Endocrine Abstracts

The chicken gonadotropin-releasing hormone receptor (cGnRH-R) is notable for having a cytoplasmic carboxyl-terminal tail, which is not present in the mammalian GnRH-Rs. We have previously shown that the cGnRH-R undergoes rapid agonist-induced internalization, and requires the carboxyl-terminal tail for this process. To investigate the role of the carboxyl-terminal tail of the cGnRH-R in relation to its rapid internalization, and to identify the key residues involved, a series ...

Background: An adrenal incidentaloma (AI) is an adrenal lesion found on imaging performed for an indication other than adrenal disease. The current European Society of Endocrinology guidelines recommend that all AIs are discussed in a dedicated adrenal multidisciplinary meeting.Method: We evaluated the outcomes of AI cases referred to the Adrenal Radiology Meeting (ARM) at Heartlands Hospital between January 2021 and Dec...

Background: Prednisolone is the most commonly prescribed exogenous glucocorticoid(GC) and its use is frequently associated with the development of iatrogenic Cushing’s Syndrome. Once administered, prednisolone is rapidly converted to inactive prednisone by renal 11β-hydroxysteroid dehydrogenase type 2(11β-HSD2) and subsequently reactivated by 11β-HSD1. We have shown previously that 11β-HSD1 inhibition(with the selective 11β-HSD1 inhibitor, AZD4017...

Background: Hypothalamic obesity (HO) is an acquired form of severe obesity characterized by rapid and excessive weight gain resulting from insult to the hypothalamus—primarily caused by tumor invasion, resection, or radiotherapy—that can impair melanocortin-4 receptor (MC4R) pathway signaling. Treatment with setmelanotide, an MC4R agonist, resulted in weight and hunger reduction at 16 weeks in a Phase 2 trial of patients with HO. Here, we report changes in weight-re...

Objectives: The crystal structures of the TSH receptor (TSHR) leucine rich repeat domain (LRD) bound to TSHR stimulating monoclonal autoantibody M22TM or to TSHR blocking monoclonal autoantibody K1-70TM and antibody free have been solved previously. Cryo-electron microscopy (cryo-EM) was now used to solve the structure of full length TSHR in complex with K1-70TM.Methods: Recombinant human TSHR expressed in CHO cells was i...

CRN04894 is a potent, orally bioavailable nonpeptide that is a highly selective antagonist for melanocortin type 2 receptor (MC2R). This receptor is found exclusively in the adrenal cortex and is the primary mediator of adrenal activation. We report results from a randomized, double-blinded, placebo-controlled (6 active:3 placebo/cohort), multiple ascending dose (40, 60, and 80 mg) study in health volunteers evaluating safety, pharmacokinetics, and pharmacodynamics of oral, on...

Background: In patients with Bardet-Biedl syndrome (BBS), signaling impairments in the melanocortin-4 receptor (MC4R) pathway lead to hyperphagia and severe obesity, which negatively impact quality of life (QOL). We evaluated the impact of setmelanotide, an MC4R agonist, on age-appropriate weight-related parameters, hunger, and QOL in a Phase 3 trial of patients with BBS to further characterize clinical benefit in this patient population.Methods: Patient...

Requirement for daily rhGH injections is a treatment burden that can compromise adherence and efficacy in patients with GHD. Somavaratan is a novel long-acting rhGH fusion protein in clinical development for pediatric and adult GHD. In a multicenter, randomized Phase 1b/2a study, somavaratan significantly improved height velocity (HV) and IGF-I in pre-pubertal children with GHD. Preliminary efficacy and safety in subjects who have completed 3 years of somavaratan treatment are...

Background: Survivors with Fontan circulation suffer from chronic systemic hypoperfusion resulting in end-organ injury. Little is known about the effects of these hemodynamic perturbations on bone. We hypothesized that chronic Fontan circulation (>5 years after surgery) would be associated with bone deficits.Methods: Peripheral quantitative computed tomography (pQCT) was performed on 10 Fontan patients (seven males, 11.8±1.7 years) and 11 health...

Osteoporosis is a challenge facing children of all ages with a variety of health conditions and physical abilities. The reality of this challenge spurred the development of the child health program’s interdisciplinary bone health project team in a tertiary care in-patient pediatric hospital. The team’s goal was to develop protocols and tools to identify ‘at risk’ children and ultimately prevent fragility fractures in this group of children. The use of stand...