Aside from their oft-exploited anti-inflammatory properties, glucocorticoids such as cortisol have number of other effects. They inhibit the uptake of glucose into muscle, shift homeostasis into a catabolic state, and promote the deposition of fat.
High levels of glucocorticoids cause visceral obesity (fat around the internal abdominal organs), insulin resistance, type 2 diabetes, adverse cholesterol levels, high blood pressure, and cardiac problems; so called “metabolic syndrome”.
Reducing levels of glucocorticoid activity in liver and adipose tissue might offer some protection against these conditions, however systemic approaches (like using a glucocorticoid receptor antagonist) would create their own adverse consequences.
While glucocorticoids serve important functions in some tissues, in others their effects may be less welcome. In these tissues their levels are typically tightly regulated by enzyme expression; for example, 11β-hydroxysteroid dehydrogenase isoenzyme 2 (11β-HSD2) changes (active) cortisol into (inactive) cortisone in mineralocorticoid-sensitive tissues (like the kidney and colon). In this way the mineralocorticoid receptor is protected from activation by cortisol and corticosterone, and free to be activated by the selective agonist aldosterone.
The other isoform of 11ß-HSD, 11β-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) is expressed in adipose tissue (fat), brain, and liver, and functions primarily as an 11-ketoreductase; that is to say, it catalyses the reverse reaction, changing inactive cortisone into active cortisol.
These nuanced local routes of corticosteroid metabolism mean that total circulating cortisol levels may be less important to health, particularly in the pathology of conditions like obesity and metabolic syndrome, than tissue-specific levels of glucocorticoid-metabolizing enzymes. An overabundance of 11ß-HSD1 can cause excess tissue-specific generation of cortisol in fat and liver, causing the afore-mentioned negative effects associated with high levels of glucocorticoids; increased hepatic glucose production, adipocyte differentiation, insulin resistance, and so on. 11β-HSD1 excess is also associated with cognitive decline seen in ageing.
The inhibition of 11ß-HSD1 has therefore become an important therapeutic target of interest to several pharmaceutical companies, and a number of patents have been issued covering whole swathes of synthetic compounds. Though none of the synthetic compounds has yet reached the market, a number of naturally-occurring 11ß-HSD1 inhibitors have been identified, however they are typically not selective enough to be of commercial interest. Liquorice, for example, or rather the active metabolite glycyrrhetinic acid, is a naturally-occurring 11ß-HSD1 inhibitor present in the food supply.
Unfortunately it is also an 11ß-HSD2 inhibitor, and as such can cause pseudoaldosteronism, (an apparent mineralocorticoid excess) resulting in water-retention and hypertension.
Other natural inhibitors of the reductase activity of 11ß-HSD1 include some endogenous steroids like 11-ketoandrostenedione (adrenosterone) and 11-ketotestosterone, and some bile acids. The risk of masculinisation (virilizing side effects) makes the androgens unsuitable to the medical community as therapeutic agents, particularly for women and children.
References and further reading:
Pereira CD, Azevedo I, Monteiro R, Martins MJ. 11β-Hydroxysteroid dehydrogenase type 1: relevance of its modulation in the pathophysiology of obesity, the metabolic syndrome and type 2 diabetes mellitus. Diabetes, Obesity and Metabolism. 2012;14(10):869–81.
Pereira CD, Martins MJ, Azevedo I, Monteiro R. 11β-Hydroxysteroid dehydrogenase type 1 and the metabolic syndrome. In: Abduljabbar H, editor. Steroids – Clinical Aspect. InTech; 2011
Monder C, Stewart PM, Lakshmi V, Valentino R, Burt D, Edwards CR. Licorice inhibits corticosteroid 11 beta-dehydrogenase of rat kidney and liver: in vivo and in vitro studies. Endocrinology. 1989 Aug;125(2):1046–53.
Latif SA, Pardo HA, Hardy MP, Morris DJ. Endogenous selective inhibitors of 11β-hydroxysteroid dehydrogenase isoforms 1 and 2 of adrenal origin. Molecular and Cellular Endocrinology. 2005 Nov 24;243(1–2):43–50.
Wyrwoll CS, Holmes MC, Seckl JR. 11β-Hydroxysteroid dehydrogenases and the brain: From zero to hero, a decade of progress. Frontiers in Neuroendocrinology. 2011 Aug;32(3):265–86.
Napolitano A, Voice MW, Edwards CR, Seckl JR, Chapman KE. 11Beta-hydroxysteroid dehydrogenase 1 in adipocytes: expression is differentiation-dependent and hormonally regulated. J Steroid Biochem Mol Biol. 1998 Mar;64(5-6):251–60.
Ge R, Huang Y, Liang G, Li X. 11beta-hydroxysteroid dehydrogenase type 1 inhibitors as promising therapeutic drugs for diabetes: status and development. Curr Med Chem. 2010;17(5):412–22.
Baker ME. Evolution of 11β-hydroxysteroid dehydrogenase-type 1 and 11β-hydroxysteroid dehydrogenase-type 3. FEBS Letters. 2010 Jun 3;584(11):2279–84.
Wamil M, Seckl JR. Inhibition of 11ß-hydroxysteroid dehydrogenase type 1 as a promising therapeutic target. Drug Discovery Today. 2007 Jul;12(13–14):504–20.
Harno E, White A. Will treating diabetes with 11β-HSD1 inhibitors affect the HPA axis? Trends Endocrinol Metab. 2010 Oct;21(10):619–27.
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