The Neuroendocrine Clinical Unit provides a multidisciplinary evaluation of patients with pituitary and hypothalamic disorders. Our neuroendocrinologists (Drs. Sharon Wardlaw, Pamela Freda, John Ausiello and Gabrielle Page-Wilson) work closely with a neurosurgeon (Jeffrey N. Bruce, MD) and neuroradiologist (Alexander N. Khandji, MD) to develop diagnostic and treatment plans for patients referred to the Unit for evaluation. Other Endocrinology faculty that participate in Neuroendocrine Unit activities are Drs. Thomas Jacobs and Judith Korner.
Our Clinical Neuroendocrine Unit physicians (Drs. Sharon Wardlaw, Pamela Freda, John Ausiello, Gabrielle Page-Wilson treat patients with all types of disorders of the pituitary gland especially Pituitary tumors including Nonfunctioning Pituitary Tumors, Acromegaly, Cushing’s Disease, Prolactinomas and other types of tumors in the region such as Craniopharyngiomas. We also care for patients with Hypopituitarism, Diabetes Insipidus, Lymphocytic Hypophysitis and other diseases that affect the pituitary or hypothalamus. We work closely with Neurosurgery, Neuroradiology, Neuro-oncology and Radiation Oncology in the care of our patients. We also offer diagnostic evaluations such as Petrosal Sinus Sampling, performed by Dr. Khandji, for the evaluation of patients with Cushings syndrome.
For patients undergoing surgery a Specialized Pituitary Surgery Hospital Team of Neuroendocrine physicians and nurses work along with Dr. Bruce and the Neurosurgery team to provide in-hospital and post-operative care, ensuring close follow up on discharge.
A weekly, multi-disciplinary Neuroendocrine rounds is coordinated by our Neuroendocrine Unit physicians and attended by Neuroendocrine Unit physicians, Endocrinology fellows, Neurosurgery (Dr. Bruce) and Neuroradiology (Dr. Khandji) provides a forum for review of radiological studies and discussion of diagnostic and treatment plans and integrates all team members into each patient’s care.
Our Neuroendocrine Unit physicians are also members of The Pituitary Tumor Center of Columbia University.
Complimenting our clinical programs are many clinical 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. Dr. Freda is currently testing several new approaches to the evaluation and treatment of acromegaly in a large cohort of acromegalic patients. She is studying novel treatments and effects on body composition and metabolism. Dr. Freda has also initiated a comprehensive prospective study of nonfunctioning pituitary adenomas. Drs. Wardllaw and Page-Wilson have been studying new approaches to diagnosing Cushings syndrome based on tumor specific differences in the processing of ACTH and its precursor, proopiomelanocortin (POMC). In more basic studies Dr. Wardlaw has been studying the role of hypothalamic POMC and the brain melanocortin system in the regulation of neuroendocrine function and energy balance in animals models. Ongoing clinical studies are developing biomarkers to assess brain melanocortin activity in humans. Collaborative studies with Drs. Judith Korner, Rudolph Leibel and Michael Rosenbaum focus on understanding and reversing the neuroendocrine changes induced by weight loss in order to help maintain weight loss after dieting. Related clinical research focuses on the mechanisms responsible for the hypothalamic obesity seen in some patients with hypothalamic tumors.
The Central Melanocortin System and the Regulation of Energy Balance.
(Dr. Sharon Wardlaw (PI))
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.
- Lee M and Wardlaw SL: The central melanocortin system and the regulation of energy balance. Frontiers in Bioscience 12: 3994-4010, 2007.
- Lee M, Kim A, Chua SC, Obici, S, Wardlaw SL: Transgenic MSH overexpression attenuates the metabolic effects of a high fat diet. Am J Physiol Endocrinol Metab 293: E121-E131, 2007.
- Plum L, Lin HV, Dutia R, Tanaka J, Aizawa KS, Matsumoto M, Kim AJ, Cawley NX, Paik J, Loh YP, DePinho RA, Wardlaw SL, Accili D. The obesity susceptibility gene Cpe links FoxO1 signaling in hypothalamic pro-opiomelanocortin neurons with regulation of food intake. Nature Medicine 15: 1195- 201, 2009.
- Wardlaw, SL: Hypothalamic proopiomelanocortin processing and the regulation of energy balance. European J of Pharmacology 660: 213-219, 2011.
- Dutia R, Meece K, Dighe S, Kim AJ, Wardlaw SL: ß-Endorphin antagonizes the effects of α-MSH on food intake and body weight. Endocrinology 153: 4246-4255, 2012.
Cerebrospinal Fluid Neuropeptide, Hormonal and Metabolomic Analysis in Human Energy Balance.
(Drs. Sharon Wardlaw (PI), 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.
