Cited by 205Adrenal Hormones and DisordersSexual Differentiation and DisordersMetabolism and Genetic Disorders

Disorders in the initial steps of steroid hormone synthesis

Miller, Walter L.·2017·The Journal of Steroid Biochemistry and Molecular Biology

Abstract

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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Crossref · 10.1016/j.jsbmb.2016.03.009

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Authors
Miller, W. L.
Affiliations
University of California, San Francisco (US)
Corresponding author
Miller, Walter L.
Venue
The Journal of Steroid Biochemistry and Molecular Biology
Publisher
Elsevier BV
Published
2017-01
Volume
165
Issue
Pt A
Pages
18-37
ISSN
0960-0760 (ISSN-L)
OpenAlex
W2298595356
Cited by
205
References
272
Citations by year
2026: 6 · 2025: 23 · 2024: 22 · 2023: 34 · 2022: 23 · 2021: 22 · 2020: 21 · 2019: 15 · 2018: 18 · 2017: 11 · 2016: 8
FWCI
2.53
Type
journal article
Language
en
Open access
closed
Locations
  • The Journal of Steroid Biochemistry and Molecular Biology (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Sexual Differentiation and Disorders
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Metabolism and Genetic Disorders
Keywords
steroidogenesis, LDL receptor, adrenoleukodystrophy, Wolman disease, cholesterol ester storage disease, Niemann-Pick disease type C, adrenal insufficiency, steroidogenic acute regulatory protein, congenital lipoid adrenal hyperplasia, cholesterol side-chain cleavage enzyme, P450scc, CYP11A1, adrenal hyperplasia, adrenal imaging, glucocorticoid deficiency, mineralocorticoid deficiency, sex steroid synthesis, disorders of sex development
MeSH terms
Steroidogenic Acute Regulatory Protein, Adrenal Glands, Adrenal Hyperplasia, Congenital, Animals, Cholesterol, Cholesterol Side-Chain Cleavage Enzyme, Computer Simulation, Cytochrome P-450 Enzyme System, Female, Glucocorticoids, Humans, Male, Mitochondria, Mutation, Phosphoproteins, Steroids, Mutagenesis, Sequence Analysis, DNA, Disorder of Sex Development, 46,XY

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