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.
The Central Melanocortin System and the Regulation of Energy Balance and Neuroendocrine Function
Dr. Sharon Wardlaw
The long-term objective of these projects has been to understand how the brain senses levels of peripheral energy stores and integrates these signals to maintain energy balance. The focus has been 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, a-MSH, ß-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. An important focus is on the regulation of 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. Current translational research is focusing on cerebrospinal fluid (CSF) neuropeptide measurements in humans as a surrogate for brain neuropeptide activity and on CSF levels of hormones that are known to regulate brain neuropeptide activity in animals. Studies have focused on diet and drug induced weight loss and on establishing biomarkers that can be used to predict the response to the pharmacotherapy of obesity. An ongoing project is studying the effects of bariatric surgery. Another clinical and basic research interest has been on the regulation of the hypothalamic-pituitary-adrenal (HPA) axis and on the bidirectional interactions between the hypothalamic melanocortin system and the HPA axis. Ongoing studies are listed below:
Targeting the Brain Melanocortin System to Attenuate the Adverse Effects of Glucocorticoids on Energy Balance and Metabolism
Drs. Gabrielle Page-Wilson, David Berger, Lori Zeltser and Sharon Wardlaw
AgRP neurons express glucocorticoid receptors and AgRP expression is stimulate by glucocorticoids in rodents. In humans, there is evidence that cortisol can stimulate AgRP as reflected by plasma AgRP measurements which we have shown can be used as a biomarker for hypothalamic AgRP. AgRP levels are elevated in patients with hypercortisolism secondary to Cushing’s disease and are correlated with cortisol concentrations; AgRP levels then fall after surgical cure along with resolution of the hypercortisolism and associated metabolic complications. Ongoing studies are focusing on AgRP as a mediator of the adverse metabolic effects of Cushing’s. Mouse models will be used to test the hypothesis that some of the adverse effects of glucocorticoid treatment on energy balance, adiposity and metabolism are mediated by AgRP neurons and that these effects will be attenuated by treatment with a melanocortin receptor agonist. The ultimate goal is to advance a clinical trial using an melanocortin receptor agonist to attenuate the adverse metabolic effects of glucocorticoids in humans.
Changes in Cerebrospinal Fluid (CSF) Biomarkers after Bariatric Surgery
Drs Sharon Wardlaw, Judith Korner and Richard Smiley
The goal of this project is to understand why bariatric surgery is such an effective treatment for obesity with a focus on brain mechanisms. CSF neuropeptides and hormones that are known to regulate energy balance hormone are being measured as a surrogate for changes in brain activity in subjects before and after bariatric surgery as compared with subjects before and after diet-induced weight loss. CSF proteomic analysis is also being used to identify novel protein changes. Understanding how the central nervous system responds to bariatric surgery could facilitate the development of alternative nonsurgical therapies for obesity and its metabolic complications.
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.
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.
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.
