Clinical Study on Circadian Genes Dysregulation in Patients With Glucocorticoid Disorders

University of Roma La Sapienza44 enrolled

Overview

This is a multicentric, prospective, intervention study on circadian genes expression in peripheral blood mononuclear cells as biomarkers of circadian rhythm derangement in patients affected by alterations of endogenous glucocorticoids secretion (Cushing's Syndrome during active phase, treatment and under remission and newly or on established glucocorticoid replacement therapy adrenal insufficiency)

This is an intervention, prospective, multicentric study. Enrolled patients will undergo 4 visits: * Adrenal insufficiency (AI) patients: patients affected by primary or secondary adrenal insufficiency, whether newly diagnosed or on established glucocorticoid therapy, will be evaluated at baseline and after one, three and six months. * Cushing's Syndrome (CS) patients: patients affected by Cushing's Syndrome will be evaluated at baseline during active phase of the disease and one, three and six months after treatment or remission. Patients affected by Cushing's Syndrome who will require glucocorticoid replacement therapy after remission will be evaluated three and six months after remission and then three and six months after the eventual glucocorticoid replacement therapy withdrawal. CS treatment will be surgery or medical therapy according to guidelines. Timing of medical therapy administration will change during protocol according to circadian rhythms. Age-, sex- and BMI- matched healthy controls will be enrolled. Patients and controls will undergo the same procedures at baseline and after 1, 3 and 6 months. The primary outcome measure will be the evaluation of circadian genes CLOCK and Aryl Hydrocarbon Receptor Nuclear Translocator Like (ARNTL) expression in peripheral blood mononuclear cells (PBMC) compared to healthy controls. Secondary Outcomes measures will be: * Circadian genes expression assessment compared to healthy controls at 7:00-8:00 Ante Meridiem (AM) (before breakfast), 12:00 AM (before lunch), 3:00-4:00 Post Meridiem (PM) (after lunch), 7:00 PM (before dinner), 12:00 PM; * Immune profiling compared to healthy controls by the quantification of peripheral blood mononuclear cells (PBMC) subpopulations assessed by flow cytometry at 7:00-8:00 AM (before breakfast), 12:00 AM (before lunch), 3:00-4:00 PM (after lunch), 7:00 PM (before dinner), 12:00 PM; * Evaluation of inflammatory cytokines and adipokines production compared to healthy controls at 7:00-8:00 AM (before breakfast), 12:00 AM (before lunch), 3:00-4:00 PM (after lunch), 7:00 PM (before dinner), 12:00 PM; * Circadian cortisol rhythm by serum and salivary dosage at 7:00-8:00 AM (before breakfast), 12:00 AM (before lunch), 3:00-4:00 PM (after lunch), 7:00 PM (before dinner), 12:00 PM; * Sleep disturbances evaluation by The Pittsburgh Sleep Quality Index (PSQI) self reported questionnaire * Evaluation of infectious diseases frequencies and severity compared to healthy controls. Infectious diseases will be evaluated by an adaptation of Infectious Diseases Questionnaire (GNC) * Circadian blood pressure using ambulatory blood pressure monitoring blood pressure waves for a noninvasive estimation * Quality of life using SF-36-Item Health Survey questionnaire * Psychometric Evaluation using Beck Depression Inventory questionnaire * Evaluation of sexual dysfunction using FSFI questionnaire in woman and IIEF questionnaire in man * Evaluation of insuline resistance calculated with HOMA index * Evaluation of body weight (kg) * Evaluation of blood lipid profile

Conditions

Cushing Syndrome Adrenal Insufficiency Cushing Disease Addison Disease

Interventions

circadian gene expression evaluationDIAGNOSTIC_TEST

patients and controls will undergo circadian gene expression (CLOCK, ARNTL) evaluation at baseline and after 1, 3 and 6 months

Eligibility

Sex: ALLMin age: 18 YearsMax age: 80 YearsHealthy volunteers:

