In recent years, the condition of subclinical hypercortisolism (SH) has become a topic of growing interest. This is due to the fact that SH prevalence is not negligible (0.8–2% in the general population) and that, although asymptomatic, this subtle cortisol excess is not harmless, being associated with an increased risk of complications, in particular of osteoporosis and fragility fractures. As specific symptoms of hypercortisolism are absent in SH, the SH diagnosis relies only on biochemical tests and it is a challenge for physicians. As a consequence, even the indications for the evaluation of bone involvement in SH patients are debatable and guidelines are not available. Finally, the relative importance of bone density, bone quality and glucocorticoid sensitivity in SH is a recent field of research. On the other hand, SH prevalence seems to be increased in osteoporotic patients, in whom a vertebral fracture may be the presenting symptom of an otherwise asymptomatic cortisol excess. Therefore, the issue of who and how to screen for SH among the osteoporotic patients is widely debated. The present review will summarize the available data regarding the bone turnover, bone mineral density, bone quality and risk of fracture in patients with endogenous SH. In addition, the role of the individual glucocorticoid sensitivity in SH-related bone damage and the problem of diagnosing and managing the bone consequences of SH will be reviewed. Finally, the issue of suspecting and screening for SH patients with apparent primary osteoporosis will be addressed.
I Chiodini, C Eller Vainicher, V Morelli, S Palmieri, E Cairoli, A S Salcuni, M Copetti and A Scillitani
V Morelli, S Palmieri, A S Salcuni, C Eller-Vainicher, E Cairoli, V Zhukouskaya, A Scillitani, P Beck-Peccoz and I Chiodini
The possible different prevalence of arterial hypertension (AH), type 2 diabetes mellitus (T2DM), dyslipidaemia (DL) and vertebral fractures (FX) between patients with bilateral and unilateral adrenal incidentalomas (BAI and UAI, respectively) with and without subclinical hypercortisolism (SH) is unknown. In this study we compared the prevalence of AH, T2DM, DL and FX in BAI and UAI patients in relation to SH.
In 175 UAI and 38 BAI patients, we evaluated BMI, spinal and femoral bone mineral density (LS and FN BMD, respectively) and the presence of AH, T2DM, DL and FX. SH was diagnosed in the presence of ≥2 of the following: urinary free cortisol levels >193 nmol/24 h, serum cortisol levels after 1 mg dexamethasone suppression test >83 nmol/l or ACTH levels <2.2 pmol/l.
Age, BMI and cortisol secretion were comparable, while FN BMD was lower in BAI than in UAI patients (−0.45±0.86 vs 0.09±1.07, P=0.004). The prevalence of SH, AH, T2DM, and DL was comparable, while the prevalence of FX was higher in BAI than in UAI (52.6 vs 28%, P=0.007). The presence of FX was associated with BAI (odds ratio (OR) 2.6, 95% confidence interval (95% CI) 1.2–5.6, P=0.016), after adjusting for SH (OR 1.77, 95% CI 0.85–3.7, P=0.12), BMI (OR 1.06, 95% CI 0.98–1.13, P=0.1), age (OR 1.07, 95% CI 1.04–1.11, P=0.0001) and LS BMD (OR 1.31, 95% CI 1.03–1.67, P=0.03).
BAI patients have an increased FX risk than UAI ones. Further studies should investigate the causes of bone involvement in BAI patients.
