The Hypothalamic-Pituitary-Adrenal (HPA) Axis as an Effector System in Weight Regulation

Study Overview
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Brief Summary
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Replacing glucocorticoid in a dose dependent manner (including doses within the physiological range) to subjects with adrenal insufficiency will increase visceral fat accumulation independently of total fat mass.

Detailed Description
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To measure total fat mass by DEXA scan, central (visceral) fat accumulation, insulin sensitivity by FSIVGTT, lipid levels, and adipocyte gene expression in subjects with AI receiving increasing doses of hydrocortisone replacement (15 mg, 25 mg, and 40 mg per day in split doses) for 4-months at a time during ad-lib feeding.

Official Title
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Cortisol, Central Obesity, and Insulin Resistance: Long Term Studies in Addison's Patients

Conditions
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Obesity, Addison's Disease

Intervention / Treatment
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* Drug: Hydrocortisone
* Dietary Supplement: Isocaloric Diet


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects with complete adrenal failure as defined as spontaneous serum cortisol of levels less than 5 g/dl after 12 hours without glucocorticoid replacement and peak serum cortisol of < 5 g/dl 60 minutes after a 250 g ACTH stimulation test. Subjects who are at their usual weight (weight stable for at least 1 year) Subjects on stable replacement doses of any required hormone such as thyroid, sex hormones, mineralocorticoid replacement, growth hormone, and hydrocortisone for at least 6 months, and 4) have a normal body weight (BMI 19-27 kg/m2). Exclusion Criteria: Possible confounders on body weight and insulin resistance Age less than 18 to exclude those who might be experiencing alterations in cortisol production or weight as a result of adolescent growth. Subjects who exercise > 30 minutes/day, 3 times a week. Smokers. Heavy alcohol drinkers (> 2 drinks/ day). Subjects with medical diagnosis including diabetes, heart disease, and cancer. Subjects with psychiatric illness (i.e., depression, psychosis, bipolar, schizophrenia; or are taking medications for these disorders).

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: 1<br>Subjects with AI will be randomized to each of three doses of hydrocortisone for 4 months on each dose. | Drug: Hydrocortisone<br>* Subjects will receive in random order daily (split) dosing of hydrocortisone: a low dose of 15 mg (10 in AM, 5 in PM); a medium dose of 25 mg (15 in AM, 10 in PM) and high dose of 40 mg (30 in AM, 10 in PM) for 4 months.<br>|
| Active Comparator: 2<br>isocaloric diet | Dietary Supplement: Isocaloric Diet<br>* Subjects will eat an isocaloric diet for 4 weeks while taking hydrocortisone<br>* Other names: Weight stable diet;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Amounts of intra-abdominal fat and total fat at the end of the treatment period for each cortisol dose. |  | After 4 months on each dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Fasting Lipid levels, fat mass by DEXA, post-heparin lipase activity, insulin sensitivity, and fat biopsy |  | After 4-months on each dose |