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Open access

Filippo Ceccato, Elisa Selmin, Giorgia Antonelli, Mattia Barbot, Andrea Daniele, Marco Boscaro, Mario Plebani, and Carla Scaroni


The low-dose short synacthen test (LDSST) is recommended for patients with suspected central adrenal insufficiency (AI) if their basal serum cortisol (F) levels are not indicative of an intact hypothalamic–pituitary–adrenal (HPA) axis.


To evaluate diagnostic threshold for salivary F before and 30 min after administering 1 μg of synacthen, performed before 09:30 h.


A cross-sectional study from 2014 to 2020.


A tertiary referral university hospital.


In this study, 174 patients with suspected AI, 37 with central AI and 137 adrenal sufficient (AS), were included.

Main outcome measure

The diagnostic accuracy (sensitivity (SE), specificity (SP)) of serum and salivary F levels measured, respectively, by chemiluminescence immunoassay and liquid chromatography-tandem mass spectrometry.


Low basal serum or salivary F levels could predict AI. For the LDSST, the best ROC-calculated threshold for serum F to differentiate AI from AS was 427 nmol/L (SE 79%, SP 89%), serum F > 500 nmol/L reached SP 100%. A salivary F peak > 12.1 nmol/L after administering synacthen reached SE 95% and SP 84% for diagnosing central AI, indicating a conclusive reduction in the likelihood of AI. This ROC-calculated threshold for salivary F was similar to the 2.5th percentile of patients with a normal HPA axis, so it was considered sufficient to exclude AI. Considering AS those patients with salivary F > 12.1 nmol/L after LDSST, we could avoid unnecessary glucocorticoid treatment: 99/150 subjects (66%) had an inadequate serum F peak after synacthen, but salivary F was >12.1 nmol/L in 79 cases, who could, therefore, be considered AS.


Salivary F levels > 12.1 nmol/L after synacthen administration can indicate an intact HPA axis in patients with an incomplete serum F response, avoiding the need to start glucocorticoid replacement treatment.

Open access

Filippo Ceccato, Elisa Selmin, Chiara Sabbadin, Miriam Dalla Costa, Giorgia Antonelli, Mario Plebani, Mattia Barbot, Corrado Betterle, Marco Boscaro, and Carla Scaroni

Introduction and Aim

The purpose of replacement therapy in adrenal insufficiency (AI) is mimicking endogenous cortisol levels as closely as possible: dual release hydrocortisone (DR-HC) has been introduced to replicate the circadian cortisol rhythm. Multiple daily saliva collections could be used to assess the cortisol rhythm during real life: our aim was to study the salivary cortisol profile in AI.

Materials and Methods

We prospectively evaluated, in an observational study, 18 adult outpatients with AI (11 primary and 7 secondary AI), switched from conventional treatment (conv-HC, 25 mg/day) to the same dose of DR-HC. We collected six samples of saliva in a day, measuring cortisol (F) and cortisone (E) with LC-MS/MS. Forty-three matched healthy subjects served as controls.


F levels were similar in the morning (and higher than controls) in patients treated with conv-HC or DR-HC; otherwise F levels and exposure were lower in the afternoon and evening in patients with DR-HC, achieving a cortisol profile closer to healthy controls. Daily cortisol exposure, measured with area under the curve, was lower with DR-HC. Morning F and E presented sensitivity and specificity >90% to diagnose AI (respectively threshold of 3 and 9.45 nmol/L). Total cholesterol and HbA1c levels reduced with DR-HC.


Salivary cortisol daily curve could be used as a new tool to assess the cortisol profiles in patients treated with conv-HC and DR-HC. A lower daily cortisol exposure was achieved with DR-HC (despite the same HC dose), especially in the afternoon-evening.

Open access

Soraya Puglisi, Paola Perotti, Mattia Barbot, Paolo Cosio, Carla Scaroni, Antonio Stigliano, Pina Lardo, Valentina Morelli, Elisa Polledri, Iacopo Chiodini, Giuseppe Reimondo, Anna Pia, and Massimo Terzolo


Metyrapone has been approved for the treatment of patients with Cushing’s syndrome (CS), but only few retrospective clinical studies are available. The aim of our study was the prospective assessment of metyrapone as pre-operative treatment.

Design and methods

Before adrenalectomy, seven patients with ACTH-independent CS due to adrenal adenoma were prospectively treated with metyrapone for 3 months in three tertiary academic centers, with endocrine work-up and clinical evaluation at screening and at predefined evaluation time points (Days 14, 31, 48, 65, 82).