B Ambrosi, C Dall'Asta, S Cannavo, R Libe, T Vigo, P Epaminonda, I Chiodini, S Ferrero, F Trimarchi, M Arosio and P Beck-Peccoz
OBJECTIVE: Rosiglitazone, a thiazolidinedione compound with peroxisome proliferator-activated receptor-gamma (PPAR-gamma)-binding affinity, is able to suppress adrenocorticotropic hormone (ACTH) secretion in treated mice and in AtT20 pituitary tumor cells. These observations suggested that thiazolidinediones may be effective as therapy for Cushing's disease (CD). PATIENTS AND METHODS: Rosiglitazone (8 mg/day) was administered to 14 patients with active CD (13 women, one man, 18-68 years). Plasma ACTH, serum cortisol (F) and urinary free cortisol (UFC) levels were measured before and then monthly during rosiglitazone administration. RESULTS: In six patients a reduction of ACTH and F levels and a normalization of UFC were observed 30-60 days after the beginning of rosiglitazone administration: there was a significant difference between basal and post-treatment values for UFC (1238+/-211 vs 154+/-40 nmol/24 h, P<0.03), but not for ACTH (15.9+/-3.7 vs 7.9+/-0.9 pmol/l) and F levels (531+/-73 vs 344+/-58 nmol/l). Two of six cases, followed up for 7 months, showed a mild clinical improvement. Eight patients were nonresponders after 30-60 days of rosiglitazone treatment: their ACTH, F and UFC levels did not differ before and during drug administration. Immunohistochemical analysis of pituitary tumors removed from two responder and two nonresponder patients showed a similar intense immunoreactivity for PPAR-gamma in about 50% of cells. CONCLUSIONS: The administration of rosiglitazone seems able to normalize cortisol secretion in some patients with CD, at least for short periods. Whether the activation of PPAR-gamma by rosiglitazone might be effective as chronic pharmacologic treatment of CD needs a more extensive investigation through a randomized and controlled study.
A Toini, A Dolci, E Ferrante, E Verrua, E Malchiodi, E Sala, A G Lania, I Chiodini, P Beck-Peccoz, M Arosio, A Spada and G Mantovani
Pituitary incidentalomas (PIs) are commonly encountered in clinical practice. The management of these asymptomatic pituitary lesions is still controversial. Systematic screening for subclinical or mild ACTH-dependent hypercortisolism (AH) is not presently recommended, due to the limited data available thus far on the epidemiological and clinical relevance of this condition in patients with PIs. As subclinical hypercortisolism (SH) was considered to be associated with chronic complications of overt cortisol excess, such as hypertension, diabetes, and osteoporosis, this disorder should be diagnosed at the early stage.
The objective of this study was to evaluate the prevalence of hypercortisolism in a population of subjects with PIs.
Design, subjects, and methods
A total of 68 consecutive patients (48 females and 20 males, aged 18–82 years) without clinically overt hypercortisolism, who were referred for evaluation of PIs between January 2010 and March 2013, were prospectively investigated for AH. Pituitary hypercortisolism was diagnosed in the presence of cortisol >50 nmol/l after 1 mg dexamethasone suppression test, non-suppressed ACTH, and the additional finding of one of the following: urinary free cortisol (UFC) >193 nmol/24 h, and midnight serum and salivary cortisol levels >207 and 2.8 nmol/l respectively.
Among patients with PIs, we found a 7.3% rate of pituitary hypercortisolism diagnosed with biochemical criteria and a 4.4% rate of histologically confirmed AH.
Subclinical or mild hypercortisolism may be more common than generally perceived in patients with PIs.
S Palmieri, V Morelli, E Polledri, S Fustinoni, R Mercadante, L Olgiati, C Eller Vainicher, E Cairoli, V V Zhukouskaya, P Beck-Peccoz and I Chiodini
The use of late-night salivary cortisol (LNSalC) for diagnosing subclinical hypercortisolism (SH) is debated. No data are available regarding the role of LNSalC as measured by liquid chromatography–tandem mass spectrometry (LC–MS/MS) in SH diagnosis. The aim of this study was to evaluate the diagnostic accuracy of LNSalC measured by LC–MS/MS in SH.
Cross-sectional prospective study of outpatients.
In 70 consecutive patients with adrenal incidentalomas (AI), without signs and symptoms of hypercortisolism, we diagnosed SH in the presence of at least two of the following: cortisol after 1 mg overnight dexamethasone suppression test (1 mg DST) >83 nmol/l, 24-h urinary free cortisol (UFC) >193 nmol/24 h, and morning ACTH <2.2 pmol/l. The LNSalC levels by LC–MS/MS at 2300 h (normal values <2.8 nmol/l) and the presence of hypertension, type 2 diabetes mellitus (T2DM), and osteoporosis (OP) were assessed.
The increased LNSalC levels (>2.8 nmol/l) had an 83.3% specificity (SP) and a 31.3% sensitivity (SN) for predicting the biochemical diagnosis of SH. The increased LNSalC had an 85.2% SP and a 55.6% SN for predicting the presence of hypertension, T2DM, and OP, while the combination of LNSalC >1.4 nmol/l (cutoff with 100% SN) plus 1 mg DST >50 nmol/l had an 88.9% SN and an 85.2% SP (similar to SH criterion at enrollment).
