Searchable abstracts of presentations at key conferences in endocrinology
Endocrine Abstracts (2005) 10 S21

SFE2005 Symposia Evolving aspects in the HPA axis (4 abstracts)

Clinical and genetic aspects of glucocorticoid sensitivity

DW Ray


University of Manchester, Manchester, United Kingdom.


Glucocorticoid hormones (Gc) are essential for human life, and synthetic glucocorticoids are widely used to treat inflammatory disease. Glucocorticoid action is mediated by the glucocorticoid receptor (GR).

Strong linkage disequilibrium exists across the GR gene (r2=0.9) with, in our study, only 4 haplotypes (from a possible 1024) accounting for 95% of all those observed in UK Caucasian healthy individuals. We identified a 3-marker haplotype, across intron B of the GR, to be associated with increased glucocorticoid sensitivity. This haplotype included the BCl2 polymorphism that had previously been associated with surrogate markers of increased Gc sensitivity. The mechanism of altered Gc sensitivity remains to be determined, but does not involve altered expression of the GRγ splice variant.

Sites of inflammation are rich in pro-inflammatory cytokines, and there is evidence for local resistance to the actions of Gc. Proposed mechanisms include activation of NFkB, which can directly interact with GR, and oppose its function. More recently macrophage migration inhibitory factor, MIF, has been shown to modulate Gc sensitivity both in vitro and in-vivo. MIF gene polymorphisms predispose to a range of inflammatory diseases, and associate with Gc treatment response.

Gc exert pro-apoptotic effects on T lymphoblasts, and slow cell cycle progression in epithelial cells. Acute T cell leukemias readily acquire resistance to Gc, by somatic mutation. The ectopic ACTH syndrome results from production of ACTH peptides by extra pituitary tumors, and the failure of such production to be inhibited by Gc. In an in-vitro model of ectopic ACTH, human small cell lung carcinoma (SCLC) cells, we identified profound Gc resistance. Such resistance has implications for understanding SCLC biology.

In summary Gc sensitivity is determined partly by heredity, and is also regulated in a tissue specific manner by disease processes, of which inflammation and neoplasia are the best characterised.

Volume 10

196th Meeting of the Society for Endocrinology and Society for Endocrinology joint Endocrinology and Diabetes Day

Society for Endocrinology 

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