Complementing our clinical programs are research programs that are funded by the National Institutes of Health and other sources. These programs offer patients the opportunity to receive novel diagnostic and therapeutic options for their pituitary tumors above and beyond those routinely available. These include the clinical management of prolactinomas, Cushing's disease, and acromegaly.
Cerebrospinal Fluid Neuropeptide, Hormonal and Metabolomic Analysis in Human Energy Balance
Drs. Sharon Wardlaw, Gabrielle Page-Wilson, Judith Korner and Richard Smiley
This proposal will focus on cerebrospinal fluid (CSF) POMC and AgRP measurements as a surrogate for hypothalamic melanocortin activity, as related to CSF leptin, insulin and nutrient levels. Recent studies in the rodent show that levels of the intact POMC prohormone in CSF reflect hypothalamic POMC activity. We have confirmed that the POMC prohormone is the predominant POMC peptide in human CSF and are examining the relationship of CSF POMC to BMI and adiposity. An important goal is to identify biomarkers in CSF that could predict responses to dieting and to pharmacotherapy for obesity that target the melanocortin system.
New Approaches to the Diagnosis of Cushing’s Disease
Drs. Gabrielle Page-Wilson, Sharon Wardlaw, Pamela Freda, Alexander Khandji and Jeffrey Bruce
New assays are being evaluated that will improve the differential diagnosis of ACTH-dependent Cushing’s syndrome based on tumor specific differences in the processing of ACTH and its precursor, proopiomelanocortin (POMC). This is being evaluated in conjunction with petrosal sinus sampling in order to develop a less invasive way to distinguish between pituitary and ectopic sources of ACTH secretion.
New Approaches to Evaluation and Treatment of Acromegaly
Drs. Pamela Freda, Tirissa Reid, Jeffrey Bruce, Anthony Ferrante, Kalmon Post, Fernando Arias-Mendoza
These NIH supported studies focuses on patients with acromegaly, a rare disease characterized by excess GH and IGF-I and their multi-system adverse effects. For these studies we utilize a large cohort of newly diagnosed and postoperative patients with acromegaly. The studies examine a novel GH-IGF-I excess specific dysregulation of adipose tissue (AT) and lipodystrophy, which we believe contributes to insulin resistance, adipokine and appetite hormone dysregulation, endothelial cell dysfunction and ultimately increased CV risk in active acromegaly. During treatment, as GH/IGF-I normalize, reversal of the lipodystrophy markedly increases central AT, macrophage infiltration and inflammation in AT and systemic inflammation. We are testing these hypotheses utilizing techniques novel to the study of acromegaly and the GH/IGF-I axis including examinations of muscle lipid by MRI and 1HMRS, hepatic lipid by 1HMRS, adipose tissue for macrophage infiltration and inflammation and function of biopsied endothelial cells. We will also relate these clinical endpoints to our modern biochemical markers of acromegaly and thereby establish clinically validated biochemical guidelines for acromegaly therapy.
Prospective Study of Clinically Non-functioning Pituitary Adenomas
Drs. Pamela Freda, Sharon L. Wardlaw, Jeffrey Bruce, Steven Isaacson, Yaakov Stern, Kalmon Post
This NIH funded, multi-disciplinary collaborative study is first comprehensive prospective study of clinically non-functioning pituitary adenomas (CNFA). This project prospectively studies asymptomatic pituitary lesions that do not require surgical intervention in order to determine the appropriate initial evaluation and follow up as well as the safety of their conservative, non-surgical management. We also prospectively assess the outcome of symptomatic CNFAs treated with surgery, the safety of conservative follow up for patients with small tumor remnants after surgery and determine which patients need radiotherapy(RT) by examining the risks vs. benefits of post-operatively RT for residual/recurrent tumors. This project also examines for the first time, prospectively, the impact of the disease and our therapies on quality of life and neurocognitive function in patients with CNFAs and establish a novel bank of pituitary tumor specimens from our cohort that will be linked to the extensive clinical data collected in our prospective study.
The Central Melanocortin System and the Regulation of Energy Balance
Dr. Sharon Wardlaw
The long-term objective of this project is to understand how the brain senses levels of peripheral energy stores and integrates these signals to maintain energy balance. This project focuses on the melanocortin neuropeptide system which plays a key role in regulating appetite and body weight and is an important target for leptin and insulin in the hypothalamus. Studies center on the regulation of proopiomelanocortin (POMC) and the POMC-derived peptides, α-MSH, γ-MSH and ß-EP, together with agouti related protein (AgRP) which is synthesized in the hypothalamus and is a potent antagonist of the MSH peptides. Transgenic and knockout mouse models are being used to study role of the melanocortin system in modulating metabolic responses to energy excess on a high fat diet and to food restriction and to characterize underlying mechanisms with respect to changes in body weight/composition and glucose and fat metabolism with a focus on energy expenditure and fuel oxidation. An important focus is on the regulation pf POMC peptide processing with respect to energy balance. These studies are highly relevant to human energy balance as mutations in POMC, POMC processing enzymes and in melanocortin receptors have all been associated with human obesity and there are many parallels with rodent models of melanocortin deficiency.