Clinical Information

The adrenal glands, ovaries, testes, and placenta produce steroid hormones, which can be subdivided into 3 major groups: mineralocorticoids, glucocorticoids, and sex steroids. Synthesis proceeds from cholesterol along 3 parallel pathways, corresponding to these 3 major groups of steroids, through successive side-chain cleavage and hydroxylation reactions. At various levels of each pathway, intermediate products can move into the respective adjacent pathways via additional, enzymatically catalyzed reactions (see Steroid Pathways).

11-Deoxycorticosterone represents the last intermediate in the mineral corticoid pathway that has negligible mineralocorticoid activity. It is converted by 11-beta-hydroxylase 2 (CYP11B2) or by 11-beta-hydroxylase 1 (CYP11B1) to the first mineralocorticoids with significant activity, corticosterone. Corticosterone is in turn converted to 18-hydroxycorticosterone and finally to aldosterone, the most active mineralocorticoid. Both reactions are catalyzed by CYP11B2, which, unlike its sister enzyme CYP11B1, also possesses 18-hydroxylase and 18-methyloxidase activity.

The major diagnostic utility of measurement of steroid synthesis intermediates is in diagnosing disorders of steroid synthesis, particularly congenital adrenal hyperplasia (CAH). All types of CAH are associated with cortisol deficiency except for CYP11B2 deficiency and isolated impairments of the 17-lyase activity of CYP17A1 (this enzyme also has 17-alpha-hydroxylase activity). In cases of severe illness or trauma, CAH predisposes patients to poor recovery or death. Patients with the most common form of CAH (21-hydroxylase deficiency, which accounts for >90% of cases), with the third most common form of CAH (3-beta-steroid dehydrogenase deficiency, which accounts for <3% of cases), or the extremely rare StAR (steroidogenic acute regulatory protein) or 20,22 desmolase deficiencies might also suffer mineralocorticoid deficiency, as the enzyme blocks in these disorders are proximal to potent mineral corticoids. These patients might suffer salt-wasting crises in infancy. By contrast, patients with the second most common form of CAH (11-hydroxylase deficiency, which accounts for <5% of cases) are normotensive or hypertensive, as the block affects either CYP11B1 or CYP11B2 but rarely both, thus ensuring that at least corticosterone is still produced.

In addition, patients with all forms of CAH might suffer the effects of substrate accumulation proximal to the enzyme block. In the 3 most common forms of CAH, the accumulating precursors spill over into the sex steroid pathway, resulting in virilization of female patients or, in milder cases, in hirsutism, polycystic ovarian syndrome, or infertility, as well as in possible premature adrenarche and pubarche in both genders.

Measurement of the various precursors of mature mineralocorticoids and glucocorticoids, in concert with the determination of sex steroid concentrations, allows diagnosis of CAH and its precise type and serves as an aid in monitoring steroid replacement therapy and other therapeutic interventions.

Measurement of 11-deoxycorticosterone and its glucocorticoid pendant, 11-deoxycortisol (also known as compound S), is aimed at diagnosing:

-CYP11B1 deficiency (associated with cortisol deficiency)

-The rarer CYP11B2 deficiency (no cortisol deficiency)

-The yet less common glucocorticoid-responsive hyperaldosteronism (where expression of the gene CYP11B2 is driven by the CYP11B1 promoter, thus making it responsive to corticotropin [previously adrenocorticotrophic hormone: ACTH] rather than renin)

For other forms of CAH, the following tests might be relevant:

11-Hydroxylase deficiency:

-DOCS / 11-Deoxycortisol, Serum

-CORTC / Corticosterone, Serum

-PRA / Renin Activity, Plasma

-ALDS / Aldosterone, Serum

3-Beta-steroid-dehydrogenase deficiency:

-17PRN / Pregnenolone and 17-Hydroxypregnenolone, Serum

17-Hydroxylase deficiency or 17-lyase deficiency (CYP17A1 has both activities):

-PREGN / Pregnenolone, Serum

-17OHP / 17-Hydroxypregnenolone, Serum

-PGSN / Progesterone, Serum

-OHPG / 17-Hydroxyprogesterone, Serum

-DHEA_ / Dehydroepiandrosterone (DHEA), Serum

-ANST / Androstenedione, Serum

Cortisol should be measured in all cases of suspected CAH.

In the diagnosis of suspected 11-hydroxylase deficiency and glucocorticoid-responsive hyperaldosteronism, this test should be used in conjunction with measurements of 11-deoxycortisol, corticosterone, 18-hydroxycorticosterone, cortisol, renin, and aldosterone.