Medical Language ↔ Plain English

Inclusion Criteria: * Primary or secondary chronic adrenal insufficiency, previously or newly diagnosed. * ACTH-dependent or ACTH-independent Cushing's Syndrome diagnosis during active disease (new diagnosis or recidivating). * Signed informed consent to participate in the study. Exclusion Criteria: \- acute adrenal insufficiency; * clinical or laboratory signs of significant respiratory, hepatobiliary, or pancreatic disease; * pregnancy; * severe infections, surgery, trauma requiring hospitalization within 3 months before study entry; * any active blood or rheumatic disorders, and active liver disease in the previous 5 years; * clinically significant chronic kidney disease; * severe psychiatric diseases; * history of neoplasms in the last 5 years (except for adrenal or pituitary adenoma in Cushing Syndrome, pituitary adenoma or related neolpasms in secondary adrenal insufficiency); * heart disease with a class III or class IV functional capacity; * BMI greater than 40 kg/m²; * use of medication that interferes with cortisol metabolism within 1 month before study entry; * treatment with systemic Glucocorticoid (GC) therapy other than hydrocortisone (HC), or cortisone acetate (CA); * alcoholism and/or drug addictions; * night-shift workers; * use of melatonin, antipsychotic medications, estroprogestinic preparations

Locations (1)

Department of Experimental Medicine, "Sapienza" University of Rome

Roma, Italy

RECRUITING

Outcomes

Primary Outcomes

Circadian genes CLOCK and ARNTL expression evaluation

Change in relative expression circadian genes of CLOCK and ARNLT from baseline compared to healthy controls. After PBMC isolation by Ficoll-Plaque gradient, complementary DNA (cDNA) pool will be extracted and used as the template for subsequent Polymerase Chain Reaction (PCR) amplification in Real time PCR; Gene expression will be quantified as relative expression compared to housekeeping genes.

Time frame: baseline, +1 month, +3 months, +6 months

Secondary Outcomes

Circadian gene expression profile

Change from baseline in relative expression and variations throughout the day of circadian genes (CLOCK and ARNTL) compared to healthy controls at 7:00-8:00 AM (before breakfast), 12:00 AM (before lunch), 3:00-4:00 PM (after lunch), 7:00 PM (before dinner), 12:00 PM. After PBMC isolation by Ficoll-Plaque gradient, cDNA pool will be extracted and used as the template for subsequent Polymerase Chain Reaction (PCR) amplification in Real time PCR; Gene expression will be quantified as relative expression compared to housekeeping genes.

Time frame: baseline, +1 month, +3 months, +6 months

Peripheral Blood Mononuclear Cells circadian profiling

Number of cells (number per mm3) of peripheral blood mononuclear cell subpopulations at 7:00-8:00 AM (before breakfast), 12:00 AM (before lunch), 3:00-4:00 PM (after lunch), 7:00 PM (before dinner), 12:00 PM

Time frame: baseline, +1 month, +3 months, +6 months

Circadian cortisol rhythm

Circadian cortisol rhythm by serum and salivary dosage at 7:00-8:00 AM (before breakfast), 12:00 AM (before lunch), 3:00-4:00 PM (after lunch), 7:00 PM (before dinner), 12:00 PM.

Time frame: baseline, +1 month, +3 months, +6 months

Sleep Disturbances

Sleep disturbances will be evaluated by The Pittsburgh Sleep Quality Index (PSQI). This questionnaire contains 19 self-related questions which are combined to create 7 component scores with a range of 0-3 points (0:no difficulty, 3: severe difficulty). Global score is the result to the addition of all component scores with a range of 0-21 points (0:no difficulty, 21: severe difficulty).

Central Contacts

Andrea Isidori, MD,PhD

CONTACT

0039649970711 andrea.isidori@uniroma1.it

Data from ClinicalTrials.gov

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