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Sexual Differentiation : Congenital Adrenal Hyperplasia

The most common form of congenital adrenal hyperplasia (CAH) is 21 hydroxylase deficiency. Because patients with this disorder cannot form cortisol in normal amounts, there is a compensatory increase in ACTH, leading to hyperplasia of the adrenal gland. The excess ACTH drives steroid production to the point of the enzymatic block, with a resultant increase in 17-hydroxyprogesterone production and testosterone. This results in virilization of female neonates.

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Congenital adrenal hyperplasia and clitoromegaly.
Credits: C. Matthew Peterson, M.D.

Congenital adrenal hyperplasia (CAH) actually describes a group of enzyme defects which are inherited in an autosomal recessive fashion. The 21hydroxylase deficiency is the most common cause (95%) and can result in a simple virilizing form or a severe form which in addition to the virilization leads to salt-wasting secondary to a lack of aldosterone production (salt wasting CAH).

Enzyme Steps
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Enzyme Steps.
Credits: C. Matthew Peterson, M.D.

This can be life-threatening in the neonatal period secondary to sodium depletion, hyperkalemia, and dehydration. Newborn female babies with ambiguous genitalia and males with dehydration must be evaluated for CAH immediately and treated (corticosteroids, mineralocorticoids, and sodium chloride) if the salt wasting form is diagnosed. A third form of the 21 hydroylase deficiency is referred to as "nonclassic" or "late onset" and results in virilization in childhood or adolescence and in females subsequent hirsutism, acne and infertility. Most of the patients with the nonclassic form do not demonstrate overactivation of the hypothalmic pituitary axis as do the other forms. Glucocorticoid therapy suppresses the overactivity of the HPO axis in the severe forms and mineralocorticoid replacement is necessary in the salt wasting form. CAH is estimated to occur in 1/14,000 births, and is much higher in the Ashknazic Jewish and Eskimo population. The other enzyme defects which can result in virilization of the female in utero are 11 beta hydroylase deficiency, and 3 beta hydroxysteroid dehydrogenase deficiency.