Endocrine Abstracts

Background: HSD-1 converts cortisone to cortisol in tissues in which cortisol excess is associated with morbidity including liver, adipose, bone, and brain. SPI-62 is a potent HSD-1 inhibitor in clinical development for treatment of Cushing’s syndrome and autonomous cortisol secretion, and as adjunctive therapy to prednisolone in polymyalgia rheumatica. In Phase 1 clinical trials SPI-62 was generally well tolerated and associated with maximal liver and brain HSD-1 inhibit...

Background: Thyrotoxicosis is a common endocrine disorder in the UK, with a prevalence of 2% in females and 0.2% in men. Endocrine services at Barnet / Chase Farm Hospitals receive ~250 new referrals per year, equating to a local incidence of 50 per 100,000. There is often a significant delay between GP referral and Endocrine clinic review, resulting in delays to commencing anti-thyroid treatment. These delays have been exacerbated by the Covid crisis. A need was identified fo...

Endocrinologists focus on circulating and excreted cortisol for diagnosis of, and to assess severity and treatment response in, Cushing’s syndrome (Cs). However, in Cs, morbidity is mediated by excess cortisol binding to intracellular glucocorticoid (GC), mineralocorticoid (MC), and non-genomic receptors. We and others have demonstrated that 11b-hydroxysteroid dehydrogenase type 1 (HSD-1) is the source of about half of intrahepatocellular cortisol in healthy adults, patie...

Previous studies have demonstrated over-expression of cyclooxygenase-2 (COX-2) enzyme and enhanced synthesis of prostanoids, such as prostaglandin E2 (PGE2), in cervical carcinomas. PGE2 mediates its is effects by interacting with one of four receptors termed EP1-4. Expression and signalling of EP receptors, including EP4, are elevated in cervical carcinomas. We have previously proposed that in addition to endogenous PGE2, EP recepto...

Previously we have demonstrated up-regulated expression of COX-2 and enhanced synthesis of PGE2 in cervical carcinomas. (Sales et al. 2001. J. Clin. Endocrinol Metab. 86(5):2243-2249). Enhanced PGE2 synthesis as a consequence of COX-2 overexpression has been associated with various carcinomas and is regarded as a promoter of neoplastic cell proliferation and angiogenesis. In sexually active women growth and invasiveness of neoplastic cervical cells may be...

11β-hydroxysteroid dehydrogenase type 1 (HSD-1) controls the intracellular cortisol pool that has access to cytosolic glucocorticoid and mineralocorticoid receptors. HSD-1 activity is elevated in patients with Cushing’s syndrome (CS).1 Patients with CS and constitutionally low HSD-1 activity showed no hypercortisolism-related symptoms despite very high 24-hour urine free cortisol.2, 3 A recent pilot trial of a HSD-1 inhibitor in patients with classical or mild CS sho...

A 72 year old gentleman with an eight month history of chronic, episodic diarrhoea had been investigated as an out-patient. Colonoscopy and biopsies, barium meal and follow-through, coeliac screen and thyroid function tests were all normal. He subsequently presented with an acute deterioration in diarrhoea, and severe hypokalaemia, acute renal failure and a profound metabolic acidosis. Haemofiltration and aggressive fluid management were required to compensate for gastro-intes...

Background: HSD-1, an intracellular enzyme, converts cortisone to cortisol in tissues where cortisol excess is associated with morbidity including liver, adipose, bone, brain, muscle, skin, and eye. SPI-62 is a potent and specific HSD-1 inhibitor in development for treatment of Cushing’s syndrome and autonomous cortisol secretion, and as adjunctive therapy to prednisolone in polymyalgia rheumatica. In Phase 1 clinical trials SPI-62 was generally well tolerated and associa...

Background: HSD-1, an intracellular enzyme, converts cortisone to cortisol in tissues where cortisol excess is associated with morbidity including liver, adipose, bone, brain, muscle, skin, and eye. SPI-62 is a potent and specific HSD-1 inhibitor in development for treatment of autonomous cortisol secretion (ACS) and Cushing’s syndrome, and as adjunctive therapy to prednisolone in polymyalgia rheumatica. In Phase 1 clinical trials SPI-62 was generally well tolerated and a...

Leptin is a pleiotropic hormone acting both centrally and peripherally. It participates in variety of biological processes including energy metabolism, reproduction and modulation of the immune response. So far structural elements affecting leptin binding to its receptor remain unknown. We employed random mutagenesis of leptin, followed by selection of high-affinity mutants by yeast-surface display and discovered that replacing residue D23 with a non-negatively charged amino a...