Searchable abstracts of presentations at key conferences in endocrinology
Endocrine Abstracts (2009) 20 PL8

ECE2009 Plenary Lectures 11β HSDs-common lessons from rare mutations (1 abstracts)

11β-hydroxysteroid dehydrogenases: common lessons from rare mutations

Paul Stewart

University of Birmingham, Birmingham, UK.

In mammalian tissues, two isozymes of 11β-hydroxysteroid dehydrogenase (11β-HSD) catalyze the interconversion of hormonally active cortisol (F) and inactive cortisone (E). 11β-HSD2 is a high affinity dehydrogenase expressed in adult kidney that inactivates F to E protecting the mineralocorticoid receptor (MR) (which has equal affinity for F and aldosterone in vitro) from cortisol excess. ‘Cushing’s disease of the kidney’ occurs in the hypertensive condition ‘Apparent Mineralocorticoid Excess (AME)’ because of mutations in the HSD11B2 gene. Acquired inhibition of 11β-HSD2 explains the mineralocorticoid excess state that characterizes excessive liquorice ingestion. Heterozygous mutations in HSD11B2 and polymorphic variation at this locus might be involved in the pathogenesis of salt-sensitive and ‘essential’ hypertension.

By contrast, 11β-HSD1 is a bi-directional enzyme but in vivo the predominant action in liver, adipose tissue and bone is E to F conversion. The putative 11β-HSD1 null state is the syndrome of Cortisone Reductase Deficiency (CRD) whereby patients are unable to convert cortisone to cortisol. Hyperandrogenism results because of increased ACTH drive to the drive secondary to increased cortisol clearance; as a result patients present with polycystic ovary syndrome and/or precocious puberty. Our clinical and laboratory studies indicate that the pivotal oxo-reductase activity of 11β-HSD1 is critically dependant upon the generation of NADPH within the endoplasmic reticulum from an accessory enzyme hexose-6-phosphate dehydrogenase (H6PDH). Mutations in the H6PDH gene explain the molecular basis for CRD – the HSD11B1 gene is normal. Recombinant mice lacking H6PDH have the predicted change in glucocorticoid metabolism (reduced oxo-hydroxyl ratios), and improved insulin sensitivity because of a failure to reactivate glucocorticoid locally within liver and fat. Lack of H6PDH specifically within muscle results in a type II fiber myopathy because of activation of ER stress pathways. Polymorphisms in HSD11B1/ H6PDH genes may be implicated in explaining the variable phenotype of patients with PCOS.

Mutations in the HSD11B2 and H6PDH genes explain the monogenic diseases AME and CRD. In turn a greater understanding of the role of 11β-HSD1, 11β-HSD2 and H6PDH has increased our understanding of the role of corticosteroids in prevalent human diseases such as hypertension, metabolic syndrome and PCOS.

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