11β-Hydroxysteroid dehydrogenases and the brain: From zero to hero, a decade of progress
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Glucocorticoids have profound effects on brain development and adult CNS function. Excess or insufficient glucocorticoids cause myriad abnormalities from development to ageing. The actions of glucocorticoids within cells are determined not only by blood steroid levels and target cell receptor density, but also by intracellular metabolism by 11β-hydroxysteroid dehydrogenases (11β-HSD). 11β-HSD1 regenerates active glucocorticoids from their inactive 11-keto derivatives and is widely expressed throughout the adult CNS. Elevated hippocampal and neocortical 11β-HSD1 is observed with ageing and causes cognitive decline; its deficiency prevents the emergence of cognitive defects with age. Conversely, 11β-HSD2 is a dehydrogenase, inactivating glucocorticoids. The major central effects of 11β-HSD2 occur in development, as expression of 11β-HSD2 is high in fetal brain and placenta. Deficient feto-placental 11β-HSD2 results in a life-long phenotype of anxiety and cardiometabolic disorders, consistent with early life glucocorticoid programming.
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11β-HSD type 1 generates bioactive glucocorticoids from inactive 11-keto derivatives while type 2 catalyzes the opposite reaction; type 1 is widely expressed by neurons and glial cells, whereas type 2 expression is more restricted.
“Briefly, 11β-HSD type 1 generates the bioactive form (cortisol or corticosterone) from inactive 11-keto derivatives while 11β-HSD type 2 catalyzes the opposite reaction. Interestingly, 11-keto derivatives do not bind to CBG in plasma nor are expelled by the efflux pumps of the BBB. As a result, 11-keto-GCs reach the CNS more readily than the bioactive form. 11β-HSD type 1 is widely expressed by”
From The HPA – Immune Axis and the Immunomodulatory Actions of Glucocorticoids in the Brain (2014) · cites this paper as [68]
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11β-hydroxysteroid dehydrogenases: Intracellular gate-keepers of tissue glucocorticoid action
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- Authors
- Wyrwoll, C. S., Holmes, M. C., & Seckl, J. R.
- Affiliations
- The Queen's Medical Research Institute (GB)
- Corresponding author
- Wyrwoll, Caitlin S.
- Venue
- Frontiers in Neuroendocrinology
- Publisher
- Elsevier BV
- Published
- 2011-08
- Volume
- 32
- Issue
- 3
- Pages
- 265-286
- ISSN
- 0091-3022 (ISSN-L)
- PMC
- PMC3149101
- OpenAlex
- W2133069858
- Cited by
- 244
- References
- 336
- Citations by year
- 2026: 9 · 2025: 12 · 2024: 10 · 2023: 17 · 2022: 12 · 2021: 18 · 2020: 18 · 2019: 22 · 2018: 12 · 2017: 15 · 2016: 20 · 2015: 17 · 2014: 22 · 2013: 23 · 2012: 12
- FWCI
- 1.10
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Frontiers in Neuroendocrinology (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- UWA Profiles and Research Repository (UWA) (submittedVersion)
- Edinburgh Research Explorer (University of Edinburgh) (submittedVersion, other-oa)
- Funders
- Wellcome Trust
- MRC
- Topics
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Hormonal Regulation and Hypertension
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
- Keywords
- 11β-hydroxysteroid dehydrogenase, 11β-hydroxysteroid dehydrogenase type 1, 11β-hydroxysteroid dehydrogenase type 2, glucocorticoids, brain development, cognitive aging, hippocampus, neocortex, placenta, fetal programming, anxiety, cardiometabolic disease, glucocorticoid metabolism
- MeSH terms
- Aging, Animals, Brain, Glucocorticoids, Humans, Isoenzymes, Signal Transduction, Gene Expression Regulation, Enzymologic, 11-beta-Hydroxysteroid Dehydrogenase Type 1, 11-beta-Hydroxysteroid Dehydrogenase Type 2
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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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