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).

21-Deoxycortisol is an intermediate steroid in the glucocorticoid pathway. While the main substrate flow in glucocorticoid synthesis proceeds from 17-hydroxyprogesterone via 21-hydroxylation to 11-deoxycortisol and then, ultimately, to cortisol, a small proportion of 17-hydroxyprogesterone is also hydroxylated at carbon number 11 by 11-beta-hydroxylase 1 (CYP11B1), yielding 21-deoxycortisol. This in turn can also serve as a substrate for 21-hydroxylase (CYP21A2), resulting in formation of cortisol.

The major diagnostic utility of measurements of steroid synthesis intermediates lies in the diagnosis of 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 case 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), 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 21-deoxycortisol can supplement or confirm 17-hydroxyprogesterone and androstenedione measurements in the diagnosis of difficult cases of CAH presumed to be due to CYP21A2 deficiency. 11-Hydroxylation remains intact in such patients. However, since the CYP21A2 enzyme block prevents formation of 11-deoxycortisol while simultaneously increasing the concentrations of the precursor, 17-hydroxyprogesterone, unoccupied CYP11B1 starts to hydroxylate the abundant 17-hydroxyprogesterone substrate into 21-deoxycortisol. The 21-deoxycortisol accumulates, as the diminished or absent CYP21A2 activity slows or prevents its conversion into cortisol.

For other forms of CAH, the following tests may 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.

It has been suggested that in the pubertal patient with 21-hydroxylase deficiency, 21-deoxycortisol may be useful and better than 17-hydroxyprogesterone for therapeutic decisions.