Novel Mediators of the Lipodystrophy and Metabolic Consequences of Cushing's Disease

This proposal will evaluate the glucocorticoid mediated changes in body fat distribution and metabolism that occur in patients with Cushing's disease. The objective is to identify the mechanisms that influence both the accumulation of lipodystrophic fat and also the changes in energy expenditure and metabolism that accompany them. The study is designed to determine if the high cortisol and AgRP levels in the blood of people living with Cushing's syndrome, either from taking steroid medications or from tumors, impact body fat and metabolism by turning off brown fat, which is a type of fat that increases one's metabolism.

Study Overview

• Status: Completed
• Conditions: Cushing's Syndrome
• Intervention / Treatment: Procedure: Treatment of Cushing's

Detailed Description

Cushing's disease (CD) is a disorder of chronic glucocorticoid (GC) excess that gives rise to a constellation of metabolic comorbidities and to a distinct lipodystrophic body habitus characterized by central adiposity, extremity wasting, and the accumulation of supraclavicular (SC) and dorsocervical (DC) fat in the region where human brown and beige adipose tissue is known to be concentrated. In spite of the recognized thermogenic capacity of select cervical adipocytes, the potential impact of lipomatous alterations in this depot on energy balance and metabolism in CD is unknown. To our knowledge, the "buffalo hump" and the supraclavicular fat pads - which are a sensitive physical finding for CD, have never been phenotypically characterized and the mechanisms underlying the GC mediated development of fat in these depots and the associated metabolic complications have not been explored in humans. The proposed research will advance our understanding of Cushing's lipodystrophy and its metabolic complications. Furthermore, it may lead to the identification of novel mediators and targetable pathways to attenuate the adverse effects of hypercortisolism on body composition and metabolism in CD, as well as in the significant population of patients treated with chronic GCs for an array of other clinical conditions. These findings may have important implications not only for those with Cushing's disease, but for the millions of Americans who are treated with chronic glucocorticoids for an array of clinical conditions.

• Study Type: Observational
• Enrollment (Actual): 8

Contacts and Locations

Study Locations

• United States
  • New York
    • New York, New York, United States, 10032
      • Columbia University Neuroendocrine Unit

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

Patients with ACTH-dependent Cushing's syndrome

Description

Inclusion Criteria:

1. Aged 18-70 yrs
2. Body mass index (BMI) <35 kg/m2
3. Urine free cortisol (UFC) ≥150ug/d
4. Pituitary tumor >6mm on MRI or an inferior petrosal sinus sampling with central to peripheral plasma adrenocorticotropic hormone (ACTH) gradient
5. Normal renal and thyroid function
6. HbA1c ≤8.0.

Exclusion Criteria:

1. Smoking
2. Alcohol >2 drinks/day
3. Uncontrolled hypertension
4. HIV given potential for lipodystrophic confounding
5. Pregnancy and nursing
6. Use of beta-blockers, β-adrenergic or diabetes medications other than insulin
7. History of claustrophobia or difficulty lying flat
8. In-dwelling metal hardware.

Study Plan

How is the study designed?

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Energy Expenditure	Resting energy expenditure (REE) will be measured by whole room indirect calorimetry prior to and following cure of Cushing's Disease (CD).	Change from baseline REE at 3 months post-treatment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Total body adipose tissue volume	Whole body MRI will be utilized to measure total body adipose tissue volume	Change in total body adipose tissue volume from baseline at 3 months post-treatment

Collaborators and Investigators

• Sponsor: Columbia University
• Collaborators: New York Obesity and Nutrition Research Center
• Investigators: Principal Investigator: Gabrielle Page-Wilson, MD, Columbia University

Study record dates

Study Major Dates

• Study Start (Actual): July 16, 2018
• Primary Completion (Actual): July 1, 2021
• Study Completion (Actual): July 1, 2021

Study Registration Dates

• First Submitted: January 15, 2019
• First Submitted That Met QC Criteria: January 24, 2019
• First Posted (Actual): January 28, 2019

Study Record Updates

• Last Update Posted (Estimated): June 4, 2024
• Last Update Submitted That Met QC Criteria: May 31, 2024
• Last Verified: May 1, 2024

More Information

Terms related to this study

• Keywords: Glucocorticoids
• Additional Relevant MeSH Terms: Metabolic Diseases; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Skin Diseases; Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Neoplasms, Glandular and Epithelial; Endocrine System Diseases; Endocrine Gland Neoplasms; Hypothalamic Diseases; Lipid Metabolism Disorders; Hyperpituitarism; Pituitary Diseases; Adenoma; Adrenocortical Hyperfunction; Adrenal Gland Diseases; Skin Diseases, Metabolic; Pituitary Neoplasms; Cushing Syndrome; ACTH-Secreting Pituitary Adenoma; Pituitary ACTH Hypersecretion; Lipodystrophy
• Other Study ID Numbers: AAAR7901

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No