Prevalence of less severe hypercortisolism in fractured patients admitted in an outpatient clinic for metabolic bone diseases.

PURPOSE: To evaluate the prevalence of less severe hypercortisolism (LSH) in fractured patients, and its association with hypertension, hyperglicemia, dyslipidemia, and obesity. METHOD: From July 2015 to October 2018 we enrolled all fractured patients admitted in our outpatient center for metabolic bone diseases, after exclusion of patients with secondary osteoporosis apart from diabetes and taking drugs known to affect bone metabolism. In all enrolled patients we collected data regarding gonadal status, history of diabetes, high blood pressure, dyslipidemia, and measured blood pressure, lipid profile, fasting glycaemia. Bone mass was measured with DXA at lumbar spine and femoral neck and the presence of fractures was evaluated with X-ray of thoracic and lumbar spine. All patients performed twice, 1 mg overnight dexametasone suppression test (DST) and, as confirmatory, 2day low-dose DST for diagnosing hypercortisolism. RESULTS: We enrolled 101 fractured patients (75 females, 26 males), aged 65 ± 10.3 years. Five out of 101 (5.0%) patients were diagnosed as LSH. Fifty-five (54.5%) out of 101 were hypertensive, 57 (56.4%) dyslipidemic, 17 (16.8%) hyperglicaemic, 28(27.7%) obese patients. LSH tended to be associated to blood hypertension [5/5 vs 50/96 (Fisher exact test, p = 0.06) hypertensive patients]. Four out five LSH patients were hypogonadic. CONCLUSIONS: Our study confirms that a nonnegligible percentage of fractured subjects actually presents an unrecognized hypercortisolism. Accordingly, regardless of age, we suggest to screen for hypercortisolism all patients with established osteoporosis and in particular hypertensive subjects.

MECHANISMS IN ENDOCRINOLOGY: Endogenous subclinical hypercortisolism and bone: a clinical review.

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.

Bilateral and unilateral adrenal incidentalomas: biochemical and clinical characteristics.

OBJECTIVE: 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. DESIGN: Prospective study. METHODS: 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. RESULTS: 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). CONCLUSION: BAI patients have an increased FX risk than UAI ones. Further studies should investigate the causes of bone involvement in BAI patients.

Carboxyl-terminal parathyroid hormone fragments: biologic effects.

Carboxyl-terminal PTH fragments (C-PTH), are generated by both direct secretion from parathyroids in relation to serum calcium levels and catabolism of PTH operated by the Kupffer cells in the liver. These molecular fragments have been till recently regarded as inert byproducts of PTH metabolism, since they do not interact with the PTH/PTH-related peptide (rP) receptor, which mediates the classical hormone actions. Current findings instead indicate that C-PTH would interact with a putative C-PTH receptor. This way, C-PTH seem to exert specific effects on calcium homeostasis and bone metabolism, opposite to those of the synthetic agonist of PTH/PTHrP receptor (i.e. PTH 1-34). In vitro and in vivo data actually indicate that C-PTH, by interacting with specific receptors, could have an anti-calcemic action, as well as a pro-apoptotic effect on both osteocytes and osteoclasts. This in turn could result in a reduced activity of the latter cells, with a consequent inhibition of bone resorption.

Subclinical hypercortisolism: correlation between biochemical diagnostic criteria and clinical aspects.

OBJECTIVE: Subclinical hypercortisolism (SH) has been associated with increased prevalence of hypertension, type 2 diabetes mellitus, dyslipidaemia, central obesity, osteoporosis and vertebral fractures. We aimed to investigate the accuracy of different SH diagnostic criteria in predicting the presence of complications. DESIGN: This was a retrospective study. PATIENTS: We evaluated data from 231 patients (120 women and 111 men) affected with adrenal incidentalomas (AI). MEASUREMENTS: We studied the accuracy of different SH diagnostic criteria (cortisol after 1 mg overnight dexamethasone suppression test - 1mg-DST - at different cut-off such as 49.7, 82.8, 137.9 nmol/l, elevated urinary free cortisol, reduced adrenal corticotroph hormone (ACTH) levels alone or various combination of these parameters) in predicting the concomitant presence of the following three complications: hypertension, type 2 diabetes and vertebral fractures. RESULTS: The criterion characterized by the presence of two of 1mg-DST >82.8 nmol/l, elevated UFC and reduced ACTH struck the best balance between sensitivity and specificity, reaching a good accuracy in predicting the cluster of complications (61.9%; 77.1% and 75.8%, respectively). The presence of this cluster was associated with this criterion (OR 4.75, 95%CI 1.8-12.7, P = 0.002) regardless of gonadal status, body mass index (BMI) and age. CONCLUSIONS: The SH criterion characterized by the presence of two of 1mg-DST >82.8 nmol/l, elevated UFC and reduced ACTH seems the best in predicting the presence of chronic manifestations of subtle cortisol excess.

Role of adrenal gland scintigraphy in patients with subclinical hypercortisolism and incidentally discovered adrenal mass.

BACKGROUND: The role of adrenal scintigraphy (AS) in the diagnosis of subclinical hypercortisolism (SH) in adrenal incidentaloma (AI) is debated. AIM: To evaluate the possible role of AS in identifying SH in AI patients. SUBJECTS AND METHODS: In the retrospective phase (2000-2004), 102 AI patients [71 females (F)/31 males (M)] referred to our center were reevaluated for SH. In the prospective phase (2005-2006), 42 patients (32F/10M) with suspected SH were evaluated performing AS and biochemical assessment of cortisol secretion. We report data of the prospective phase of the study. In these patients AS was performed at baseline; the difference between the uptake of the affected and the controlateral gland [mean Delta uptake (MDeltau)] was calculated. Cortisol secretion was evaluated in 3 different occasions. Patients were considered affected with SH if they presented at least twice 2 of the following criteria: urinary free cortisol >193 nmol/l, cortisol after 1 mg dexamethasone suppression test >83 nmol/l, ACTH levels <2.2 pmol/l. RESULTS: MDeltau was higher in patients with SH (no.=27, 5/22 M/F) than in patients without SH (83.7+/-12.5 vs 54.7+/-24.1%, p<0.001), and directly correlated with UFC (beta=0.387, p=0.015) and was predictive of SH (odds ratio 1.12, 95% confidence interval 1.03-1.22, p=0.009) regardless of age, body mass index, and diameter of the mass. A 75% MDeltau cut-off has 86.7% specificity and 81.5% sensitivity in diagnosing SH. CONCLUSIONS: AS is not recommended as screening test in AI patients, but it can be useful to exclude the presence of a subtle cortisol excess in patients with unclear biochemical diagnosis of SH.