Clinical trial NCT04860180: Effect of Surgical or Conservative Approach in Patients With Adrenal Incidentalomas
Official title: Effect of Surgical or Conservative Approach in Patients With Adrenal Incidentalomas on Cardiovascular, Metabolic, Neuropsychological and Bone Manifestations: Respective Roles of Cortisol Secretion and Glucocorticoid Sensitivity
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: NA
Conditions: Adrenal Incidentaloma
Subclinical Hypercortisolism
Lead sponsor: Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico
Sponsor class: OTHER
Collaborators: name: Casa Sollievo della Sofferenza IRCCS
name: I.R.C.C.S Ospedale Galeazzi-Sant'Ambrogio
name: Ministry of Health, Italy
First posted: 2021-04-26
Enrollment: 61
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

Brief summary: Subclinical hypercortisolism (SH) is a status of asymptomatic hypercortisolism, frequently found in patients with adrenal adenomas (estimated prevalence: 0.8-2% after 60 years of age). Although SH may lead to diabetes, hypertension and osteoporosis, the diagnostic SH criteria and those suggesting the need of adrenalectomy are debated. Indeed, beside the cortisol secretion, the individual cortisol sensitivity may play a role in determining the SH consequences.

Subjects with possible SH due to adrenal adenoma will be randomized to surgery/conservative follow up. The effects of surgery on the cardiovascular, bone, metabolic complications of SH and on neuropsychological aspects and quality of life (QoL) and the possibility to predict them by using cortisol sensitivity and secretion markers will be studied. The study may clarify how to individuate patients who can benefit from surgery. These results will help reducing the costs of both useless surgical operations and SH consequences.

Detailed description: Subclinical hypercortisolism (SH) is a status of asymptomatic hypercortisolism, which is present in up to the 30% of patients with incidentally discovered adrenal adenomas (adrenal incidentalomas, AI). Since AI are present in 7-10% of individuals after 60 years of age, the estimated SH prevalence in this population is 0.8-2%. In patients with SH due to an adrenal adenoma the risk of diabetes, hypertension, cardiovascular events, osteoporosis and mortality seems to be increased, and monolateral adrenalectomy beneficial. However, no randomized studies evaluated the effects of surgery on SH consequences and established the criteria indicating the need of surgery itself. Thus, in many patients the SH diagnosis is uncertain and the best approach (surgical or conservative) unknown. These uncertainties are also due to the influence of the individual glucocorticoid (GC) sensitivity. Indeed, in the single individual the various polymorphisms of GC receptor (GR) and the different 11ß-hydroxysteroid-dehydrogenase type 2 enzyme (11HSD2) activity, regulating the tissue exposure to the active GC, may differently predispose to the consequences of GC excess. Therefore, in AI patients, beside the evaluation of the degree of the cortisol hypersecretion, the assessment of the cortisol sensitivity may be useful in establishing the individual risk of SH consequences and the possible usefulness of a surgical approach.

Specific Aim:

In AI subjects with uncertain SH the combined evaluation of the clinical features together with the parameters of cortisol secretion and sensitivity will consent to decide which patient has the greatest probability to ameliorate after surgery.

1. To assess the variation of blood pressure control, lipids and glucose metabolism, vascular damage, bone mineral density (BMD), clinical and morphometric vertebral fractures, body composition, coagulation parameters, neuropsychological aspects and quality of life (QoL) in AI patients with uncertain SH after the surgical removal of the adrenal mass or after a conservative treatment.
2. To assess in AI patients and uncertain hypercortisolism the effect of the surgical and conservative approach on cardiovascular, metabolic and bone manifestations, neuropsychological aspects and quality of life (QoL), in relation to the degree of cortisol secretion and sensitivity.
3. To establish the best clinical-biochemical criteria for diagnosing SH, on the basis of the changes of the outcomes after the surgical or conservative approach, and therefore, for addressing the treatment of choice in the individual patient with AI.

Methods. During the enrollment period (24 months), all patients between 40 and 75 years of age referred for unilateral AI larger than 1 cm will be evaluated.

In all subjects, adrenocorticotroph hormone (ACTH), urinary free cortisol (UFC), cortisol after 1-mg overnight dexamethasone suppression test (1mgDST) and the GR polymorphisms of N363S, BclI and ER22/23EK will be assessed. Patients with 1mgDST \>1.8 mcg/dL will undergo a low dose (2 mg for 2 days) dexamethasone suppression test (LDDST). Patients with 1mgDST and LDDST \>5 mcg/dL and suppressed (\<5 pg/mL) ACTH levels will be excluded as affected by biochemically overt hypercortisolism, that requires surgery. AI patients with 1mgDST or LDDST \<1.8 mcg/dL will be excluded as certainly not affected with SH. AI patients with AI \>5 cm will leave the study as in this case surgery is mandatory.

