Laboratory Studies
No biochemical differences between male and female patients are recognized.
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Classic 3-beta–hydroxysteroid dehydrogenase (3BHSD) deficiency
Plasma concentrations of pregnenolone, 17-hydroxypregnenolone, and DHEA are elevated.
17-Hydroxyprogesterone levels may be increased because of conversion of 17-hydroxypregnenolone to 17-hydroxyprogesterone by peripheral type I 3-beta–hydroxysteroid dehydrogenase isoenzyme and may be detected by neonatal screening for 21-hydroxylase deficiency. [15, 16]
Peripheral type I 3-beta–hydroxysteroid dehydrogenase activity may also increase androstenedione levels. [15] However, in 3-beta–hydroxysteroid dehydrogenase deficiency, the plasma ratio of 17-hydroxypregnenolone to 17-hydroxyprogesterone is markedly elevated. Plasma cortisol and aldosterone levels are low in 3-beta–hydroxysteroid dehydrogenase.
Adrenocorticotropic hormone (ACTH) levels are elevated because of the lack of cortisol secretion, and gonadotropin follicle-stimulating hormone (FSH) and luteinizing hormone (LH) are elevated secondary to deficient sex steroid production.
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Late-onset or nonclassic 3-beta–hydroxysteroid dehydrogenase deficiency: Baseline (unstimulated) measurements of pregnenolone, 17-hydroxypregnenolone, and dehydroepiandrosterone (DHEA) may be unremarkable in patients with late-onset or nonclassic 3-beta–hydroxysteroid dehydrogenase deficiency. In such patients, diagnosis is based on an excessive response of 17-hydroxypregnenolone (delta 5-17Preg) and delta 5-17Preg-to-F ratios at or greater than 201 nmol/L and 487 nmol/L, respectively; this is equivalent to or greater than 36 standard deviations (SD) and 52 SD above matched control mean, respectively. [19]
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Carriers: Carriers of type II 3-beta–hydroxysteroid dehydrogenase deficiency can have hormone profiles (both stimulated and unstimulated) within the reference range and, therefore, can only be detected by genotype studies.
Imaging Studies
Imaging studies may reveal polycystic ovaries in older patients or enlarged adrenal glands; such findings are nonspecific and not diagnostic for any particular type of enzyme deficiency.
Other Tests
Genotyping is not routinely required for diagnosis but may be helpful if hormone testing is inconclusive. Molecular genetic studies are indicated, as noted above, to detect carriers as well as for genetic counseling of the individual and family. [20]
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Normal adrenal steroid biosynthesis results in 3 products: mineralocorticoid (aldosterone), glucocorticoids (cortisol), and androgens (androstenedione). Cortisol production is regulated by feedback with adrenocorticotropic hormone (ACTH). ACTH stimulates the enzyme P-450scc (20,22 desmolase) with subsequent increased production of all adrenal steroids.
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Representation of typical congenital adrenal hyperplasia (CAH). In this example, both the mineralocorticoid and glucocorticoid pathways are deficient. Decreased serum cortisol levels stimulate adrenocorticotropic hormone (ACTH) release via negative feedback. Increased ACTH secretion results in overproduction of adrenal steroids preceding the missing enzyme as well as those not requiring the missing enzyme. In this example, a deficiency of 21-hydroxylase results in deficient mineralocorticoid and glucocorticoid production and excessive androgen production.
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3-beta-hydroxysteroid dehydrogenase (3BHSD) is required for the synthesis of all three groups of adrenal steroids: mineralocorticoids, glucocorticoids, and sex steroids. 3BHSD catalyzes the conversion of pregnenolone to progesterone (mineralocorticoid pathway), 17-alpha-hydroxypregnenolone to 17-alpha-hydroxyprogesterone (glucocorticoid pathway), and dehydroepiandrosterone to androstenedione (sex steroid pathway). Complete absence of this enzyme thus impairs all steroid production. 17OH Preg = 17-alpha-hydroxypregnenolone; DHEA = Dehydroepiandrosterone; 17OH Prog = 17-alpha-hydroxyprogesterone; Andros = Androstenedione; DOC = Deoxycorticosterone; Cmp S = Compound S.
