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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:
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:
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Patients with Adrenal Insufficiency | Experimental | Patients with Adrenal Insufficiency established or newly diagnosed, under glucocorticoid replacement therapy. |
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| Patients with Cushing's Syndrome | Experimental | patients with adrenocorticotropic hormone (ACTH)-dependent or ACTH-independent Cushing's Syndrome diagnosis during active disease (new diagnosis or recidivating) at enrollment. |
|
| Healthy Controls | Experimental | Age-, sex- and BMI- matched patients referring to our center for diagnostic procedures not affected by Adrenal Insufficiency or Cushing's Syndrome. |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| circadian gene expression evaluation | Diagnostic Test | patients and controls will undergo circadian gene expression (CLOCK, ARNTL) evaluation at baseline and after 1, 3 and 6 months |
| Measure | Description | Time Frame |
|---|---|---|
| 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. | baseline, +1 month, +3 months, +6 months |
| Measure | Description | Time Frame |
|---|---|---|
| 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. |
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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).
Exclusion Criteria:
- acute adrenal insufficiency;
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| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Andrea Isidori, MD,PhD | Contact | 0039649970711 | andrea.isidori@uniroma1.it |
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| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Department of Experimental Medicine, "Sapienza" University of Rome | Recruiting | Roma | 00161 | Italy |
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| ID | Term |
|---|---|
| D003480 | Cushing Syndrome |
| D000309 | Adrenal Insufficiency |
| D047748 | Pituitary ACTH Hypersecretion |
| D000224 | Addison Disease |
| ID | Term |
|---|---|
| D000308 | Adrenocortical Hyperfunction |
| D000307 | Adrenal Gland Diseases |
| D004700 | Endocrine System Diseases |
| D006964 | Hyperpituitarism |
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patients will undergo circadian genes evaluation in peripheral blood mononuclear cells
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| 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 | 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. | 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). | baseline, +1 month, +3 months, +6 months |
| Infectious Diseases Frequency and Severity | Frequencies and severity of infectious diseases will be evaluated by modified Infectious Diseases Questionnaire (GNC). This questionnaire includes questions on infectious diseases of upper and lower respiratory tract, gastrointestinal tract, skin and urogenital tract contracted during the previous 12 months. Questions investigate on the number and duration of infections, necessity of antibiotic or antifungal therapy, hospital stay and days of absence from work. Final score represents the frequency of infections. Moreover, some questions investigate possible susceptible or protective factors for infectious diseases: vaccinations, use of corticosteroids, concomitant diseases, previous appendectomy, tonsillectomy, adenoidectomy, splenectomy or thymectomy. | baseline, +1 month, +3 months, +6 months |
| Circadian blood pressure | Circadian blood pressure will be evaluated using ambulatory blood pressure monitoring blood pressure waves for a noninvasive estimation | baseline, +1 month, +3 months, +6 months |
| Quality of life evaluation | Quality of life will be evaluated by the Physical Component score and the Mental Component score of the self-administered questionnaire SF-36-Item Health Survey questionnaire. This questionnaire measures eight scales: physical functioning, role physical, bodily pain, general health (physical component) and vitality, social functioning, role emotional, mental health (mental component). Interpretation of the score will be the following: at each item of the questionnaire corresponds a percentage value (from 0% to 100%). The average of the single items constitutes the scale total percentage (from 0% to 100%); missing data are not considered during calculation. High score defines a more favorable health state. | baseline, +1 month, +3 months, +6 months |
| Psychometric Evaluation | Psychometric Evaluation will be evaluated using Beck Depression Inventory questionnaire. : a 21-item measure of depressive symptoms. Each answer is scored on a scale value (from 0 to 3 points). The global score is obtained adding all single scores, with a range of 0-63. Higher score constitutes worse burden of symptoms (0-13: minimal depression, 14-19: mild depression, 20-28: moderate depression, 29-63: severe depression). | baseline, +1 month, +3 months, +6 months |
| Sexual dysfunction in women | Evaluation of sexual dysfunction will be evaluated in women using FSFI questionnaire. This is a 19-item questionnaire that covers six domains: desire, arousal, lubrication, and orgasm, satisfaction, and pain. The ranges of the domain scores are as follows: for desire 1.2 - 6.0, for arousal, lubrication, orgasm and pain 0 - 6.0 and for satisfaction 0.8 - 6.0. The higher scores of the six domains indicate better sexual functioning about that domain. The overall FSFI score is obtained by summing the six domain scores. The overall FSFI scores range from 2.0 to 36.0, with higher scores indicating better sexual functioning. | baseline, +1 month, +3 months, +6 months |
| Sexual dysfunction in men | Evaluation of sexual dysfunction will be evaluated in men using IIEF questionnaire. The IIEF is an internationally validated test. It is used to assign a score of erectile dysfunction: severe score 1 to 10; moderate score 11 to 16; low to moderate score 17 to 21; Low score 22 to 25; no erectile dysfunction score 26 to 30 | baseline, +1 month, +3 months, +6 months |
| insuline resistance | Measurement of HOMA index calculated according to the formula: fasting insulin (microU/L) x fasting glucose (nmol/L)/22.5. | baseline, +1 month, +3 months, +6 months |
| blood lipid profile | Measurement of Total Cholesterol, LDL cholesterol, HDL cholesterol, Triglyceredes | baseline, +1 month, +3 months, +6 months |
| Inflammatory cytokines levels | Evaluation of Tumor Necrosis Factor alpha (TNFα), Transforming Growth Factor beta (TGF-β), Interferon gamma (IFN-γ), Leptin, Resistin, Adiponectin, Adipsin, Monocyte Chemoattractant Protein-1 (MCP-1), Serpin, C Reactive Protein (CRP), Interleukin 6 (IL-6), Interleukin 10 (IL-10) serum concentrations 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 | baseline, +1 month, +3 months, +6 months |
| D010900 | Pituitary Diseases |
| D007027 | Hypothalamic Diseases |
| D001927 | Brain Diseases |
| D002493 | Central Nervous System Diseases |
| D009422 | Nervous System Diseases |
| D001327 | Autoimmune Diseases |
| D007154 | Immune System Diseases |