In Vivo Study of Interactions Between the Endocannabinoid System and the Corticotropic Axis in Man

Study Overview
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Brief Summary
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Working hypothesis: the interactions between the endogenous endocannabinoïds (ECS) - and cortisol, the end product of the Hypothalamo-Pituitary-Adrenal (HPA) axis may play a role in the pathophysiology of Cushing's syndrome. The investigators speculate that: acute or chronic variations in plasma cortisol may induce changes in the activity of the ECS that there is a circadian rhythm of the ECS driven by the rythm of plasma cortisol

Detailed Description
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The study aim to identify the relationship between the ECS and the HPA axis in humans with a main objective to assess if Cushing's syndrome induces changes in the ECS activity. For this purpose: the investigors will compare plasma levels of ECS between obese controls and patients with Cushing's syndrome the investigors will compare plasma levels of ECS in patients with Cushing's syndrome before and immediately after curative surgery the investigors will compare plasma levels of ECS in patients with hypoadrenalism before and after the intake of substitutive doses of hydrocortisone the investigors will evaluate the plasma levels of ECS during a short synacthen test in healthy subjects.

Official Title
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In Vivo Study of Interactions Between the Endocannabinoid System and the Corticotropic Axis in Man

Conditions
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Cushing's Syndrome

Intervention / Treatment
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* Other: Obese
* Procedure: Hypercortisolism
* Other: Hydrocortisone
* Other: Control


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: For all patients groups: Age ≥ 18, Social security.  Hypercortisolism  group: 18 < BMI < 40 kg/m2, Cushing's syndrome in front of : impaired 1 mg dexamethasone test (08:00 A.M. cortisol > 50 nmol/L) qualitative and quantitative disrupted circadian rhythm of cortisol with increased plasma concentrations free urinary cortisol upper normal range (90 µg/24H), Hypercortisolism that can be treated with surgery (adrenal adenoma treated with adrenalectomy or Cushing disease treated with pituitary surgery).  Obese  group: Obese patients: 30 < BMI < 40 kg/m2, Normal HPA axis function: 08:00 A.M. cortisol > 250 nmol/L and peak above 550 nmol/L after 1 mg SST, Normal 24H free urinary cortisol and dexamethasone test.  Control  group: Lean or overweight patients (18 < BMI < 30 kg/m2), Non cortisol secreting pituitary or adrenal tumor, Patient in whom a biological evaluation of the HPA axis is recommended.  Hydrocortisone  group: Lean or overweight patients (18 < BMI < 30 kg/m2), Primary or secondary adrenal insufficiency, With a need for hydrocortisone supplementation. Exclusion Criteria: Patients with eating disorders, major depressive disorders or psychiatric disorders other than Cushing's syndrome, Cannabis consumption, alcoholism or drug addiction, Active smoking, cortisone treatment other than hydrocortisone, Pregnancy or feeding, Surgery for obesity, Incapability, Pathology that is life-threatening in the short term, Any situation that interfere with study or is risked for patient.

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: Other
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Obese<br>Subjects with BMI between 30 - 40 kg/m2 and no alteration of corticotrope axis. | Other: Obese<br> <br> |
| Experimental: Hypercortisolism<br>Subject with BMI between 18 - 40 kg/m2 and presenting a hypercortisolism defined by HAS (Haute Autorité de Santé). | Procedure: Hypercortisolism<br> <br> |
| Experimental: Hydrocortisone<br>Subject with BMI between 18 - 30 kg/m2 and with adrenal or corticotrope failure | Other: Hydrocortisone<br> <br> |
| Experimental: Control<br>Subject with BMI between 18 - 30 kg/m2 and with a pituitary or adrenal tumor without effect on corticotrope axis. | Other: Control<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Fluctuations of 2-AG (2-arachidonoyl-Glycérol) plasma concentration in relationship to cortisol plasma concentration in obese arm compare to hypercortisolism arm. | The primary outcome will be assessed by a measurement of plasma concentration of 2-AG during the circadian rhythm of ACTH/cortisol. | Baseline | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Measurement of plasma concentration of AEA (Anandamide), OEA (Oleoyl-EthanolAmide) and PEA (Palmitoyl-EthanolAmide) endocannabinoïds associated with variations of plasma cortisol in hypercortisolism arm | The secondary outcome wille be assessed by a measurement of plasma concentration of AEA, OEA and PEA during the circadian rhythm of ACTH/cortisol. | Baseline and day 6 | 
| Measurement of plasma concentration of AEA (Anandamide), OEA (Oleoyl-EthanolAmide) and PEA (Palmitoyl-EthanolAmide) endocannabinoïds associated with variations of plasma cortisol in hydrocortisone arm | Measurement of plasma concentration of AEA, OEA and PEA on 07:30 A.M. ± 1 hour (fasting), 08:00 A.M. ± 1 hour (fasting), 09:00 A.M. ± 1 hour, 10:00 A.M. ± 1 hour, 04:00 P.M. ± 1 hour | Baseline | 
| Measurement of plasma concentration of AEA (Anandamide), OEA (Oleoyl-EthanolAmide) and PEA (Palmitoyl-EthanolAmide) endocannabinoïds in control arm who have no cortisol production problem. | Measurement of plasma concentration of AEA, OEA and PEA during the circadian rhythm of ACTH/cortisol | Baseline | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Obesity, Cortisol, Hydrocortisone, Endocannabinoïds