Monogenic Disorders of Adrenal Steroidogenesis

Abstract

Disorders of adrenal steroidogenesis comprise autosomal recessive conditions affecting steroidogenic enzymes of the adrenal cortex. Those are located within the 3 major branches of the steroidogenic machinery involved in the production of mineralocorticoids, glucocorticoids, and androgens. This mini review describes the principles of adrenal steroidogenesis, including the newly appreciated 11-oxygenated androgen pathway. This is followed by a description of pathophysiology, biochemistry, and clinical implications of steroidogenic disorders, including mutations affecting cholesterol import and steroid synthesis, the latter comprising both mutations affecting steroidogenic enzymes and co-factors required for efficient catalysis. A good understanding of adrenal steroidogenic pathways and their regulation is crucial as the basis for sound management of these disorders, which in the majority present in early childhood.

Keywords: Androgen excess; Congenital adrenal hyperplasia; Steroidogenesis.

Fig. 1

Schematic representation of human adrenal steroidogenesis. Steroidogenic enzymes are depicted in grey boxes supporting catalytic activities indicated by the black arrow. Co-factors for steroidogenic enzymes are represented by white boxes. The three main steroidogenic pathways are coloured as green for the mineralocorticoid, yellow for the glucocorticoid, and blue for the androgen pathway. An asterisk marks enzymes that are predominantly expressed in extra-adrenal tissues. StAR, steroidogenic acute regulatory protein; CYP11A1, cholesterol side-chain cleavage enzyme; CYP17A1, 17α-hydroxylase/17,20 lyase; CYB5A, cytochrome b5; SULT2A1, DHEA sulfotransferase; POR, P450 oxidoreductase; CYP21A2, 21-hydroxylase; HSD3B2, 3β-hydroxysteroid dehy­drogenase; CYP11B1, 11β-hydroxylase; CYP11B2, aldosterone synthase; HSD17B3, 17β-hydroxysteroid dehydrogenase type 3; SRD5A2, 5α-reductase type 2; Adx, adrenodoxin; AdR, adrenodoxin reductase.

Fig. 2

Schematic diagram illustrating the known implications of co-factors CYB5A, PAPSS2, and POR beyond steroid hormone biosynthesis on haemoglobin, hepatic, and chondrocyte metabolism. CYB5A, cytochrome b5; PAPSS2, PAPS synthase 2; POR, P450 oxidoreductase.