DIAGNOSIS OF ENDOCRINE DISEASE: 18-Oxocortisol and 18-hydroxycortisol: is there clinical utility of these steroids?
Open accessAbstract
Since the early 1980s 18-hydroxycortisol and 18-oxocortisol have attracted attention when it was shown that the urinary excretion of these hybrid steroids was increased in primary aldosteronism. The development and more widespread use of specific assays has improved the understanding of their role in the (patho)physiology of adrenal disorders. The adrenal site of synthesis is not fully understood although it is clear that for the synthesis of 18-hydroxycortisol and 18-oxocortisol the action of both aldosterone synthase (zona glomerulosa) and 17α-hydroxylase (zona fasciculata) is required with cortisol as main substrate. The major physiological regulator is ACTH and the biological activity of both steroids is very low and therefore only very high concentrations might be effectivein vivo. In healthy subjects, the secretion of both steroids is low with 18-hydroxycortisol being substantially higher than that of 18-oxocortisol. The highest secretion of both steroids has been found in familial hyperaldosteronism type 1 (glucocorticoid-remediable aldosteronism) and in familial hyperaldosteronism type 3. Lower but yet substantially increased secretion is found in patients with aldosterone-producing adenomas in contrast to bilateral hyperplasia in whom the levels are similar to patients with hypertension. Several studies have attempted to show that these steroids, in particular, peripheral venous plasma 18-oxocortisol, might be a useful discriminatory biomarker for subtyping PA patients. The current available limited evidence precludes the use of these steroids for subtyping. We review the biosynthesis, regulation and function of 18-hydroxycortisol and 18-oxocortisol and their potential utility for the diagnosis and differential diagnosis of patients with primary aldosteronism.
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18-Hydroxycortisol and 18-oxocortisol are particularly important in patients with glucocorticoid remediable aldosteronism or with aldosterone-producing adenomas associated with KCNJ5 mutations.
“They are particularly important in patients in glucocorticoid remediable aldosteronism or with aldosterone-producing adenomas associated with KCNJ5 mutations [261,[264], [265], [266], [267], [268], [269], [270], [271], [272]].”
From Human steroid biosynthesis, metabolism and excretion are differentially reflected by serum and urine steroid metabolomes: a comprehensive review (2019) · cites this paper as [261]
18-Hydroxycortisol and 18-oxocortisol are often referred to as 'hybrid steroids' because they require enzymatic machinery from both the glucocorticoid and mineralocorticoid pathways.
“These metabolites are often referred to as “hybrid steroids” as they require enzymatic machinery from both the glucocorticoid and mineralocorticoid pathways [[261], [262], [263]].”
From Human steroid biosynthesis, metabolism and excretion are differentially reflected by serum and urine steroid metabolomes: a comprehensive review (2019) · cites this paper as [261]
In 18-hydroxylase deficiency, urinary excretion of 18OHTHA and THAldo is low whereas corticosterone metabolites are high.
“As a consequence, urinary excretion of 18OHTHA and THAldo is low whereas corticosterone metabolites are high [Fig. 6 (50, 112–124)].”
From Steroid Metabolome Analysis in Disorders of Adrenal Steroid Biosynthesis and Metabolism (2019) · cites this paper as [115]
In glucocorticoid-remediable aldosteronism, urinary excretion of aldosterone metabolites is increased, the urinary (18OHF+18oxoF)/THAldo ratio further supports diagnosis, and the urinary metabolite 18oxoTHF is characteristically increased.
“Urinary excretion of aldosterone metabolites is increased (Fig. 6) (115, 124), with the urinary (18OHF+18oxoF)/THAldo ratio further supporting diagnosis (116); the urinary metabolite 18oxoTHF (Fig. 7) is characteristically increased.”
From Steroid Metabolome Analysis in Disorders of Adrenal Steroid Biosynthesis and Metabolism (2019) · cites this paper as [115]
Some primary aldosteronism patients have high circulating levels of the two hybrid cortisol metabolites, 18-hydroxycortisol and 18-oxocortisol.
“Some PA patients have high circulating levels of the two “hybrid” cortisol metabolites, 18-hydroxycortisol and 18-oxocortisol (Fig. 7) (115, 171, 172).”
From Steroid Metabolome Analysis in Disorders of Adrenal Steroid Biosynthesis and Metabolism (2019) · cites this paper as [115]
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- Authors
- Lenders, J. W. M., Williams, T. A., Reincke, M., & Gomez-Sanchez, C. E.
- Affiliations
- Radboud University Medical Center (NL)
- LMU Klinikum (DE)
- 4Medizinische Klinik und Poliklinik IV, Klinikum der Ludwig-Maximilians-Universität München, Munich, Germany
- 5Division of Endocrinology, G.V. (Sonny) Montgomery VA Medical Center and the University of Mississippi Medical Center, Jackson, Mississippi, USA
- Corresponding author
- Lenders, Jacques W M
- Venue
- European Journal of Endocrinology
- Publisher
- Oxford University Press (OUP)
- Published
- 2018-01
- Volume
- 178
- Issue
- 1
- Pages
- R1-R9
- ISSN
- 0804-4643 (ISSN-L)
- 1479-683X
- PMC
- PMC5705277
- OpenAlex
- W2754113200
- Cited by
- 56
- References
- 49
- Citations by year
- 2026: 7 · 2025: 5 · 2024: 7 · 2023: 7 · 2022: 2 · 2021: 4 · 2020: 8 · 2019: 12 · 2018: 4
- FWCI
- 0.96
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- European Journal of Endocrinology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Institutional Research Information System University of Turin (University of Turin) (submittedVersion, other-oa)
- Radboud Repository (Radboud University) (submittedVersion)
- Funders
- European Commission (694913)
- Deutsche Forschungsgemeinschaft (RE 752/20–1, 205/1)
- National Heart, Lung, and Blood Institute (R01HL027255)
- National Institute of General Medical Sciences (GM115428, U54GM115428)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Hormonal Regulation and Hypertension
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
- Health Sciences › Medicine › Surgery › Adrenal and Paraganglionic Tumors
- Keywords
- 18-hydroxycortisol, 18-oxocortisol, primary aldosteronism, aldosterone-producing adenoma, bilateral adrenal hyperplasia, aldosterone synthase, 17α-hydroxylase, ACTH regulation, adrenal steroidogenesis, differential diagnosis, diagnostic biomarkers
- MeSH terms
- Diagnosis, Differential, Female, Humans, Hydrocortisone, Hyperaldosteronism, Hypertension, Male, Biomarkers
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