Endocrine Abstracts

Glucocorticoid excess results in central obesity and insulin resistance/diabetes mellitus. At a pre-receptor level, 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) modulates glucocorticoid levels and has been implicated in the pathogenesis of the metabolic syndrome. 11beta-HSD1 is a bi-directional NADP(H) dependant enzyme, but keto-reductase activity predominates in-vivo. Recent studies indicate that the enzyme H6PDH ensures reductive metabolism (cortisone to c...

Glucocorticoids are an important adipogenic factor. In man, circulating cortisol excess causes visceral obesity, but in simple obesity glucocorticoid levels are usually normal. However, in adipose tissue cortisol availability to bind to the glucocorticoid receptor (GR) is modulated by 11 beta-hydroxysteroid dehydrogenase type 1 (11 beta-HSD1). Human preadipocytes display both dehydrogenase (cortisol to cortisone) and oxo-reductase (cortisone to cortisol) activity. Recent genet...

In humans, glucocorticoids (GC) are implicated in the pathogenesis of obesity and insulin resistance. GCs are regulated at the prereceptor level by 11beta-HSDs. 11beta-HSD1 predominately displays oxo-reductase activity (cortisone/11-dehydrocorticosterone to cortisol/ corticosterone), requiring the cofactor NADPH. Recently, studies in humans have shown that the enzyme H6PDH, by generating NAPDH in the endoplasmic reticulum (ER) is crucial for oxo-reductase activity. This study ...

Glucocorticoids regulate transcription of many genes through the binding to the glucocorticoid receptor (GR) however, their intracellular levels are tightly regulated by the microsomal enzyme 11beta-hydroxysteroid dehydrogenase. Two isozymes of this enzyme have been cloned and characterised; 11beta- hydroxysteroid dehydrogenase type 1 (11beta-HSD1) which is mainly expressed in the liver and adipose tissue and 11beta-HSD type 2 expressed in the kidney and placenta. Within 2.5kb...

We have recently identified inactivating mutations in the electron donor enzyme P450 oxidoreductase as the cause of disease in patients with apparent combined P450c17 and P450c21 deficiency, a variant of congenital adrenal hyperplasia (CAH) (1). Additionally, we suggested that P450 oxidoreductase deficiency (ORD) reveals the existence of an alternative pathway in human androgen synthesis present in fetal life only, explaining the concurrent presence of low circulating androgen...

Mutations in the HSD11B2 gene explain the syndrome of apparent mineralocorticoid excess (AME), which is characterised by severe hypokalaemic hypertension. Cortisol acts as a mineralocorticoid through failure of its inactivation to cortisone by 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2). Patients are diagnosed by a raised THF+allo-THF/THE ratio. To date, approximately 30 mutations have been described in HSD11B2. Recently, three apparently unrelated kindreds with A...

Mutations in the HSD11B2 gene explain the syndrome of apparent mineralocorticoid excess (AME), which is characterised by severe hypokalemic hypertension. The enzyme product of the HSD11B2 gene, 11-beta hydroxysteroid dehydrogenase type 2 (11beta HSD2), converts cortisol to its inactive form, cortisone. This reaction occurs primarily in the kidney, preventing the mineralocorticoid effects of cortisol, and in the placenta where it is believed to regulate fetal growth by protecti...

11beta-hydroxysteroid dehydrogenase regulates glucocorticoid action, by interconverting cortisone (E) to cortisol (F). The Type 1 isozyme (11betaHSD1) is an oxoreductase expressed in adipose tissue, where it may play a role in the pathogenesis of visceral obesity.We have characterised two polymorphic (CA)n microsatellite markers within intron 4 of the HSD11B1 gene, termed (CA)15 and (CA)19. In an earlier study evaluating a 'normal' population (MONICA co...

A form of congenital adrenal hyperplasia (CAH) is associated with accumulation of steroid metabolites indicating impaired 17alpha-hydroxylase and 21-hydroxylase activities. However, sequencing of CYP17 and CYP21 genes does not reveal mutations, suggesting the involvement of a co-factor interacting with both enzymes. Affected females present with ambiguous genitalia at delivery, but circulating androgens are low and virilisation does not progress, a paradox yet to be explained....

11beta-Hydroxysteroid dehydrogenase (11beta-HSD) catalyses the interconversion of hormonally active cortisol (F) and inactive cortisone (E). 11beta-HSD1 is an NADP(H) dependent enzyme expressed in human liver and adipose that is targeted to the ER membrane with a lumenal catalytic domain. In vivo the enzyme acts predominantly as a reductase, generating F from E. The inherited condition, Apparent Cortisone Reductase Deficiency (ACRD) is a form of PCOS characterised by ACTH medi...