Description

BACKGROUND AND RATIONALE Adrenal disease encompasses a wide spectrum of clinical and pathological conditions characterized by morphological and/or functional alterations of the adrenal glands, frequently associated with hormone hyposecretion or hypersecretion. The increasing use and technical improvement of abdominal imaging over recent years have led to a rise in the incidence and prevalence of adrenal disorders, mainly driven by the detection of adrenal incidentalomas \[1-3\]; autopsy and radiological series report a prevalence of adrenal tumors of up to 8.7% \[4\]. In addition, the growing use of immune checkpoint inhibitors in oncology has increased the incidence of drug-induced adrenal insufficiency \[5\].

To date, no large-scale data on the actual burden of adrenal disease in the Modena area are available outside of specific research protocols. Accurate estimation and detailed characterization of affected subjects would allow assessment of the epidemiological impact of these conditions in the local population and identification of potential risk or predisposing factors, supporting early and targeted diagnostic pathways in at-risk populations. Moreover, a detailed characterization of signs and symptoms, hormonal work-up, imaging and medical or surgical treatments in a large case series may improve the diagnostic and therapeutic management of these patients, reducing complications and healthcare and social costs.

STUDY AIMS

The project aims to build a dedicated, structured and continuously updated database of patients with adrenal disease, in order to:

• investigate still poorly understood aspects of the pathophysiology, phenotypic variability and natural history of adrenal disorders;
• evaluate, in a real-life setting, the effectiveness, tolerability and long-term impact of recently introduced treatments;
• identify potential predictors of treatment response or adverse events;
• analyze the role of diagnostic imaging in the classification and risk stratification of adrenal disease;
• support the development of shared, evidence-based diagnostic and therapeutic pathways and facilitate future multicenter studies.

STUDY DESIGN Observational, single-center study with a retrospective and a prospective component, conducted at the Adrenal Diseases Outpatient Clinic of the Endocrinology Unit, Azienda Ospedaliero-Universitaria (AOU) di Modena. The sponsor is the Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia. No intervention is administered and routine clinical practice is not modified: data are recorded only when available and when required by standard clinical care. Internal comparisons are performed within the enrolled population.

• Retrospective phase: review of the electronic medical records stored in the hospital information system for all patients with adrenal disease seen at the outpatient clinics of the Endocrinology Unit from January 1, 2010 to June 30, 2025.
• Prospective phase: consecutive enrollment of patients with adrenal disease attending the Adrenal Diseases Outpatient Clinic for 5 years from Ethics Committee approval (approximately October 1, 2025 to September 30, 2030). Patients already included in the retrospective phase who return for follow-up visits are asked to provide consent to participate.

Prospectively enrolled patients will be compared with the retrospective cohort in terms of treatment response, disease recurrence and mortality.

DATA COLLECTED

For each patient, the following data are recorded in a pseudonymized database:

