Risk of new vertebral fractures in patients with adrenal incidentaloma with and without subclinical hypercortisolism: a multicenter longitudinal study.

In patients with adrenal incidentalomas (AIs), cross-sectional studies suggested the presence of an association between subclinical hypercortisolism (SH) and an increased prevalence of vertebral fractures (VFx) and spinal deformity index (SDI), which is a clinical index of bone quality. No longitudinal studies investigated the incidence of VFx and SDI changes over time in SH. The aim of this study was to evaluate VFx risk and SDI changes in SH over time. One-hundred-three consecutive AI patients were studied at baseline and after 12 and 24 months. Patients were divided into SH(+) (n = 27) and SH(-) (n = 76) groups on the basis of the presence of two or more among urinary free cortisol greater than 70 µg/24 hours, serum cortisol after 1-mg dexamethasone suppression test greater than 3.0 µg/dL, and adrenocorticotropic hormone (ACTH) less than 10 pg/mL in 2 or more of the 3 evaluations. At baseline and after 24 months, bone mineral density (BMD) by dual-energy X-ray absorptiometry and the presence of VFx and SDI by summing the grade of deformity for each vertebra were evaluated. At the end of follow-up, the SH(+) group showed a higher prevalence of VFx (81.5%) as compared with baseline (55.6%, p = .04) and a worsening of SDI (2.11 ± 1.85 versus 1.11 ± 1.47, p = .032) associated with SH regardless of age, gender, body mass index , BMD, baseline SDI, menopause duration [odds ratio (OR) = 12.3, 95% confidence interval (CI) 4.1-36.5, p = .001]. The incidence of new vertebral fractures was higher in the SH(+) group (48%) than in the SH(-) group (13%; p = .001). It is concluded that subclinical hypercortisolism is associated with an increased risk of VFx and a possible deterioration of bone quality.

Accuracy of several parameters of hypothalamic-pituitary-adrenal axis activity in predicting before surgery the metabolic effects of the removal of an adrenal incidentaloma.

CONTEXT: It is unknown whether the metabolic effects of the removal of an adrenal incidentaloma (AI) can be predicted by the assessment of cortisol hypersecretion before surgery. OBJECTIVE: To evaluate the accuracy of several criteria of hypothalamic-pituitary-adrenal axis activity in predicting the metabolic outcome after adrenalectomy. DESIGN: Retrospective longitudinal study. PATIENTS: In 55 surgically treated AI patients (Group 1) before surgery and in 53 nontreated AI patients (Group 2) at the baseline, urinary free cortisol (UFC), cortisol after 1 mg overnight dexamethasone-suppression test (1 mg-DST), ACTH, and midnight serum cortisol (MSC) were measured. In Groups 1 and 2, metabolic parameters were evaluated before and 29.6 ± 13.8 months after surgery and at the baseline and after 35.2 ± 10.9 months respectively. MAIN OUTCOME MEASURES: The improvement/worsening of weight, blood pressure, glucose, and cholesterol levels (endpoints) was defined by the presence of a >5% weight decrease/increase and following the European Society of Cardiology or the ATP III criteria respectively. The accuracy of UFC, 1 mg-DST, ACTH, and MSC, singularly taken or in combination, in predicting the improvement/worsening of ≥ 2 endpoints was calculated. RESULTS: The presence of ≥ 2 among UFC>70 µg/24 h (193 nmol/l), ACTH<10 pg/ml (2.2 pmol/l), 1 mg-DST>3.0 µg/dl (83 nmol/l) (UFC-ACTH-DST criterion) had the best accuracy in predicting the endpoints' improvement (sensitivity (SN) 65.2%, specificity (SP) 68.8%) after surgery. In the nontreated AI patients, this criterion predicted the worsening of ≥ 2 endpoints (SN 55.6%, SP 82.9%). CONCLUSIONS: The UFC-ACTH-DST criterion seems to be the best for predicting the metabolic outcome in surgically treated AI patients.

d3-Growth hormone receptor polymorphism in acromegaly: effects on metabolic phenotype.

