Endocrine Abstracts

Background: Glucocorticoids have pleiotropic metabolic functions and acute glucocorticoid excess causes dramatic disruption of human metabolism. Whether glucocorticoids exert adipose tissue depot-specific effects on the nontargeted metabolome in unknown.Aim: Assess the nontargeted metabolome in the systemic circulation and in femoral adipose tissue-specific blood samples in response to physiological hyperinsulinaemia and acute hypercortisolaemia.<p c...

Insulin resistance and androgen excess are the cardinal features of polycystic ovary syndrome (PCOS). Severity of hyperandrogenism and metabolic dysfunction in PCOS are closely correlated, but underlying mechanisms remain poorly understood. Aldoketoreductase type 1C3 (AKR1C3) is a key source of adipose androgen generation, activating androstenedione to testosterone (T). We postulated that AKR1C3 plays a critical role linking androgen metabolism and metabolic ...

Polycystic ovary syndrome (PCOS) is prevalent metabolic disorder in women, associated with androgen excess and insulin resistance. These two major features are closely correlated, but the direction of causality remains unclear. Aldoketoreductase type 1C3 (AKR1C3) converts the androgen precursor androstenendione to testosterone (T), and is highly expressed in subcutaneous (SC) adipose tissue. We hypothesised that adipose tissue represents an important site linking androgen acti...

Adrenocortical Carcinoma (ACC) is an aggressive malignancy with poor response to chemotherapy. Here we evaluated a potential new treatment target for ACC, focusing on the mitochondrial NADPH generator Nicotinamide Nucleotide Transhydrogenase (NNT). NNT has a central role within the mitochondrial antioxidant pathways, protecting cells from oxidative stress. Inactivating NNT mutations lead to isolated primary adrenal insufficiency, suggesting a selective vulnerability of adrenoc...

Adrenocortical Carcinoma (ACC) is an aggressive malignancy with poor response to chemotherapy. Here we evaluated a potential new treatment target for ACC, focusing on the mitochondrial NADPH generator Nicotinamide Nucleotide Transhydrogenase (NNT). NNT has a central role within the mitochondrial antioxidant pathways, protecting cells from oxidative stress. Inactivating NNT mutations lead to isolated primary adrenal insufficiency, suggesting a selective vulnerability of adrenoc...

Polycystic ovary syndrome (PCOS) affects 10% of women and is associated with an increased risk of type 2 diabetes and fatty liver disease. Androgen excess is an important driver of metabolic risk in PCOS. In adipose tissue from women with PCOS, increased activation of androstenedione (A4) to testosterone (T) by the enzyme AKR1C3 results in systemic lipotoxicity. Recent in-vitro studies also demonstrated that T and 11-ketotestosterone (11KT) activate the androgen recep...

Background and aims: 5α reductase 1 and 2 (SRD5A1 (expressed in liver and adipose), SRD5A2 (expressed in liver) inactivate cortisol to 5α-dihydrocortisol in addition to their role in the generation of dihydrotestosterone and therefore regulate the tissue availability of cortisol. Dutasteride (dual SRD5A1 and SRD5A2 inhibitor) and Finasteride (selective SRD5A2 inhibitor) are commonly prescribed, but their potential metabolic effects have only recently been identified....

Adrenocortical Carcinoma (ACC) is an aggressive malignancy with poor response to chemotherapy. Here we evaluated a potential new treatment target for ACC, focusing on the mitochondrial NADPH generator Nicotinamide Nucleotide Transhydrogenase (NNT). NNT has a central role within mitochondrial antioxidant pathways, protecting cells from oxidative stress. Inactivating human NNT mutations result in congenital adrenal insufficiency. We hypothesized NNT silencing in ACC cells will i...

Background: Benign adrenal tumours are found in 3-10% of adults and can be non-functioning (NFAT) or associated with adrenal hormone excess. Analysing 1305 prospectively recruited patients with benign adrenal tumours, we recently demonstrated that 45% had mild autonomous cortisol secretion (MACS), i.e. biochemical cortisol excess without signs of Cushing’s syndrome (CS). MACS increases the prevalence and severity of hypertension and type 2 diabetes (Ann Int Med. 2022 Doi:...