Adrenalectomy Versus Follow-up in Patients With Subclinical Cushings Syndrome

Study Overview
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Brief Summary
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Incidental findings of adrenal tumours,incidentalomas, occur in 1-5 % in the general population and 10-25 % of these patients will exhibit biochemical mild hypercortisolism. Although the patients do not have clinical signs of classical Cushing's syndrome, they have an increased risk for hypertension, dyslipidemia, diabetes mellitus, osteoporosis and obesity. The hypothesis of the study is, that surgery of the adrenal adenoma responsible for the increased secretion of cortisol, will in part cure or ameliorate the metabolic syndrome.

Detailed Description
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Adrenal incidentalomas, adrenal tumours detected without symptoms and signs of hormonal hypersecretion or malignancy, are common. Depending on modality (MRI, CT. Ultrasonography) adrenal tumours occur in approximately 1-5% of the population. In about 10% of patients, the tumours are bilateral. At autopsy studies adrenal tumours occur in 1% of patients under the age of 30, but in approximately 7% of patients older than 70 years. Investigation of the adrenal tumours focus on to exclude malignancy (which is uncommon), and an increased secretion of hormones (adrenaline, aldosterone, cortisol), so-called functional tumours. However, most often adrenal incidentalomas are non-functional. The most common functional disorder is increased secretion of cortisol, and then usually without clinical stigmata, known as subclinical Cushing's syndrome (or mild hypercortisolism). Clinical stigmata, Cushing's syndrome, is empirically associated with elevated levels of urinary cortisol. Subclinical Cushing's syndrome occurs in 10-25% of patients with adrenal incidentalomas. The incidence has been estimated at 0.8 / 1,000 inhabitants, making it a common disease. Diagnosis is based to detect an autonomous release of cortisol from the adrenal gland (a disorder of the so-called hypothalamic-pituitary-adrenal axis). Fundamental to the diagnosis is that the secretion of cortisol is not inhibited <50 nmol / L at 8.00, after an overnight test with 1 mg of oral dexamethasone. In addition, at least one of the following criteria for disturbance of the hypothalamic-pituitary-adrenal axis is suggested to be present: attenuated or abolished circadian rhythm of cortisol ACTH in the low normal range or supressed DHEAS low or supressed (age dependent) Numerous studies have shown that high blood pressure, diabetes, impaired glucose tolerance, and unfavourable lipid profile, is common in patients with subclinical Cushing's syndrome, and basically do not differ from patients with overt Cushing's syndrome. At follow-up of patients with adrenal incidentalomas, some patients exhibit intermittent mild hypersecretion of cortisol, others develop overt Cushing's syndrome (unusual) and still some patients with initially normal hypothalamic-pituitary-adrenal axis, develop a subclinical Cushing's syndrome. The aim of this study is to investigate if adrenalectomy for subclinical Cushing's syndrome (mild hypercortisolism without clinical signs), result in an improvement in cardiovascular risk factors, cardiac function, and arteriosclerosis compared to follow-up

Official Title
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Adrenalectomy Versus Follow-up in Patients With Mild Hypercortisolism: a Prospective Randomized Controlled Trial

Conditions
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Adrenal Tumour With Mild Hypercortisolism

Intervention / Treatment
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* Procedure: Adrenalectomy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adrenal tumour with biochemical mild hypercortisolism defined as pathological dexamethasone suppression test (cortisol > 50 nmol/L at 8.00 am after 1 mg dexamethasone at 10 pm, plus one of the following criteria Low or suppressed adrenocorticotropic hormone (ACTH) Low or suppressed dehydroepiandrosterone (DHEA) No or pathological circadian rhythm of cortisol Exclusion Criteria: Increased levels of 24 hours urinary excretion of cortisol Pregnancy or lactation Inability to understand information or to comply with scheduled follow-up Mild hypercortisolism with bilateral adrenal tumours, without a gradient (lateralization on venous sampling)

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: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| No Intervention: Follow-up<br>Patients who are diagnosed with biochemically mild hypercortisolism (so-called subclinical Cushing´s syndrome), who are followed only. | |
| Experimental: Surgery<br>Patients diagnosed with adrenal tumour and with biochemically mild hypercortisolism (so-called subclinical Cushing´s syndrome), operated with adrenalectomy | Procedure: Adrenalectomy<br>* Adrenalectomy (open or laparoscopic)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Improvement of blood pressure as assessed by 24 hours blood pressure measurement | Blood pressure assessed by 24 hours measurement is considered to be improved if at least one of the following outcomes has occurred, and is sustained, during 2 years of follow-up: Normalization of hypertension without medical treatment Unchanged or decreased blood pressure in patients with hypertension if the number or dose of the patient's antihypertensive drug (s) has been reduced Unchanged normal blood pressure in patients who were normotensive at the time of randomization. | At two years after intervention | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Normalization of diabetes mellitus | Normalization of diabetes mellitus according to the criteria of the World Health Organization and assessed by oral glucose tolerance test | At two years after intervention | 
| Decreased body mass index (BMI) to < 30 | Standard assessment of BMI | At two years post intervention | 
| Bone density | Bone density assessed with dual energy x-ray absorptiometry (DEXA) at the lumbar spine and hip | At two years post intervention | 
| Blood lipids | Triglyceride and cholesterol changes of whole serum and of the lipoprotein classes; low-density-lipoprotein (LDL), very-low-density-lipoprotein (VLDL) and high-density-lipoprotein (HDL) | At two years post intervention | 
| Cardiac function | Cardiac function assessed by echocardiography; left ventricular ejection fraction (EF), left ventricular end-diastolic diameter (LVDD), left ventricular mass index (LVMI), ratio between mitral peak velocity flow of the early filling wave and the atrial wave (E/A ratio) | At two years post intervention | 
| Cognitive function | Mini Mental State Examination (MMSE) for cognitive function | At two years after intervention | 
| Quality of Life assessed by SF 36 | Quality of Life assessed by the generic instrument short form 36 (SF-36). | At two years after intervention | 
| Atherosclerosis | Carotid ultrasound/duplex scans with evaluation of intimal thickness and plaques. Blood pressure measurement for ankle index | At two years after intervention | 
| Adrenal cortical insufficiency | Rate of patients with postoperative adrenal cortical insufficiency in patients operated due to subclinical Cushings syndrome | At two years after intervention | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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mild hypercortisolism, adrenal tumour, surgical procedures, elective, indication