Effect of Surgical or Conservative Approach in Patients With Adrenal Incidentalomas

April 22, 2021 updated by: Iacopo Chiodini, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico

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

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.

Study Overview

Status

Active, not recruiting

Conditions

Intervention / Treatment

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.

Study Type

Interventional

Enrollment (Anticipated)

61

Phase

  • Not Applicable

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 75 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Sequential Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: A, surgery
adrenalectomy
Procedure: adrenalectomy
No Intervention: B, observation
conservative follow up

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
variation of blood pressure
Time Frame: 6 months
To assess the variation of blood pressure ambulatory systolic and diastolic blood pressure (BP, mmHg), and antihypertensive treatment at baseline and follow-up will be assessed; BP will be considered improved or worsened if the non-hypertensive patients passed from a pre-hypertension category to another or the hypertensive patients from a hypertension grade to another in accordance to giudelines, of if if antihypertensive treatment was reduced by 50%
6 months
variation of glucose levels
Time Frame: 6 months
To assess the variation of glucose levels, fasting glucose levels and glucose levels after oral glucose tolerance test will be evaluated at baseline and follow-up. Glucose levels will be considered improved or worsened if fasting glucose levels pass from a category to another, following the Adult Treatment Panel III criteria or if antidiabetic treatment was reduced by 50%
6 months
variation of lipids
Time Frame: 6 months
At baseline and follow up triglyceride levels; total cholesterol levels, HDL and LDL levels (mg/dl) will be evaluated. Dyslipidemia will be diagnosed 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. dyslipidemia will be defined improved or worsened if cholesterol levels pass from a category to another, following the Adult Treatment Panel III criteria
6 months
variation of body weight
Time Frame: 6 months
At baseline and follow up body weight (kilograms) will be evaluated. the improvement/worsening during follow-up will be defined in the presence of a >5% BW decrease/increase
6 months
variation of bone mineral density (BMD)
Time Frame: 24 months
To assess the variation of bone mineral density at baseline and follow-up a Dual-energy X-ray absorptiometry (DXA) scan will be performed
24 months
occurrence of vertebral fractures
Time Frame: 24 months
A dorso-lumbar spine x-ray to evaluate the presence of morphometric fractures (presence/absence) will be performed
24 months
variation of intimal medial thickness
Time Frame: 12 months
To assess the variation of vascular damage a supra-aortic trunk echo-Doppler to evaluate at baseline and follow-up variations of intimal medial thickness will be performed
12 months
variation of Relative wall thickness (RWT)
Time Frame: 12 months
the variation of Relative wall thickness (RWT) will be evaluated by an echocardiography. It will be calculated from Left ventricular end diastolic dimension (LVEDD) (mm); Interventricular septal end diastole (IV Sd, mm) and Posterior wall thickness at end-diastole (PWd) parameters (mm)
12 months
variation of Sheehan Disability Scale
Time Frame: 6 months
Sheehan Disability Scale will be evaluated to assess perceived stress (SDS-stress scale ranges 1-10, a higher score means higher levels of stress)
6 months
Cognitive evaluation by Brief Assessment Cognition in Schizophrenia (BACS) score
Time Frame: 6 months
BACS evaluate verbal memory score (normal if >33); working memory (normal if >14.9); verbal fluency (normal if >31.6), symbol coding (normal if >40.5), tower of london (>12.4)
6 months

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
cortisol secretion and sensitivity
Time Frame: 24 months
To correlate the effect of the surgical and conservative approach in relation to the degree of cortisol secretion and sensitivity we will evaluate the GR polymorphisms of N363S, BclI and ER22/23EK ,midnight salivary cortisol (MSalC) and urinary free cortisone (UFCo) levels and the UFC/UFCo ratio (index of 11HSD2 activity)
24 months
variation of Inflammation markers and bone metabolism markers
Time Frame: 6 months
irisine, Tumor Necrosing Factor (TNF)- alpha, interleukin (IL)-6, adiponectin, resistin, sclerostin, Dickkopf-related protein (DKK) 1, N-terminal propeptide of type 1 collagen (P1NP) , monocytechemoattractant protein 1 (CCL2/MCP-1) levels will be assessed (pg/ml). Paired samples T-test will be used to compare baseline and follow-up levels.
6 months

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico

Collaborators

Istituto Ortopedico Galeazzi
Ministry of Health, Italy
Casa Sollievo della Sofferenza IRCCS

Investigators

  • Principal Investigator: Iacopo Chiodini, Professor, Istituto Auxologico Italiano

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

September 29, 2016

Primary Completion (Actual)

February 22, 2021

Study Completion (Anticipated)

December 8, 2022

Study Registration Dates

First Submitted

February 16, 2021

First Submitted That Met QC Criteria

April 22, 2021

First Posted (Actual)

April 26, 2021

Study Record Updates

Last Update Posted (Actual)

April 26, 2021

Last Update Submitted That Met QC Criteria

April 22, 2021

Last Verified

April 1, 2021

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • RF-2013-02356606

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

No

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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