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ABSTRACT

  • Congenital adrenal hyperplasia (CAH, MIM 300200) is a group of diseases whose common feature is an enzymatic defect in the steroidogenic pathway leading to the biosynthesis of cortisol. This relative decrease in cortisol production causes an increase in adrenocorticotropic hormone (ACTH) secretion and consequent hyperplasia of the adrenal cortex. All forms of CAH are inherited in an autosomal recessive manner. The variable phenotypes are determined by the effects produced by deficient hormones and by excess production of steroids unaffected by the enzymatic block.

  • The biochemical pathways of adrenal steroid production are interrelated. The three zones of the adrenal cortex produce three classes of steroid hormones: glucocorticoids and androgens (zona fasciculata/reticularis) and mineralocorticoids (zona glomerulosa). All but one of the enzymatic steps are mediated by members of the cytochrome P450 (CYP) family of mixed-function oxidases. The first step in the production of all steroid hormones, mediated by CYP11A, is the conversion of cholesterol to pregnenolone. Pregnenolone may then be acted on by CYP17 to form 17-hydroxypregnenolone and then dehydroepiandrosterone (DHEA), or it may be converted to progesterone by the non-P450 enzyme 3β-hydroxysteroid dehydrogenase (3β-HSD). 3β-HSD also converts 17-hydroxypregnenolone to 17-hydroxyprogesterone and DHEA to androstenedione, an androgen precursor. Progesterone and 17-hydroxyprogesterone are then converted by CYP21 to 11-deoxycorticosterone (a mineralocorticoid) and 11-deoxycortisol, respectively. These two products are then converted by CYP11B1 to corticosterone and cortisol (the major glucocorticoid), respectively. Aldosterone, the major mineralocorticoid, is produced from corticosterone by the enzyme CYP11B2 (aldosterone synthase).

  • Control of adrenal steroid production is multifaceted. Glucocorticoid production is stimulated primarily by the anterior pituitary hormone ACTH, which itself is controlled by the hypothalamic corticotropin-releasing hormone (CAH). Aldosterone secretion is modulated by the renin-angiotensin system. Adrenal androgen secretion is stimulated by excessive ACTH, but physiologic control is through an unidentified factor.

  • In keeping with their different physiologic regulations, the secretion rates of the various adrenocortical hormones vary independently. The cortisol secretion rate is approximates 12 mg/m2 of body surface area per day. This rate is somewhat higher—but quite variable—in newborn infants and significantly higher during periods of physiologic stress, such as fever and surgery. The aldosterone secretion rate (approximately 100 μg/day) remains fairly constant throughout life. Adrenal androgen secretion is quite low during infancy and childhood and increases gradually to maximal levels during puberty and early adulthood, with age-related declines thereafter.

  • 21-Hydroxylase (CYP21) deficiency is the most common form of CAH, accounting for over 90 percent of cases. The incidence varies from 1 in 10,000 to 18,000 live births. There is a continuum of degrees of CYP21 deficiency that results in a continuum of severity of clinical presentations. The most marked deficiency results in the salt-losing form of CAH, characterized by both mineralocorticoid and glucocorticoid deficiencies. The steroid precursors prior to the enzymatic block (progesterone and 17-hydroxyprogesterone) accumulate due to excessive ACTH stimulation of the gland and are shunted into the androgen biosynthetic pathway, which is unaffected by the block. The resulting androgen excess produces prenatal masculinization ...

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