- Xiao E, Kim AJ, Dutia R, Conwell I, Ferin M, Wardlaw SL: Effects of estradiol on cerebrospinal fluid levels of agouti-related protein in ovariectomized rhesus monkeys. Endocrinology 151: 1002-1009, 2010.
- Page-Wilson G, Reitman-Ivashkov E, Meece K, White A, Rosenbaum M, Smiley RM, Wardlaw SL: Cerebrospinal fluid levels of leptin, proopiomelanocortin and agouti-related protein in human pregnancy: Evidence for leptin resistance. J Clin Endocrinol Metab 98:264-271, 2013.
New approaches to the Treatment of Prolactinomas and Elevated Prolactin Levels
Elevated prolactin levels are commonly caused by pituitary tumors that produce prolactin (prolactinomas). These tumors are primarily treated with medications instead of surgery. Both bromocriptine and cabergoline lower prolactin levels and promote tumor shrinkage. However, these medications can have side effects and their prolonged use may be associated with heart valve disease.
Ropinirole is a medication that is FDA approved for use in patients with Parkinson's disease and Restless Leg Syndrome that has been show to lower prolactin levels in patients with Parkinson's disease and in healthy volunteers with few side effects.
The purpose of these studies is to determine if ropinirole can be used to effectively lower prolactin levels without significant side effects in patients with elevated prolactin levels. Study 1 evaluates how ropinirole affects prolactin levels over 24hrs. Study 2 examines the long-term effectiveness of ropinirole for treating high prolactin levels.
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New Approaches to the Diagnosis of Cushing’s Disease.
(Drs. Gabrielle Page-Wilson (PI), 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.
- Page-Wilson G, Freda PU, Jacobs T, Khandji AG, Bruce JN, Meece K, White A, Wardlaw SL: Elevated plasma POMC and AgRP levels in ectopic ACTH tumors: Use in the differential diagnosis of ACTH-dependent Cushing’s syndrome. 94th Annual Meeting of the Endocrine Society, Houston, TX, 2012.
New Approaches to Evaluation and Treatment of Acromegaly.
(Pamela U. Freda MD (PI), Tirissa J. Reid MD, Jeffrey N. Bruce MD, Anthony Ferrante MD, Kalmon Post MD, Fernando Arias-Mendoza MD, PhD)
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.
- Freda PU, Wendy K. Chung, Naoki Matsuoka, Jane E Walsh, M. Nabi Kanibir, George Kleinman, Yuanjia Wang, Jeffrey N. Bruce, Kalmon D. Post. Analysis of GNAS Mutations in 60 Growth Hormone Secreting Pituitary Tumors; Correlation with Clinical and Pathological Characteristics and Surgical Outcome Based on Highly Sensitive GH and IGF-I Criteria for Remission Pituitary 10(3); 275-282, 2007
- Freda PU, Shen W, Heymsfield SB, Geer EB, Reyes-Vidal CM, Gallagher D. Lower visceral and subcutaneous, but higher intermuscular adipose tissue depots in patients with GH and IGF-I excess due to acromegaly. J Clin Endocrinol Metab 93(6); 2334-2343, 2008.
- Freda PU. Medical management of the patient with acromegaly. In Pituitary Tumors; Diagnosis and Management. Humana Press, Inc. Ed. Biller BMK & Swearingen B. 2008, pp. 151-170.
- Reid TJ, Post KD, Bruce JN, Kanibir MN, Reyes-Vidal CM, Freda P. Features at diagnosis of 324 patients with acromegaly did not change from 1981 to 2006; Acromegaly remains under-recognized and under-diagnosed. Clin Endocrinol. 2009 May 16 [Epub].
- Freda PU, Shen, W, Reyes-Vidal CM, Geer EB, Arias-Mendoza F, Gallagher D, Heymsfield SB. Skeletal Muscle Mass in Acromegaly Assessed by Magnetic Resonance Imaging and Dual Photon X-ray Absorptiometry. J Clin Endocrinol Metab. 2009 Aug; 94(8): 2880-6.
Prospective Study of Clinically Non-functioning Pituitary Adenomas.
(Pamela U. Freda MD (PI), Sharon L. Wardlaw MD (Co-I), Jeffrey N. Bruce (Co-I), Steven Isaacson MD, Yaakov Stern, PhD, Kalmon Post MD)
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.
- Ausiello JC, Bruce JN, Freda PU. Postoperative assessment of the patient after pituitary surgery. Pituitary 11(4); 391-401, 2008.
- Freda PU, Bruce JN. Surgery: Risks of pituitary surgery in the elderly. Nat Rev Endocrinol. 2010 Nov;6(11):606-8. No abstract available. PMID: 20962868
- Freda P, Beckers AM, Katznelson L, Molitch M, Montori VM, Post KD, and Vance ML. Pituitary Incidentaloma: An Endocrine Society Clinical Practice Guideline. J. Clin Endocrinol Metab 2011 Apr;96(4):894-904.