Prostate cancer androgen biosynthesis relies solely on CYP17A1 downstream metabolites.

Prostate cancer (PC) is dependent on androgen receptor (AR) activation by testosterone and 5α-dihydrotestosterone (DHT). Intratumoral androgen accumulation and activation despite systemic androgen deprivation therapy underlies the development of castration-resistant PC (CRPC), but the precise pathways involved remain controversial. Here we investigated the differential contributions of de novo androgen biosynthesis and androgen precursor conversion to androgen accumulation.

The role of 11-oxygenated androgens in prostate cancer.

11-oxygenated androgens are a class of steroids capable of activating the androgen receptor (AR) at physiologically relevant concentrations. In view of the AR as a key driver of prostate cancer (PC), these steroids are potential drivers of disease and progression. The 11-oxygenated androgens are adrenal-derived, and persist after androgen deprivation therapy (ADT), the mainstay treatment for advanced PC.

Androgen receptor mutations modulate activation by 11-oxygenated androgens and glucocorticoids.

Background: Androgen receptor (AR) ligand-binding domain (LBD) mutations occur in ~20% of all castration-resistant prostate cancer (CRPC) patients. These mutations confer ligand promiscuity, but the affinity for many steroid hormone pathway intermediates is unknown. In this study, we investigated the stimulation of clinically relevant AR-LBD mutants by endogenous and exogenous steroid hormones present in CRPC patients to unravel their potential contribution to AR pathway reactivation.

Validation of circulating steroid hormone measurements across different matrices by liquid chromatography-tandem mass spectrometry.

Background: Steroid hormones are essential signalling molecules in prostate cancer (PC). However, many studies focusing on liquid biomarkers fail to take the hormonal status of these patients into account. Steroid measurements are sensitive to bias caused by matrix effects, thus assessing potential matrix effects is an important step in combining circulating tumour DNA (ctDNA) analysis with hormone status.

Circulating steroid hormone variations throughout different stages of prostate cancer.

Steroid hormones play a central role in the maintenance and progression of prostate cancer. The androgen receptor is the primary driver of tumor cell proliferation and is activated by the androgens testosterone and 5α-dihydrotestosterone. Inhibition of this pathway through medical or surgical castration improves survival in the majority of advanced prostate cancer patients.

Central GLP-1 receptor signalling accelerates plasma clearance of triacylglycerol and glucose by activating brown adipose tissue in mice.

Aims/hypothesis: Glucagon-like peptide 1 (GLP-1) receptor (GLP-1R) agonism, used in the treatment of type 2 diabetes, has recently been shown to increase thermogenesis via the brain. As brown adipose tissue (BAT) produces heat by burning triacylglycerol (TG) and takes up glucose for de novo lipogenesis, the aim of this study was to evaluate the potential of chronic central GLP-1R activation by exendin-4 to facilitate clearance of lipids and glucose from the circulation by activating BAT.

Methods: Lean and diet-induced obese (DIO) C57Bl/6J mice were used to explore the effect of a 5 day intracerebroventricular infusion of the GLP-1 analogue exendin-4 or vehicle on lipid and glucose uptake by BAT in both insulin-sensitive and insulin-resistant conditions.