Disorders in the initial steps of steroid hormone synthesis
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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CYP11A1 defects were once considered incompatible with term pregnancy; however, more than 30 cases of such defects have been reported.
“CYP11A1 defects were once considered incompatible with term pregnancy; however, more than 30 cases of such defects have been reported (40).”
From Congenital Adrenal Hyperplasia—Current Insights in Pathophysiology, Diagnostics, and Management (2022) · cites this paper as [40]
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MLN64 Mediates Mobilization of Lysosomal Cholesterol to Steroidogenic Mitochondria
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Niemann-Pick Type C Disease and Intracellular Cholesterol Trafficking
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Mutations at the lysosomal acid cholesteryl ester hydrolase gene locus in Wolman disease
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Construction and function of fusion enzymes of the human cytochrome P450scc system
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Self-citationHuman adrenodoxin: cloning of three cDNAs and cycloheximide enhancement in JEG-3 cells
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Self-citationSTARD4 abundance regulates sterol transport and sensing
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A novel, highly sensitive and specific biomarker for Niemann-Pick type C1 disease
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Comparative Structural Analysis of Lipid Binding START Domains
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The changing landscape in translocator protein (TSPO) function
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The Nova Scotia (Type D) Form of Niemann-Pick Disease Is Caused by a G3097→T Transversion in NPC1
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Self-citationLinkage of Niemann-Pick disease type C to human chromosome 18.
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Differential gene regulation of StarD4 and StarD5 cholesterol transfer proteins
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Self-citationOxidative stress in NPC1 deficient cells: protective effect of allopregnanolone
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Nonvesicular Lipid Transfer from the Endoplasmic ReticulumPreprint
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Miglustat: A Review of Its Use in Niemann-Pick Disease Type C
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Modeling the structure of the StART domains of MLN64 and StAR proteins in complex with cholesterol
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START ships lipids across interorganelle space
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Self-citationIntermediates in the conversion of cholesterol to pregnenolone: Kinetics and mechanism
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De Novo Synthesis of Steroids and Oxysterols in Adipocytes
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Molecular recognition and electron transfer in mitochondrial steroid hydroxylase systems
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Cholesterol ester storage disease: Clinical, biochemical, and pathological studies
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Psychosis as the initial manifestation of adult-onset Niemann-Pick disease type C
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Self-citationCholesterol binding does not predict activity of the steroidogenic acute regulatory protein, StAR
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Congenital lipoid adrenal hyperplasia in an eight-year-old phenotypic female
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Inherited ACTH insensitivity illuminates the mechanisms of ACTH action
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Prenatal diagnosis of congenital lipoid adrenal hyperplasia.
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Imaging of the adrenal gland in children.
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Self-citationGonadal and extragonadal functions of Ad4BP/SF-1: developmental aspects
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A genetic isolate of congenital lipoid adrenal hyperplasia with atypical clinical findings
Chen, X., Baker, B. Y., Abduljabbar, M. A., & Miller, W. L. (2005) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2004-1323 · Cited by 76 · see citing works
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snoRNA U17 Regulates Cellular Cholesterol Trafficking
Jinn, S., Brandis, K. A., Ren, A. A., Chacko, A., Dudley-Rucker, N., Gale, S. E., Sidhu, R., Fujiwara, H., Jiang, H., Olsen, B. N., et al. (2015) · Cell Metabolism · doi:10.1016/j.cmet.2015.04.010 · Cited by 74 · see citing works
StAR-like activity and molten globule behavior of StARD6, a male germ-line protein
Bose, H. S., Whittal, R. M., Ran, Y., Bose, M., Baker, B. Y., & Miller, W. L. (2008) · Biochemistry · doi:10.1021/bi701966a · Cited by 74 · see citing works
Self-citationHow Does Progesterone Relax the Uterus in Pregnancy?
Zakár, T., & Mesiano, S. A. (2011) · New England Journal of Medicine · doi:10.1056/nejmcibr1100071 · Cited by 72 · see citing works
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Functional characterization of the MENTAL domain
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Whole-Exome Sequencing in the Differential Diagnosis of Primary Adrenal Insufficiency in Children
Chan, L. F., Campbell, D. C., Novoselova, T. V., Clark, A., & Metherell, L. (2015) · Frontiers in Endocrinology · doi:10.3389/fendo.2015.00113 · Cited by 70 · see citing works
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Induction of steroidogenic cells from adult stem cells and pluripotent stem cells [Review]
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- Authors
- Miller, W. L.
- Affiliations
- University of California, San Francisco (US)
- Corresponding author
- Miller, Walter L.
- ORCID
- 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
- Semantic Scholar
- fe8733103b7e517d495e8f1bac7db018713287f1
- 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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