COMPLICANZE DELL'IPERCORTISOLISMO SUBCLINICO: RISCHIO DI INSORGENZA DI FRATTURE VERTEBRALI E POSSIBILE RUOLO DELL'ORMONE DELLA CRESCITA.

Title: Subclinical hypercortisolism’ s complications: vertebral fracture’s risk and possible role of GH deficiency. In patients with adrenal incidentalomas (AI), subclinical hypercortisolism (SH) has been associated with vertebral fractures and reduction of bone mass and quality. Spinal deformity index (SDI) has been proposed as a surrogate index of bone quality. The incidence of vertebral fractures in AI patients is unknown. Moreover, overt cortisol excess is known to be associated with blunted GH secretion that generally normalizes after successful surgery. Subclinical Hypercortisolism (SH), has been not associated with reduced GH secretion. Data about the GH reserve in SH patients after adrenalectomy are lacking. Aim of this prospective, multicenter study is to evaluate, in AI patients, bone mass changes and vertebral fracture’s risk, and assess GH secretory reserve in a subgroup of AI patients without and with SH and, in these latter, before and after surgery. In 104 patients (36 M, 68 F) at baseline, after 12 and 24 months pituitary-adrenal axis secretion and bone status were evaluated. We diagnosed SH in the presence of at least 2 out of urinary free cortisol (UFC) levels >70 μg/24h; serum cortisol levels after 1–mg dexamethasone (Dex) suppression test (1mg-DST) >3.0 μg/dL; ACTH levels <10 pg/mL in at least 2 out of 3 evaluations. On the basis of the presence of SH we divided patients into SH- and SH+ groups. We evaluated: bone mineral density (BMD) by Dual-energy X-ray Absorptiometry at lumbar spine and femoral neck; presence of vertebral fractures using the semi-quantitative visual assessment of spinal radiographs; SDI by summing the grade of deformity for each vertebra. In AI 23 patients we also assessed GH secretion and reserve by GH Releasing Hormone+Arginine (GHRH-ARG) test and age-adjusted IGF1 levels (IGF1-SDS). On the basis of the presence or absence of SH patients were divided in SH+ (8F; 3M; age 58±6.1 yrs) and SH- (12F; age 62±8.3 yrs) group. Six out of eight SH+ patients, who underwent surgery, were re-evaluated after withdrawal of steroid substitutive therapy. At the end of follow-up SH+ patients (27/104) showed an higher prevalence of vertebral fractures (81.5 %) as compared to baseline (48.1%; P= 0.021), and a worsening of SDI (1.39±2.83 vs 0.41±1.44; P=0.008 respectively) that was associated with the presence of SH regardless for age, gender, BMI, BMD, basal SDI and years since menopause (OR 11.92, 95%CI 4.0-35.5; P=0.001). In SH- patients the prevalence of vertebral fractures was not different between baseline (29.9%) and the end of follow-up (36.4%). The incidence of new vertebral fractures was higher in SH+ than in SH- group (48% vs 13%, P=0.001). Among the 23 patients evaluated for GH secretion, the GH peak and the GH secretory response to GHRH-ARG (expressed as the area under the curve, GH-AUC) were lower in SH+ as compared to SH- patients (22.0±19.4 vs 42.6±27.9 ng/ml, P<0.05; 1931.4±1710.8 vs 3864.2±2294.4, P=0.03 respectively) without correlations with metabolic and adrenal function parameters. After adrenalectomy, in the six SH+ patients operated on, GH-AUC values tended to increase (1645.8±1032.9 pre-surgery; 3244.8±2207.5 post-surgery; P=0.072). In conclusion, in AI patients subclinical hypercortisolism is associated with an increased risk to develop new vertebral fractures over time. The role of GH secretion, that appears to be decreased in these patients, should be evaluated in larger samples.