No abstract

The 13th Acromegaly Consensus Conference was held in November 2019 in Fort Lauderdale, Florida, and comprised acromegaly experts including endocrinologists and neurosurgeons who considered optimal approaches for multidisciplinary acromegaly management. Focused discussions reviewed techniques, results, and side effects of surgery, radiotherapy, and medical therapy, and how advances in technology and novel techniques have changed the way these modalities are used alone or in combination. Effects of treatment on patient outcomes were considered, along with strategies for optimizing and personalizing therapeutic approaches.Expert consensus recommendations emphasize how best to implement available treatment options as part of a multidisciplinary approach at Pituitary Tumor Centers of Excellence.

Cushing disease is a condition in which the pituitary gland releases excessive adrenocorticotropic hormone (ACTH) as a result of an adenoma arising from the ACTH-secreting cells in the anterior pituitary. ACTH-secreting pituitary adenomas lead to hypercortisolemia and cause significant morbidity and mortality. Pituitarydirected medications are mostly ineffective, and new treatment options are needed. As these tumors express EGFR, we tested whether EGFR might provide a therapeutic target for Cushing disease. Here, we show that in surgically resected human and canine corticotroph cultured tumors, blocking EGFR suppressed expression of proopiomelanocortin (POMC), the ACTH precursor. In mouse corticotroph EGFR transfectants, ACTH secretion was enhanced, and EGF increased Pomc promoter activity, an effect that was dependent on MAPK. Blocking EGFR activity with gefitinib, an EGFR tyrosine kinase inhibitor, attenuated Pomc expression, inhibited corticotroph tumor cell proliferation, and induced apoptosis. As predominantly nuclear EGFR expression was observed in canine and human corticotroph tumors, we preferentially targeted EGFR to mouse corticotroph cell nuclei, which resulted in higher Pomc expression and ACTH secretion, both of which were inhibited by gefitinib. In athymic nude mice, EGFR overexpression enhanced the growth of explanted ACTH-secreting tumors and further elevated serum corticosterone levels. Gefitinib treatment decreased both tumor size and corticosterone levels; it also reversed signs of hypercortisolemia, including elevated glucose levels and excess omental fat. These results indicate that inhibiting EGFR signaling may be a novel strategy for treating Cushing disease.

Somatostatin (SRIF) is a major regulator of pituitary function, mostly inhibiting hormone secretion and to a lesser extent pituitary cell growth. Five SRIF receptor subtypes (SSTR1-5) are ubiquitously expressed G-protein coupled receptors. In the pituitary, SSTR1, SSTR2, SSTR3 and SSTR5 are expressed, with SSTR2 and SSTR5 predominating. As new SRIF-analogs have recently been introduced for treatment of pituitary disease, we evaluate the current knowledge of cell-specific pituitary SRIF receptor signaling and highlight areas of future research for comprehensive understanding of these mechanisms. Elucidating pituitary SRIF receptor signaling enables understanding of pituitary hormone secretion and cell growth, and also points to future therapeutic development for pituitary disorders. Keywords somatostatin receptors; pituitarySomatotropin-release inhibitory factors (SRIF) or somatostatins are cyclic peptides cleaved from a precursor pre-pro-somatostatin peptide to produce two bioactive products SRIF14 (14 amino acids) and SRIF28 which comprises an additional 14 N-terminal amino acids [1]. SRIFs are phylogenetically ancient, as SRIF-like immunoreactivity is found in protozoans, primitive intervertebrates and vertebrates [1,2]. SRIFs are produced from specialized cells in the brain, gastrointestinal tract (GIT), liver, pancreas, lungs, immune system, kidneys, adrenals and urogenital tracts [1]. SRIF exerts broad, mostly inhibitory effects on endocrine and exocrine secretions. Other than pituitary hormones discussed in this review, SRIF also inhibits secretion of gastro intestinal tract (GIT) hormones including insulin, glucagon, gastrin, cholecystokinin, vasoactive intestinal peptide and secretin. SRIF also inhibits exocrine gastric acid, pepsin, pancreatic enzymes, bile and intestinal fluids secretions [3]. SRIF inhibits gastric emptying, gallbladder contraction, and small intestine segmentation, but inducess migrating motor complex activity and splanchnic vasoconstriction [1]. Brain SRIF inhibits release of hypothalamic hormones including corticotropin releasing hormone (CRH), thyrotropin releasing hormone (TRH), and also dopamine and norepinephrine [1].Hypothalamic SRIF is a major regulator of pituitary gland hormone secretion and to a lesser extent, pituitary cell development and growth. The peptide is produced predominantly in the Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Released SRIF is rapidly inactivated by tissue and blood peptidases, and the very short halflife (~ 2 minutes) limits its therapeutic use. Octreotide and lanreotide are clinically approved ...

Although acromegaly is a rare disease, the clinical, economic and health-related quality of life (HRQoL) burden is considerable due to the broad spectrum of comorbidities as well as the need for lifelong management. We performed a comprehensive literature review of the past 12 years (1998–2010) to determine the benefit of disease control (defined as a growth hormone [GH] concentration <2.5 μg/l and insulin-like growth factor [IGF]-1 normal for age) on clinical, HRQoL, and economic outcomes. Increased GH and IGF-1 levels and low frequency of somatostatin analogue use directly predicted increased mortality risk. Clinical outcome measures that may improve with disease control include joint articular cartilage thickness, vertebral fractures, left ventricular function, exercise capacity and endurance, lipid profile, and obstructive apnea events. Some evidence suggests an association between controlled disease and improved HRQoL. Total direct treatment costs were higher for patients with uncontrolled compared to controlled disease. Costs incurred for management of comorbidities, and indirect cost could further add to treatment costs. Optimizing disease control in patients with acromegaly appears to improve outcomes. Future studies need to evaluate clinical outcomes, as well as HRQoL and comprehensive economic outcomes achieved with controlled disease.