In all patients, UFC levels decreased up to normal range from baseline to Day 82 (609 (188–1476) vs 69 (28–152) nmol/24 h, P < 0.02), with a reduction of serum and salivary cortisol levels, and no significant increase of plasma ACTH and serum DHEAS levels. Clinical improvement was reported on quality of life (+16.7 (+4.2; +52.00) points, P < 0.04) and pressure control (systolic pressure, −25 (−52; −10) mmHg, P < 0.01; diastolic pressure, −16 (−50; +2 mmHg), P < 0.03). No significant change in weight, electrolytes, glycemic and lipid profile was reported. Although in women a significant increase of testosterone and androstenedione was reported, no worsening of clinical hyperandrogenism was observed. All drug-related adverse events (nausea, fatigue, low grade fever, edema of lower limbs and facial rash) were grade 1 or 2 and generally transient.


This prospective pilot study demonstrated that metyrapone is effective in normalizing biochemical and clinical parameters in patients with CS due to adrenal adenoma before surgical intervention, with minimal side effects.

Open access

Filippo Ceccato, Diego Cecchin, Michele Gregianin, Giacomo Ricci, Cristina Campi, Filippo Crimì, Marta Bergamo, Annibale Versari, Carmelo Lacognata, Federico Rea, Mattia Barbot, and Carla Scaroni

Introduction and aim

Ectopic ACTH secretion (EAS) is mostly secondary to thoracic/abdominal neuroendocrine tumours (NETs) or small cell-lung carcinoma (SCLC). We studied the diagnostic accuracy of CT with 68Ga-Dota derivatives (68Ga-SSTR) PET in localizing ACTH-secreting tumor in patients with EAS.

Materials and methods

68Ga-SSTR-PET/CT was performed and compared with the nearest enhanced CT in 18 cases (16 primary and 2 recurrent neoplasms). Unspecific, indeterminate and false-positive uptakes were assessed using conventional imaging, follow-up or histology.


We diagnosed 13 thoracic (9 primary and 2 recurrent bronchial carcinoids, 2 SCLCs) and 1 abdominal (pancreatic NET) tumors. Eight ACTH-secreting tumors were promptly identified at EAS diagnosis (’overt’, four pulmonary carcinoids with two recurrences and two SCLC); six EAS have been discovered during the subsequent follow-up (’covert’, five bronchial carcinoids and one pancreatic NET). At the time of EAS diagnosis, imaging was able to correctly detect the ACTH-secreting tumour in 8/18 cases (6 new diagnosis and 2 recurrences). During the follow-up, six out of initially ten ‘occult’ cases became ‘covert’. At last available follow-up, CT and 68Ga-SSTR-PET/CT were able to diagnose 11/18 and 12/18 ACTH-secreting tumours, respectively (11/14 and 12/14 considering only overt and covert cases, respectively). Four cases have never been localized by conventional or nuclear imaging (’occult EAS’), despite an average follow-up of 5 years.


The 68Ga-SSTR-PET/CT is useful in localizing EAS, especially to enhance positive prediction of the suggestive CT lesions and to detect occult neoplasms.

Open access

Carla Scaroni, Nora M Albiger, Serena Palmieri, Davide Iacuaniello, Chiara Graziadio, Luca Damiani, Marialuisa Zilio, Antonio Stigliano, Annamaria Colao, Rosario Pivonello, and the Altogether to Beat Cushing’s Syndrome (ABC) study group

The distinction between pseudo-Cushing’s states (PCS) and Cushing’s syndrome (CS) poses a significant clinical challenge even for expert endocrinologists. A patient’s clinical history can sometimes help to distinguish between them (as in the case of alcoholic individuals), but the overlap in clinical and laboratory findings makes it difficult to arrive at a definitive diagnosis. We aim to describe the most common situations that can give rise to a condition resembling overt endogenous hypercortisolism and try to answer questions that physicians often face in clinical practice. It is important to know the relative prevalence of these different situations, bearing in mind that most of the conditions generating PCS are relatively common (such as metabolic syndrome and polycystic ovary syndrome), while CS is rare in the general population. Physicians should consider CS in the presence of additional features. Appropriate treatment of underlying conditions is essential as it can reverse the hormonal abnormalities associated with PCS. Close surveillance and a thorough assessment of a patient’s hormone status will ultimately orient the diagnosis and treatment options over time.