Future Directions in the Study and Management of Congenital Adrenal Hyperplasia due to 21-Hydroxylase Deficiency

View larger version (29K): [in a new window]   Figure 1. Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency. In a person with normal adrenal function (left), the adrenal gland produces both cortisol and androgen. The hypothalamic-pituitary-adrenal axis is controlled by negative feedback. In the untreated patient with CAH (middle), a block in cortisol biosynthesis leads to a buildup of cortisol precursors and lack of negative feedback. Corticotropin (ACTH) is oversecreted, and adrenal hyperplasia occurs. The combination of accumulated cortisol precursors and increased ACTH results in massive androgen production. In the treated patient with CAH (right), exogenous hydrocortisone replacement reduces androgen production. Supraphysiologic doses of hydrocortisone are often necessary to adequately suppress androgen production. CRH = corticotropin-releasing hormone.

View larger version (24K): [in a new window]   Figure 2. The 10 most common genetic mutations found in 21-hydroxylase deficiency. The location and nature of each microconversion and the expected clinical phenotype (salt-losing [SL], non-salt-losing [NSL], and nonclassic congenital adrenal hyperplasia [NC]) are shown. The 10 exons and 9 introns of CYP21B are drawn to scale. Arg = arginine; Asn = asparagine; Asp = aspartate; Glu = glutamate; Ile = isoleucine; Leu = leucine; Lys = lysine; Met = methionine; Pro = proline; Trp = tryptophan; Val = valine.

View larger version (56K): [in a new window]   Figure 3. The 21-hydroxylase-deficient mouse.Top. Steroidogenic acute regulatory protein (StAR) expression is increased in the adrenal glands of mice with 21-hydroxylase deficiency, as compared with wild-type animals. Quantitative steroidogenic acute regulatory protein was determined by TaqMan PCR Core Reagents Kit (Applied Biosystems, Foster City, California) (n = 4 adrenal glands; P < 0.05). Amounts of RNA were calculated with relative standard curves for both steroidogenic acute regulatory protein and 18S. The amount of messenger RNA was corrected by division by the amount of 18S RNA in each sample. Middle. Electroµgraph showing catecholamine-storing secretory vesicles in chromaffin cells of control animals (size range, 50 to 450 nm). Bottom. Electroµgraph of chro-maffin cells. Secretory granules are markedly reduced in chromaffin cells of 21-hydroxylase-deficient mice. The remaining granules are predominantly electron-dense, norepinephrine-containing vesicles, lying in large lucent vacuoles (arrows). For parts B and C, stain is uranyl acetate and lead citrate, and magnification is x 15 000. MIT = mitochondria.

View larger version (39K): [in a new window]   Figure 4. Patients with salt-losing 21-hydroxylase deficiency. The treatment outcome in classic congenital adrenal hyperplasia is often suboptimal because of incomplete suppression of hyperandrogenism (top), treatment-induced hypercortisolism (bottom), or both. At 16 years of age, a female patient with salt-losing 21-hydroxylase deficiency due to undertreatment with glucocorticoid and elevated androgen levels had hirsutism, acne, amenorrhea, and hyperpigmentation (top). Increased glucocorticoid treatment resulted in weight gain with cushingoid features and short stature in a male patient with classic 21-hydroxylase deficiency (bottom).

View larger version (42K): [in a new window]   Figure 5. An investigational approach to the treatment of classic congenital adrenal hyperplasia. Fludrocortisone is given in the usual manner. The hydrocortisone dose is reduced to physiologic levels, resulting in elevated androgen production. An antiandrogen agent is administered to block the effect of the elevated androgen levels, and an inhibitor of androgen-to-estrogen conversion is given to block conversion of the increased amount of androgen to estrogen.

View larger version (37K): [in a new window]   Figure 6. Mechanisms of adrenal hyperandrogenism. Elevations in adrenocorticotropic hormone, increases in neural-adrenomedullary input, and presence of insulin-mediated metabolic input may lead to adrenal hyperandrogenism and premature adrenarche. In turn, adrenal hyperandrogenism, insulin resistance, or both may lead to full-blown polycystic ovary syndrome in a woman with an inherent ovarian vulnerability. ACTH = adrenocorticotropic hormone; CRH = corticotropin-releasing hormone; E = epinephrine; NE = norepinephrine; NPY = neuropeptide Y.

View larger version (19K): [in a new window]   Figure 7. Venn diagram including the overlapping populations of women with insulin resistance, the polycystic ovary syndrome (PCOS), and nonclassic congenital adrenal hyperplasia (NCCAH).

View larger version (154K): [in a new window]   Figure 8. Characteristic radiologic features of testicular adrenal rest tumors. Testicular adrenal rest tissue masses often surround the mediastinum testes (arrow) (A), and are bilateral, intratesticular, and hypoechoic (B). Testicular adrenal rest tissue masses are seen equally as well on ultrasonography and magnetic resonance imaging. Most of these masses are hypointense on T2-weighted images (C) and isointense on T1-weighted images, with diffuse enhancement post-contrast (D). Large testicular adrenal rest tissue (E) typically shrinks or disappears (F) with higher-dose glucocorticoid therapy.