls or adult women with nonclassic CYP21A2 deficiency who are not pursuing fertility, we suggest oral contraceptives or antiandrogen therapy as first-line therapy for hyperandrogenic symptoms (acne and hirsutism) (Grade 2C). (See 'Women' above and "Treatment of hirsutism".)

• We suggest oral contraceptives over glucocorticoids as first-line therapy for menstrual cycle management (Grade 2C). (See 'Women' above.)

• For women with nonclassic CYP21A2 deficiency with anovulatory cycles who desire fertility, we suggest glucocorticoids as initial therapy for ovulation induction (Grade 2C). In women who do not ovulate with glucocorticoid therapy alone, we suggest adding clomiphene citrate (Grade 2C). (See 'Women' above.)

• In men with a testicular mass and/or oligospermia, we suggest glucocorticoid therapy (Grade 2C).

Genetics and clinical presentation of the nonclassic form, prenatal diagnosis and prenatal therapy are discussed separately. (See "Genetics and clinical presentation of nonclassic (late-onset) congenital adrenal hyperplasia due to 21-hydroxylase deficiency" and "Treatment of classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency in infants and children", section on 'Prenatal therapy'.)