Eventually, after the enrollment period, 54 AI patients with uncertain SH will be included and randomized to surgery (Group1) or conservative treatment (Group 2). The follow-up period will last 24 months (after withdrawal of GC substitution therapy, if needed, for Group 1). Group 1 patients will undergo laparoscopic or laparotomic adrenalectomy, depending on the AI size and their clinical characteristics.

Evaluations at baseline, 6, 12 and 24 months: blood pressure (BP), body weight (BW), body mass index (BMI), waist circumference, glucose, lipid and coagulation parameters, body composition and adenoma size by CT (Group 2 patients).

Group 2 patients with a \>1 cm adenoma increase or appearance of overt SH will leave the study. At baseline and after 24 months, bone mineral density (BMD) and quality (by trabecular bone score, TBS), vertebral fractures (VFx), carotid atherosclerosis, neuropsychological aspects and QoL, will be assessed.

The patients will be defined: i) obese, in the presence of BMI \>30 kg/m2; ii) hypertensive in the presence of systolic BP \>130 mmHg and/or diastolic BP \>85 mmHg and/or any antihypertensive treatment; iii) diabetic, in the presence of the World Health Organization criteria, and/or any hypoglycemic drug, iv) dyslipidemic, in the presence of triglyceride levels \>150 mg/dl or high-density lipoprotein (HDL) cholesterol levels \<40 or 50 mg/dl in males and females, respectively.

The improvement/worsening during follow-up will be defined as follows: for obesity in the presence of a \>5% BW decrease/increase, for hypertension if the non-hypertensive patients passed from a pre-hypertension category to another or the hypertensive patients from a hypertension grade to another; for diabetes and dyslipidemia if fasting glucose and cholesterol levels pass from a category to another, respectively, following the Adult Treatment Panel III criteria.

The efficacy of the surgical and conservative approach on the basis of the changes of BP, BW, glucose and lipid control, BMD, VFx incidence (primary outcomes) will be compared. The effect of surgery on the coagulation parameters, carotid atherosclerosis, body composition, neuropsychological aspects and QoL (secondary outcomes) will be also evaluated.

At baseline, and at 6, 12 and 24 months, beside ACTH, 1mgDST and UFC, the midnight salivary cortisol (MSalC) and urinary free cortisone (UFCo) levels and the UFC/UFCo ratio (index of 11HSD2 activity) will be assessed In Group 1 and Group 2 patients the association between the changes of the primary and secondary outcomes with the cortisol secretion parameters and the presence/absence of GC sensitizing GR polymorphisms and the degree of 11HSD2 activity, will be evaluated.

An algorithm for predicting the effect of the surgical or conservative approach on the primary outcomes in the individual AI patient with uncertain SH. The algorithm, based on the combination of the SH complications at baseline (hypertension, osteoporotic fractures, diabetes) with the presence/absence of GC sensitizing GR polymorphisms, degree of 11HSD2 activity and parameters of cortisol secretion, will be retrospectively tested on the study population, will be elaborated. This would consent to evaluate positive and negative predictive value of the algorithm for predicting the response to surgery in the individual patient with AI.

Eligibility criteria: Inclusion Criteria:

* unilateral adrenal incidentaloma larger than 1 cm
* cortisol after 1-mg overnight dexamethasone suppression test (1mgDST) between 1.8 and 5 mcg/dl

Exclusion Criteria:

* hypogonadism, thyrotoxicosis, chronic renal failure and hepatic disease, alcoholism, eating, rheumatologic or hematological disorders;
* intake of drugs influencing cortisol and dexamethasone metabolism or cortisol secretion;
* signs of hypercortisolism (moon facies, striae rubrae, easy bruising);
* possible metastatic disease or radiologic features not consistent with adrenocortical adenoma at computed tomography (CT);
* pheochromocytoma and aldosteronoma;
* non-adrenal SH.

Primary outcomes:
measure: variation of blood pressure
timeFrame: 6 months
measure: variation of glucose levels
timeFrame: 6 months
measure: variation of lipids
timeFrame: 6 months
measure: variation of body weight
timeFrame: 6 months
measure: variation of bone mineral density (BMD)
timeFrame: 24 months
measure: occurrence of vertebral fractures
timeFrame: 24 months
measure: variation of intimal medial thickness
timeFrame: 12 months
measure: variation of Relative wall thickness (RWT)
timeFrame: 12 months
measure: variation of Sheehan Disability Scale
timeFrame: 6 months
measure: Cognitive evaluation by Brief Assessment Cognition in Schizophrenia (BACS) score
timeFrame: 6 months
Secondary outcomes:
measure: cortisol secretion and sensitivity
timeFrame: 24 months
measure: variation of Inflammation markers and bone metabolism markers
timeFrame: 6 months
Other outcomes:
Locations:
Study officials:
affiliation: Istituto Auxologico Italiano
name: Iacopo Chiodini, Professor
role: PRINCIPAL_INVESTIGATOR
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