Endocrine Abstracts

The adrenal steroid dehydroepiandrosterone (DHEA) and its sulphate ester, DHEAS have been shown to oppose the effects of glucocorticoids, thereby producing beneficial effects on insulin sensitivity in rodent models of diabetes and obesity and in hypoadrenal patients. Glucocorticoids, key regulators of adipose differentiation and insulin sensitivity, are reactivated locally by 11β-hydroxysteroid dehydrogenase type (11β-HSD1) oxoreductase activity, which increases with...

Dehydroepiandrosterone (DHEA) and its sulphate ester DHEAS, have been shown to oppose the effects of glucocorticoids in vivo, thus producing beneficial effects on insulin sensitivity in rodent models of diabetes and obesity as well as in hypoadrenal patients. Glucocorticoids play a key role in regulating fat metabolism and distribution and are reactivated locally by 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) oxoreductase activity, which increases with ...

The adrenal steroid dehydroepiandrosterone (DHEA) has been shown in vivo, to mimic the effects of peroxosome proliferator-activated receptor (PPAR) ligands and oppose those of glucocorticoids, thus producing beneficial effects on insulin sensitivity and adipogenesis in obese and diabetic rodents. Furthermore, DHEA treatment has recently been shown to reduce subcutaneous and visceral fat in humans in vivo. However, the mechanism by which DHEA produces these anti-a...

A key component of androgen synthesis is the availability of the pro-hormone DHEA, which is either converted to active androgens or inactivated to its sulfate ester DHEAS by DHEA sulfotransferase (SULT2A1). The latter reaction requires provision of the universal sulfate donor 3′-phosphoadenosine-5′-phosphosulfate, PAPS. In humans, PAPS is generated by the PAPS synthase isoforms PAPSS1 and PAPSS2. Recently, inactivating PAPSS2 mutations have been identified i...

Human sulfation depends on provision of the universal sulfate donor PAPS by the two PAPS synthase isoforms PAPSS1 and PAPSS2. Mutations in PAPSS2 have been identified as a monogenic cause of androgen excess presenting with premature adrenarche and polycystic ovary syndrome, due to decreased sulfation of the androgen precursor DHEA by DHEA sulfotransferase (SULT2A1) and hence increased conversion of DHEA to active androgens (New Eng J Med 2009 360 (22)...

Mutations in the gene for 3′-phospho-adenosine-5′-phosphosulfate synthase 2 (PAPSS2) are linked to bone and cartilage mal-formation. More recently, we could identify PAPSS2-mutations as mono-genetic cause for androgen excess in women due to apparent SULT2A1 deficiency, the enzyme responsible for sulfation of the testosterone precursor DHEA that relies on PAPS provision by PAPS synthases. The only human orthologue, PAPSS1, is expressed in the affected tissu...

Androgen excess is a key feature of the polycystic ovary syndrome; however the molecular mechanisms underlying its pathogenesis largely remain elusive. Dehydroepiandrosterone sulfate (DHEAS) is the most abundant steroid in the human circulation but only unconjugated dehydroepiandrosterone (DHEA) can be converted to active androgens. Conversely, conversion of DHEA to its sulfate ester DHEAS by DHEA sulfotransferase, SULT2A1, diminishes the DHEA pool available for androgen gener...