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II. Adrenal Function And 21-Hydroxylase Deficiency

It is typical to distinguish three forms of 21-hydroxylase deficiency which, in order of severity, are: the salt-losing form (most severe), the simple-virilizing form (moderate severity) and the late-onset or nonclassical form (least severe).

A. Salt-Losing Form of CAH

There is a total or near-total deficiency of the 21-hydroxylase enzyme. This results in the complete inability to produce cortisol and aldosterone.

The body's total inability to produce cortisol leads to an increase in ACTH and a build-up of precursors to cortisol (i.e., 17-hydroxyprogesterone and androgens).

Aldosterone production is also impaired due to the total absence of 21-hydroxylase. Although there is an increase in both renin and angiotensin, aldosterone productions remains low or nonexistent.

Salt-Losing CAH

a. No cortisol = hypoglycemia

b. No aldosterone = salt and water loss

c. Increased cortisol precursors (17-hydroxyprogesterone) = salt-losing tendency

d. Increased androgens = masculinization

B. Simple-Virilizing Form of CAH

This refers to a partial deficiency of the 21-hydroxylase enzyme. Because this enzyme deficiency is only partial, these subjects are able to produce near normal or normal amounts of cortisol due to of increased ACTH output. However, similar to the salt-losing patients, simple-virilizing patients experience an increase in the production of 17-hydroxyprogesterone as well as adrenal androgens. The elevated 17-hydroxyprogesterone produces a salt-losing tendency. Because the 21-hydroxylase deficiency is partial, the adrenals are able to increase production of aldosterone to compensate for salt loss.

Simple-Virilizing CAH

a. Normal or near normal cortisol

b. Increased cortisol precursors (17-hydroxyprogesterone)

c. Increased aldosterone to compensate for salt losing tendency

d. Increased androgens = masculinization

C. Adrenal Androgens in Salt-Losing & Simple-Virilizing CAH

In both forms of CAH, the increased production of adrenal androgens is of concern.

The most important adrenal androgen secreted in large amounts is androstenedione. This steroid is not androgenic by itself. However, approximately 10% of androstenedione is metabolized in the body to testosterone, a potent androgen.

Excess androgen production during fetal life, associated with salt-losing and simple-virilizing CAH, masculinizes the external genitalia of female infants. This includes an enlargement of the clitoris and variable degrees of fusion of the labia.

The simple virilizing form of CAH results in a moderate excess of androgen production with moderate masculinization of the external genitalia in females. Salt-losing CAH results in greater masculinization than simple-virilizing CAH due to greater production of androgens.

Figure 4
Figure 4: Click to enlarge

D. Nonclassic or Late-Onset Form of CAH

Late-onset CAH refers to a mild deficiency of the 21-hydroxylase enzyme. People with late-onset CAH start to exhibit symptoms related to excess androgen production in childhood or adolescence. Because the 21-hydroxylase deficiency is mild, patients are able to produce normal amounts of cortisol and aldosterone. However, affected individuals produce increased amounts of cortisol precursors (17-hydroxyprogesterone) and adrenal androgens. In boys and girls, this results in rapid growth and early virilization. In girls, this can also result in masculinization and abnormal menses.

Late-Onset CAH

a. Normal cortisol

b. Normal aldosterone

c. Increased 17-hydroxyprogesterone (moderate)

d. Increased androgens = masculinization

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