OBJECTIVE: A common polymorphic variant of the growth hormone receptor (GHR) is because of genomic deletion of exon 3 and has been linked with increased responsiveness to exogenous GH. The impact of this polymorphism in acromegaly, a disease characterized by endogenous excess of GH and partial loss of IGF-I feedback on tumoural GH secretion, is not clear. The aim of this study was to investigate possible influences of d3GHR on the GH/IGF-I relationship and metabolic parameters in acromegaly. DESIGN AND METHODS: Retrospective study on 76 acromegalic patients. Genotype analysis was carried out on leucocyte DNA by multiplex PCR assay. Clinical, hormonal and biochemical parameters at diagnosis were collected from patients' medical records. RESULTS: Forty-two patients (55.3%) were homozygotes for the allele encoding the full-length GHR (fl/flGHR), 27 patients were heterozygotes (fl/d3) and seven homozygotes (d3/d3) for the genomic deletion of exon 3. Heterozygotes and homozygotes for the d3 allele were considered together (d3GHR) and compared with fl/flGHR patients. d3GHR and fl/flGHR patients showed no difference in GH and IGF-I levels or in the relationship between these two parameters. Patients bearing d3GHR had a lower body mass index (BMI) than patients bearing fl/flGHR (25.8 +/- 2.1 vs. 28.1 +/- 4.8 kg/m(2), P < 0.05). Diabetes mellitus and hypertension were equally distributed, but more d3GHR patients had a normal glucose tolerance (66.7%vs. 56.3%, P < 0.05). The presence of d3GHR allele, and not BMI or age, was a significant negative predictor of insulin levels 120 min after oral glucose load (beta = -80.8, P < 0.05). CONCLUSIONS: This study supports the hypothesis that the d3GHR is functionally different from the fl/fl variant mostly for the effects on body weight regulation and on glucose metabolism.

Beneficial metabolic effects of prompt surgical treatment in patients with an adrenal incidentaloma causing biochemical hypercortisolism.

CONTEXT: In patients with adrenal incidentalomas, subclinical hypercortisolism (SH) is associated with an increased prevalence of the metabolic syndrome. The effect of surgical/conservative approach is debated. OBJECTIVE: The objective of the study was to determine the effect of the surgical and conservative approaches on the metabolic syndrome in patients with adrenal incidentalomas. DESIGN: This was a retrospective longitudinal study (18-48 months follow-up). SETTING: The study was conducted on an in- and outpatient basis. PATIENTS: One hundred eight patients with adrenal incidentalomas were studied for the presence of SH, which was diagnosed in the presence of more than two of the following: urinary free cortisol greater than 70 microg per 24 h (193 nmol per 24 h), cortisol after 1 mg dexamethasone suppression test greater than 3.0 microg/dl (83 nmol/liter), ACTH less than 10 pg/ml (2.2 pmol/liter). INTERVENTIONS: Surgery was performed in 25 patients with SH (group TrSH+) and 30 without SH (group TrSH-), whereas the conservative approach was chosen by 16 patients with SH (group UntrSH+) and 37 without SH (group UntrSH-). MAIN OUTCOME MEASURES: During the follow-up, the improvement/worsening of body weight, blood pressure, or glucose and cholesterol levels was defined in the presence of a greater than 5% weight decrease/increase and following the European Society of Cardiology or the Adult Treatment Panel III criteria, respectively. RESULTS: In group TrSH+, weight, blood pressure, and glucose levels improved (32, 56, and 48%, respectively) more frequently than in group UntrSH+ (12.5%, P = 0.05; 0.0%, P < 0.0001; 0.0%, P = 0.001; and 0.0%, P = 0.0014, respectively). In group UntrSH+, blood pressure, glucose, and low-density lipoprotein levels worsened more frequently (50.0, 37.5, and 50.0%, respectively) than in group TrSH+ (0.0%, P < 0.0001; 0.0%, P = 0.001; and 20.0%, P = 0.05, respectively). CONCLUSIONS: Regarding the various components of the metabolic syndrome, in patients with adrenal incidentalomas and SH, surgery is beneficial.

Post-surgical hypocortisolism after removal of an adrenal incidentaloma: is it predictable by an accurate endocrinological work-up before surgery?

OBJECTIVE: Few data are available regarding the need of steroid substitutive therapy after unilateral adrenalectomy for adrenal incidentaloma (AI). It is unknown whether, before surgery, the hypothalamic-pituitary-adrenal (HPA) axis secretion parameters can predict post-surgical hypocortisolism. AIM: This study aimed to evaluate whether, in AI patients undergoing unilateral adrenalectomy, post-surgical hypocortisolism could be predicted by the parameters of HPA axis function. DESIGN: Prospective, multicenter. METHODS: A total of 60 patients underwent surgical removal of AI (surgical indication: 29 subclinical hypercortisolism (SH); 31 AI dimension). Before surgery, SH was diagnosed in patients presenting at least three criteria out of urinary free cortisol (UFC) levels>60 microg/24 h, cortisol after 1-mg dexamethasone suppression test (1 mg-DST)>3.0 microg/dl, ACTH levels<10 pg/ml, midnight serum cortisol (MSC)>5.4 microg/dl. Two months after surgery, HPA axis function was assessed by low dose ACTH stimulation test or insulin tolerance test when needed: 39 patients were affected (Group B) and 21 were not affected (Group A) with hypocortisolism. The accuracy in predicting hypocortisolism of pre-surgical HPA axis parameters or their combinations was evaluated. RESULTS: The presence of >2 alterations among 1 mg-DST>5.0 microg/dl, ACTH<10 pg/ml, elevated UFC and MSC has the highest odds ratio (OR) for predicting post-surgical hypocortisolism (OR 10.45, 95% confidence interval, CI 2.54-42.95, P=0.001). Post-surgical hypocortisolism was predicted with 100% probability by elevated UFC plus MSC levels, but not ruled out even in the presence of the normality of all HPA axis parameters. CONCLUSION: Post-surgical hypocortisolism cannot be pre-surgically ruled out. A steroid substitutive therapy is indicated after unilateral adrenalectomy for SH or size of the adenoma.

