Inborn errors of steroid metabolism explained

An inborn error of steroid metabolism is an inborn error of metabolism due to defects in steroid metabolism.

Types

A variety of conditions of abnormal steroidogenesis exist due to genetic mutations in the steroidogenic enzymes involved in the process, of which include:

Generalized

• 20,22-Desmolase (P450scc) deficiency: blocks production of all steroid hormones from cholesterol
• 3β-Hydroxysteroid dehydrogenase 2 deficiency: impairs progestogen and androgen metabolism; prevents the synthesis of estrogens, glucocorticoids, and mineralocorticoids; causes androgen deficiency in males and androgen excess in females
• Combined 17α-hydroxylase/17,20-lyase deficiency: impairs progestogen metabolism; prevents androgen, estrogen, and glucocorticoid synthesis; causes mineralocorticoid excess
• Cytochrome P450 oxidoreductase deficiency: prevents production of numerous but not all sex steroids,^[1] as well as other metabolic reactions

Androgen- and estrogen-specific

• Isolated 17,20-lyase deficiency: prevents androgen and estrogen synthesis.^[2]
  • Cytochrome b₅ deficiency: subtype of isolated 17,20-lyase deficiency; additionally results in elevated methemoglobin and/or methemoglobinemia
• 17β-Hydroxysteroid dehydrogenase 3 deficiency: impairs androgen and estrogen metabolism; results in androgen deficiency in males and androgen excess and estrogen deficiency in females
• 5α-Reductase 2 deficiency: prevents the conversion of testosterone to dihydrotestosterone; causes androgen deficiency in males
• Aromatase deficiency: prevents estrogen synthesis; causes androgen excess in females
• Aromatase excess: causes excessive conversion of androgens to estrogens; results in estrogen excess in both sexes and androgen deficiency in males.

Glucocorticoid- and mineralocorticoid-specific

• 21-Hydroxylase deficiency: prevents glucocorticoid and mineralocorticoid synthesis; causes androgen excess in females
• 11β-Hydroxylase 1 deficiency: impairs glucocorticoid and mineralocorticoid metabolism; causes glucocorticoid deficiency and mineralocorticoid excess as well as androgen excess in females
• 11β-Hydroxylase 2 deficiency: impairs corticosteroid metabolism; results in excessive mineralocorticoid activity
• 18-Hydroxylase deficiency: prevents mineralocorticoid synthesis; results in mineralocorticoid deficiency
• 18-Hydroxylase overactivity: impairs mineralocorticoid metabolism; results in mineralocorticoid excess

Miscellaneous

In addition, several conditions of abnormal steroidogenesis due to genetic mutations in receptors, as opposed to enzymes, also exist, including:

• Gonadotropin-releasing hormone (GnRH) insensitivity: prevents synthesis of sex steroids by the gonads in both sexes
• Follicle-stimulating (FSH) hormone insensitivity: prevents synthesis of sex steroids by the gonads in females; merely causes problems with fertility in males
• Luteinizing hormone (LH) insensitivity: prevents synthesis of sex steroids by the gonads in males; merely causes problems with fertility in females
• Luteinizing hormone (LH) oversensitivity: causes androgen excess in males, resulting in precocious puberty; females are asymptomatic

No activating mutations of the GnRH receptor in humans have been described in the medical literature,^[3] and only one of the FSH receptor has been described, which presented as asymptomatic.^{[4] [5]}

Further reading

• Miller WL, Auchus RJ . The molecular biology, biochemistry, and physiology of human steroidogenesis and its disorders . Endocrine Reviews . 32 . 1 . 81–151 . February 2011 . 21051590 . 3365799 . 10.1210/er.2010-0013 .

Notes and References

1. Parween . Shaheena . Fernández-Cancio . Mónica . Benito-Sanz . Sara . Camats . Núria . Rojas Velazquez . Maria Natalia . López-Siguero . Juan-Pedro . Udhane . Sameer S . Kagawa . Norio . Flück . Christa E . Audí . Laura . Pandey . Amit V . Molecular Basis of CYP19A1 Deficiency in a 46,XX Patient With R550W Mutation in POR: Expanding the PORD Phenotype . The Journal of Clinical Endocrinology & Metabolism . April 2020 . 105 . 4 . e1272–e1290 . 10.1210/clinem/dgaa076 . 32060549 . free .
2. Fernández-Cancio. Mónica. Camats. Núria. Flück. Christa E.. Zalewski. Adam. Dick. Bernhard. Frey. Brigitte M.. Monné. Raquel. Torán. Núria. Audí. Laura. 2018-04-29. Mechanism of the Dual Activities of Human CYP17A1 and Binding to Anti-Prostate Cancer Drug Abiraterone Revealed by a Novel V366M Mutation Causing 17,20 Lyase Deficiency. Pharmaceuticals. en. 11. 2. 37. 10.3390/ph11020037. 29710837. 6027421. free.
3. Karges B, Karges W, de Roux N . Clinical and molecular genetics of the human GnRH receptor . Human Reproduction Update . 9 . 6 . 523–30 . 2003 . 14714589 . 10.1093/humupd/dmg040. free .
4. Book: Eberhard Nieschlag . Hermann M. Behre . Susan Nieschlag . Andrology: Male Reproductive Health and Dysfunction . 11 June 2012 . 3 December 2009 . Springer . 978-3-540-78354-1 . 226.
5. Book: Mark A. Sperling . Pediatric Endocrinology E-Book . 11 June 2012 . 25 April 2008 . Elsevier Health Sciences . 978-1-4377-1109-7 . 35.