In AI patients, LNSalC measured by LC–MS/MS appears to be useful in combination with 1 mg DST for diagnosing SH, while it is not useful as a single criterion.
M Terzolo, A Stigliano, I Chiodini, P Loli, L Furlani, G Arnaldi, G Reimondo, A Pia, V Toscano, M Zini, G Borretta, E Papini, P Garofalo, B Allolio, B Dupas, F Mantero and A Tabarin
To assess currently available evidence on adrenal incidentaloma and provide recommendations for clinical practice.
A panel of experts (appointed by the Italian Association of Clinical Endocrinologists (AME)) appraised the methodological quality of the relevant studies, summarized their results, and discussed the evidence reports to find consensus.
Unenhanced computed tomography (CT) is recommended as the initial test with the use of an attenuation value of ≤10 Hounsfield units (HU) to differentiate between adenomas and non-adenomas. For tumors with a higher baseline attenuation value, we suggest considering delayed contrast-enhanced CT studies. Positron emission tomography (PET) or PET/CT should be considered when CT is inconclusive, whereas fine needle aspiration biopsy may be used only in selected cases suspicious of metastases (after biochemical exclusion of pheochromocytoma).
Pheochromocytoma and excessive overt cortisol should be ruled out in all patients, whereas primary aldosteronism has to be considered in hypertensive and/or hypokalemic patients. The 1 mg overnight dexamethasone suppression test is the test recommended for screening of subclinical Cushing's syndrome (SCS) with a threshold at 138 nmol/l for considering this condition. A value of 50 nmol/l virtually excludes SCS with an area of uncertainty between 50 and 138 nmol/l.
Surgery is recommended for masses with suspicious radiological aspects and masses causing overt catecholamine or steroid excess. Data are insufficient to make firm recommendations for or against surgery in patients with SCS. However, adrenalectomy may be considered when an adequate medical therapy does not reach the treatment goals of associated diseases potentially linked to hypercortisolism.
F Ermetici, F Donadio, L Iorio, A E Malavazos, A Dolci, E Peverelli, A M Barbieri, L Morricone, I Chiodini, M Arosio, A Lania, P Beck-Peccoz, B Ambrosi and S Corbetta
Background and aim
Hypogonadism frequently occurs in men with type 2 diabetes mellitus (T2DM), while the role of glycemic control and visceral obesity is still unclear. This study aimed to assess the Leydig cell function, including the new sensitive marker insulin-like factor 3 (INSL3), in T2DM patients without overt hypogonadism and the influence of either glycemic control or visceral adiposity.
Subjects and methods
Thirty T2DM patients (age 57.1±6.2 years, body mass index (BMI) 28.0±4.3) without overt hypogonadism and 30 age- and BMI-matched controls were studied. Anthropometric, glycometabolic parameters and testosterone, SHBG, LH, INSL3 levels, bioavailable and free testosterone (BT and cFT) were evaluated. The human chorionic gonadotrophin (hCG) test was also performed.
Patients had lower total testosterone (452.6±130.0 vs 512.6±117.3 ng/dl, P=0.06), BT (189.7±36.4 vs 237.1±94.1 ng/dl, P=0.002), cFT (8.1±1.6 vs 10.1±4.0 ng/dl, P=0.002), and higher LH levels (3.5±1.6 vs 2.6±1.2 mU/ml, P=0.01) versus controls. Serum INSL3 concentrations were also lower in patients (1.1±0.3 vs 1.5±0.7 ng/ml, P=0.01). These hormonal parameters, including INSL3, did not differ between T2DM patients with poor or good glycemic control (HbA1c>9 or <7% respectively). In patients, waist circumferences (97.9±12.4 cm) negatively correlated with INSL3 (P=0.03) and basal, as well as hCG-stimulated testosterone levels (P=0.04 and 0.004 respectively). Basal or stimulated hormonal levels and INSL3 concentrations were not different between patients with (40%) or without erectile dysfunction.
An early impairment of the overall Leydig cell function is present in men with T2DM, mainly related to visceral adiposity rather than to glycemic control.