Bone mineral density, prevalence of vertebral fractures, and bone quality in patients with adrenal incidentalomas with and without subclinical hypercortisolism: an Italian multicenter study.

CONTEXT: In patients with adrenal incidentalomas and subclinical hypercortisolism (SH), the factors influencing bone and the prevalence of vertebral fractures are debated. Spinal deformity index (SDI), which reflects bone quality, has never been evaluated. OBJECTIVE: The objective of the study was to investigate in these patients SDI and factors influencing the prevalence of fractures. DESIGN: This was a retrospective, multicenter study. SETTING: The study was conducted on an in- and outpatient basis. PATIENTS: Patients included 287 adrenal incidentaloma patients (111 eugonadal males, 31 premenopausal, 145 postmenopausal females) and 194 controls (90 eugonadal males, 29 premenopausal, 75 postmenopausal females). MAIN OUTCOME MEASURE: Bone mineral density (BMD) was measured by dual X-ray absorptiometry at lumbar spine and femoral neck. By radiograph each vertebra was assessed as intact (grade 0) or grade 1 (20-25%), 2 (25-40%), or 3 (>40%) deformity; SDI was calculated by summing the grade of deformity for each vertebra. SH was diagnosed in the presence of at least two of the following: urinary free cortisol greater than 70 microg per 24 h (193.1 nmol/liter), cortisol after 1-mg dexamethasone test greater than 3.0 microg/dl (>82.8 nmol/liter), ACTH less than 10 pg/ml (<2.2 pmol/liter). RESULTS: BMD was significantly lower in SH+ than SH- patients and controls (lumbar spine -0.73 +/- 1.43, 0.17 +/- 1.33, 0.12 +/- 1.21, respectively; femoral neck -0.37 +/- 1.06, 0.07 +/- 1.09, 0.17 +/- 1.02). Patients with SH had higher fracture prevalence and SDI than those without SH and controls (70.6, 22.2, 21.8%, respectively, P < 0.0001; 0.31 +/- 0.68, 0.39 +/- 0.93, 1.35 +/- 1.27, respectively, P < 0.0001). Fractures and SDI were associated with SH (odds ratio 7.27, 95% confidence interval 3.94-13.41, P = 0.0001; beta = 0.352, t = 6.241, P = 0.0001, respectively) regardless of age, BMD, menopause, and gender. CONCLUSION: SH is associated with low BMD, high fracture prevalence, and reduced bone quality as measured by SDI.

Eugonadal male patients with adrenal incidentalomas and subclinical hypercortisolism have increased rate of vertebral fractures.

OBJECTIVE: Subclinical hypercortisolism (SH) is suggested to exert a deleterious effect on bone. This effect and the role of gonadal status in male subjects are not fully elucidated. We evaluated bone mineral density (BMD) and prevalence of vertebral fractures in eugonadal male subjects with adrenal incidentalomas (AI) and without SH. DESIGN: This 12-month observational multicentre study was performed between January and December 2006 on inpatient basis in three referral Italian centres. PATIENTS: Eighty-eight consecutive eugonadal male patients with AI and 90 matched control subjects were studied. MEASUREMENTS: All subjects underwent the determination of BMD by dual-energy X-ray absorptiometry at lumbar spine (LS) and femoral neck (FN), and spinal radiograph. In AI patients SH was diagnosed in the presence of two of the following: urinary free cortisol > 193.1 nmol/l, cortisol after 1 mg dexamethasone suppression test > 82.8 nmol/l, ACTH levels < 2.2 pmol/l. RESULTS: As compared to patients without SH (SH-, n = 66) and controls, patients with SH (SH+, n = 22) had lower BMD at LS (Z-score: SH+, -1.04 +/- 1.84; SH-, 0.19 +/- 1.34, Controls 0.20 +/- 1.28, P = 0.001 and FN (Z-score: SH+, -0.63 +/- 1.01; SH-, 0.01 +/- 1.01, Controls 0.26 +/- 1.06, P = 0.002) and higher prevalence of fractures (SH+, 72.7%; SH-, 21.2%, Controls 20.0%, P = 0.0001). Multivariable analyses showed that SH was associated to BMD at LS (beta = -0.378, P = 0.0001) and vertebral fractures (OR = 7.81, 95% CI 1.96-31.17, P = 0.004). CONCLUSION: In eugonadal male patients with AI, SH is associated with low BMD and high prevalence of vertebral fractures.