The Influence of Different Hydrocortisone Replacement Doses on the Partitioning and Flexibility of Ectopic Lipids in Patients With Corticotropic Hypopituitarism

Study Overview
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Brief Summary
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This study aims at assessing the effect of today's standard of hydrocortisone dosage versus previous hydrocortisone dosage on flexibility and partitioning of ectopic lipid depots (IMCL and IHCL) after a standardised fat load followed by a short-term aerobic exercise in patients with corticotropic pituitary insufficiency.

Detailed Description
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Background The investigators and others have shown that long-term hydrocortisone replacement therapy at higher doses of hydrocortisone replacement therapy at higher doses of hydrocortisone replacement (as previously recommended) is associated with higher mortality. The pathophysiology for the association of hydrocortisone-replacement dose and mortality remains unclear. A possible underlying mechanism is nonalcoholic fatty liver disease which is more prevalent in patients with hypopituitarism. Patients with non-alcoholic fatty liver disease are at a higher risk for overall-mortality. It remains to be established whether the insulin resistance, associated with increased intrahepatocellular lipids and increased intramusculoskeletal lipids, is implicated in the pathophysiology of these epidemiological findings. Interestingly, it has been shown that a reduction of hydrocortisone replacement dose from 20-30mg/d to 10-15mg/d resulted in a loss of body fat and a significant decrease of plasma total cholesterol and triglyceride concentration. The effect of IMCL and IHCL is so far unknown. Patients with hypopituitarism with hydrocortisone replacement therapy provide a unique disease model to study the short-term effects of previously recommended dose (higher dose) of hydrocortisone versus lower dose of HC replacement therapy on ectopic lipids (IMCL; IHCL) lipids, as well as on subcutaneous and visceral fat mass and on parameters of insulin resistance. Combining MRI and MR-spectroscopy techniques, different fat mass (subcutaneous and visceral) and ectopic lipids can be repeatedly and non-invasively assessed. Objective To investigate the impact of today's standard of hydrocortisone dosage (lower) versus previous (higher) hydrocortisone dosage on flexibility and partitioning of ectopic lipid depots after a standardised fat load followed by a short-term aerobic exercise in patients with corticotropic pituitary insufficiency. Methods Ectopic lipids are measured by MR-spectroscopy, separate assessment of visceral and subcutaneous fat mass will be performed by MR-imaging, standardized exercise capacity test using spiroergometry. Short-time exercise consists of 2h aerobic cycling at 50% VO2max. Laboratory analysis include lipid profile, free fatty acids, HOMA-Index, hormones.

Official Title
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The Influence of Different Hydrocortisone Replacement Doses on the Partitioning and Flexibility of Ectopic Lipids (Intrahepatocellular IHCL and Intramyocellular IMCL) in Patients With Corticotropic Hypopituitarism, a Randomised Placebo-controlled Double-blind Trial

Conditions
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Lipids, Hypopituitarism, Hydrocortisone, Fatty Acids, Nonesterified, Insulin Sensitivity

Intervention / Treatment
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* Drug: Hydrocortisone
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Written informed consent Male and female patients Corticotropic pituitary insufficiency Capable to exercise during 120 minutes on a bicycle Normal ECG during ergometry Exclusion Criteria Concomitant medication with NSAID, anticoagulants, digoxin, salbutamol, anticonvulsants, cholinesterase inhibitor, pancuronium Abnormal liver, renal or thyroid function, heart failure Hemophilia Diabetes mellitus Severe dyslipidemia Active neoplasia Women who are pregnant or breast feeding Intention to become pregnant during the course of the study Lack of safe contraception Known or suspected non-compliance Drug or alcohol abuse Inability to follow the procedures of the study Participation in another study with investigational drug within the 30 days preceding and during the study Previous enrolment into current study Enrolment of the investigator, his/her family members, employees and other dependent persons Inability to exercise Contraindications to exposure to a 3 T magnetic field Major depression, psychosis, claustrophobia

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: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Higher hydrocortisone dose<br>Established hydrocortisone replacement therapy plus 10mg of hydrocortisone | Drug: Hydrocortisone<br>* Established Hydrocortisone replacement therapy plus Hydrocortisone (10mg/day)<br>|
| Other: Lower hydrocortisone dose<br>Established hydrocortisone replacement therapy plus placebo | Drug: Placebo<br>* Established Hydrocortisone replacement therapy plus Placebo (0mg Hydrocortisone)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline in flexibility of Intramyocellular Lipids (IMCL) Measured in mmol/L | Measured in mmol/L | 3 months | 
| Change from baseline in flexibility of Intrahepatocellular Lipids (IHCL) Measured in mmol/L | Measured in mmol/L | 3 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Free Fatty Acids (FFA) availability during exercise before and after additional hydrocortisone/placebo Measured in mmol/L | Measured in mmol/L | At baseline, 3 months | 
| Flexibility of ectopic fat stores, defined as difference between intramyocellular/intrahepatocellular lipid concentration before and after exercise, and their possible relation to insulin sensitivity before and after additional hydrocortisone/placebo |  | At baseline, 3 months | 
| Free Fatty Acids (FFA) availability during exercise and the possible relation to insulin sensitivity before and after additional hydrocortisone/placebo Measured in mmol/L | Measured in mmol/L | At baseline, 3 months | 
| Effect of exercise on insulin at baseline |  | At baseline | 
| Effect of exercise on insulin at 3 months |  | 3 months | 
| Effect of exercise on catecholamines at baseline |  | At baseline | 
| Effect of exercise on catecholamines at 3 months |  | 3 months | 
| Effect of exercise on growth hormone at baseline |  | At baseline | 
| Effect of exercise on growth hormone at 3 months |  | 3 months | 
| Effect of exercise on cortisol at baseline |  | At baseline | 
| Effect of exercise on cortisol at 3 months |  | 3 months | 
| Effect of exercise on lactate at baseline |  | At baseline | 
| Effect of exercise on lactate at 3 months |  | 3 months | 
| Effect of exercise on glucose at baseline |  | At baseline | 
| Effect of exercise on glucose at 3 months |  | 3 months | 
| Effect of exercise on inflammatory markers at baseline |  | At baseline | 
| Effect of exercise on inflammatory markers at 3 months |  | 3 months |