ReviewDisorders in the initial steps of steroid hormone synthesis

- The complex biology of intracellular cholesterol trafficking and its delivery to steroidogenic mitochondria is incompletely understood.
- Paradoxically, the known human disorders of intracellular cholesterol trafficking have only modest effects on adrenal steroidogenesis.
- The Steroidogenic Acute Regulatory Protein (StAR) does not deliver cholesterol to mitochondria but instead promotes its transfer from the outer to inner mitochondrial membrane.
- Congenital lipoid adrenal hyperplasia (mutant StAR) typically presents with severe adrenal insufficiency and 46,XY sex reversal but may also be seen in milder non-classic, adult forms.
- Disorders of P450scc, the cholesterol side-chain cleavage enzyme are much rarer and resemble lipoid CAH clinically and hormonally, but do not exhibit its massive adrenal enlargement.

Steroidogenesis begins with cellular internalization of low-density lipoprotein particles and subsequent intracellular processing of cholesterol. Disorders in these steps include Adrenoleukodystrophy, Wolman Disease and its milder variant Cholesterol Ester Storage Disease, and Niemann-Pick Type C Disease, all of which may present with adrenal insufficiency. The means by which cholesterol is directed to steroidogenic mitochondria remains incompletely understood. Once cholesterol reaches the outer mitochondrial membrane, its delivery to the inner mitochondrial membrane is regulated by the steroidogenic acute regulatory protein (StAR). Severe StAR mutations cause classic congenital lipoid adrenal hyperplasia, characterized by lipid accumulation in the adrenal, adrenal insufficiency, and disordered sexual development in 46,XY individuals. The lipoid CAH phenotype, including spontaneous puberty in 46,XX females, is explained by a two-hit model. StAR mutations that retain partial function cause a milder, non-classic disease characterized by glucocorticoid deficiency, with lesser disorders of mineralocorticoid and sex steroid synthesis. Once inside the mitochondria, cholesterol is converted to pregnenolone by the cholesterol side-chain cleavage enzyme, P450scc, encoded by the CYP11A1 gene. Rare patients with mutations of P450scc are clinically and hormonally indistinguishable from those with lipoid CAH, and may also present as milder non-classic disease. Patients with P450scc defects do not have the massive adrenal hyperplasia that characterizes lipoid CAH, but adrenal imaging may occasionally fail to distinguish these, necessitating DNA sequencing.

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