• Demographics: sex and age only, linked to a unique identification code.
• Adrenal disease: type of disease, age at diagnosis, disease duration, symptoms at onset, presence of adrenal hormone deficiency or hypersecretion.
• Symptoms at diagnosis: asthenia, depression or psychosis, hyperhidrosis, headache, polyuria/polydipsia/nocturia, obstructive sleep apnea, muscle cramps, nausea/vomiting, visual field defects, history of opportunistic infections or sepsis; menstrual disorders and number of pregnancies (women); reduced libido and erectile dysfunction (men).
• Physical examination: weight, height, waist and hip circumference, blood pressure, heart rate, facies, plethora, dorsocervical fat pad, proximal myopathy, purple striae, acanthosis, ecchymoses, hirsutism and acne.
• Radiological imaging: type of examination and findings (e.g., contrast-enhanced and unenhanced abdominal CT and MRI, total-body CT).
• Nuclear medicine imaging: type of examination and findings (e.g., 18F-FDG PET/CT, 18F-DOPA PET/CT, 68Ga-DOTATOC PET/CT, MIBG scintigraphy, 131I-cholesterol scintigraphy).
• Surgery: date and site, surgical approach, re-interventions.
• Histopathology: size, macroscopic examination, histology, immunohistochemistry, MIB-1 (Ki-67), p53, mitotic count, PASS score, GAPP score, Weiss score.
• Routine laboratory tests: complete blood count, glucose, HbA1c, creatinine, urea, lipid profile, electrolytes (sodium, potassium, calcium, phosphate, ionized calcium), 24-hour urinary calcium and phosphate, albumin, liver enzymes, alkaline phosphatase, INR, homocysteine, fibrinogen, CRP, procalcitonin.
• Hormonal tests: ACTH, serum, salivary and 24-hour urinary free cortisol, aldosterone, renin, DHEA-S, DHEA, 17-OH-progesterone, androstenedione, 24-hour urinary metanephrines, thyroid function, gonadotropins and sex steroids, SHBG, prolactin, GH, IGF-1, IGFBP-3, PTH, vitamin D, FGF-23, bone turnover markers, C-peptide and insulin. Adrenal and gonadal steroid profiles measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS) in serum, saliva and urine are also collected, as well as results of dynamic stimulation/suppression tests (e.g., ACTH stimulation test, 1 mg overnight dexamethasone suppression test, low- and high-dose dexamethasone suppression tests, CRH test, CRH/dexamethasone test, mixed-meal test, saline infusion test, captopril challenge test).
• Interventional diagnostic procedures: hormone measurements and complications of adrenal venous sampling and inferior petrosal sinus sampling.
• Body composition and bone: DXA (bone mineral density and body composition) and bioelectrical impedance analysis.
• Treatments: hormone replacement therapies and anti-secretory medical therapies (drug, dose, start and discontinuation dates), other concomitant medications.
• Comorbidities: hypertension, major cardiovascular events, dyslipidemia, diabetes mellitus, obesity, metabolic syndrome, vitamin D deficiency, osteoporosis, fractures, chronic kidney disease, malignancies, major psychiatric disorders, associated genetic syndromes.

SAMPLE SIZE AND STATISTICAL ANALYSIS Given its observational nature, the study enrolls all eligible patients and no formal sample size calculation is required. The retrospective phase includes data from approximately 6,000 outpatient visits performed between 2010 and 2025; since patients are usually seen about once a year, the number of subjects will be lower than the number of visits. For the prospective phase, approximately 1,100 visits per year (about 5,500 over 5 years) are expected, corresponding to an estimated enrollment of about 2,500 patients. Statistical analyses will include descriptive, univariate and multivariate analyses.

DATA MANAGEMENT AND ETHICAL ASPECTS Data are pseudonymized: each patient is identified by a code, and the information needed for re-identification is stored separately under technical and organizational safeguards. The database is kept on a password-protected computer accessible only to the study physicians. Results will be disseminated only in anonymous, aggregate form. Data processing complies with Regulation (EU) 2016/679 (GDPR), Italian Legislative Decree 196/2003 as amended, and the Italian Data Protection Authority provision of May 9, 2024 on health-related scientific research. Written informed consent is obtained from participants; for retrospective subjects who are deceased or cannot be contacted, data may be processed under the conditions set by the above provision, and consent will be sought if contact is re-established. The study involves no additional procedures or costs for patients or the hospital.

BIBLIOGRAPHY

1. Fassnacht M, Tsagarakis S, Terzolo M, et al. European Society of Endocrinology clinical practice guidelines on the management of adrenal incidentalomas, in collaboration with the European Network for the Study of Adrenal Tumors. Eur J Endocrinol. 2023;189(1):G1-G42. doi:10.1093/ejendo/lvad066
2. Lopez D, Luque-Fernandez MA, Steele A, Adler GK, Turchin A, Vaidya A. "Nonfunctional" adrenal tumors and the risk for incident diabetes and cardiovascular outcomes: a cohort study. Ann Intern Med. 2016;165(8):533-542. doi:10.7326/M16-0547
3. Patrova J, Jarocka I, Wahrenberg H, Falhammar H. Clinical outcomes in adrenal incidentaloma: experience from one center. Endocr Pract. 2015;21(8):870-877. doi:10.4158/EP15618.OR
4. Sherlock M, Scarsbrook A, Abbas A, et al. Adrenal incidentaloma. Endocr Rev. 2020;41(6):775-820. doi:10.1210/endrev/bnaa008
5. Martella S, Lucas M, Porcu M, et al. Primary adrenal insufficiency induced by immune checkpoint inhibitors: biological, clinical, and radiological aspects. Semin Oncol. 2023;50(6):144-148. doi:10.1053/j.seminoncol.2023.11.00