Calcium/phosphate ratio: an additional tool for the clinical management of asymptomatic primary hyperparathyroidism?

PURPOSE: Serum calcium/phosphate ratio (Ca/P) has been recently proposed as an additional tool to identify primary hyperparathyroidism (PHPT), especially in patients with subclinical presentation, with a proposed cut-off of 3.3 when both values are expressed in mg/dL. No data are available on the relationship between Ca/P and the clinical presentation of PHPT. We thus evaluated this relationship in a large, single-center, unselected series. METHODS: 515 consecutive PHPT patients (mean age 65 ± 13.15 years, 77.1% females) were retrospectively evaluated at diagnosis. RESULTS: Mean Ca/P was 4.54 ± 1.5 (range 2.36-13.9), being higher than 3.3 in 88.5% of patients. Ca/P was significantly higher in (1) males, (2) symptomatic PHPT, (3) patients with 25-hydroxy vitamin D levels lower than 20 µg/L, (4) patients with osteitis fibrosa cystica, (5) patients with T score < - 2.5 at the radial site. In a multivariate regression analysis, Ca/P resulted significantly associated with PTH levels. After the exclusion of 57 patients with asymptomatic PHPT (aPHPT) patients and serum Ca higher than 1 mg/dL above the upper limit of normal range, no differences were found in Ca/P between aPHPT meeting or not surgical criteria. CONCLUSIONS: In PHPT Ca/P ratio is associated with increased biochemical and clinical severity of disease and represents a direct indicator of clinical bone damage. However, it does not seem an additional tool to identify aPHPT patients reaching surgical indication.

Disease control of acromegaly does not prevent excess mortality in the long term: results of a nationwide survey in Italy.

OBJECTIVE: This study aimed to assess the long-term outcome of patients with acromegaly. DESIGN: This is a multicenter, retrospective, observational study which extends the mean observation period of a previously reported cohort of Italian patients with acromegaly to 15 years of follow-up. METHODS: Only patients from the centers that provided information on the life status of at least 95% of their original cohorts were included. Life status information was collected either from clinical records or from the municipal registry offices. Standardized mortality ratios (SMRs) were computed comparing data with those of the general Italian population. RESULTS: A total of 811 patients were included. There were 153 deaths, with 90 expected and an SMR of 1.7 (95% CI 1.4-2.0, p < 0.001). Death occurred after a median of 15 (women) or 16 (men) years from the diagnosis, without gender differences. Mortality remained elevated in the patients with control of disease (SMR 1.3, 95% CI 1.1-1.6). In the multivariable analysis, only older age and high IGF1 concentrations at last available follow-up visit were predictors of mortality. The oncological causes of death outweighed the cardiovascular ones, bordering on statistical significance with respect to the general population. CONCLUSIONS: Mortality remains significantly high in patients with acromegaly, irrespectively of disease status, as long as the follow-up is sufficiently long with a low rate of patients lost to follow-up. Therapy strategy including radiotherapy does not have an impact on mortality. Oncological causes of death currently outweigh the cardiovascular causes.

Italian guidelines for the management of adult individuals with overweight and obesity and metabolic comorbidities that are resistant to behavioral treatment.

AIM: This guideline (GL) is aimed at providing a clinical practice reference for the management of adult patients with overweight or obesity associated with metabolic complications who are resistant to lifestyle modification. METHODS: Surgeons, endocrinologists, gastroenterologists, psychologists, pharmacologists, a general practitioner, a nutritionist, a nurse and a patients' representative acted as multi-disciplinary panel. This GL has been developed following the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. A systematic review and network meta-analysis was performed by a methodologic group. For each question, the panel identified potentially relevant outcomes, which were then rated for their impact on therapeutic choices. Only outcomes classified as "critical" and "important" were considered in the systematic review of evidence. Those classified as "critical" were considered for clinical practice recommendations. Consensus on the direction (for or against) and strength (strong or conditional) of recommendations was reached through a majority vote. RESULTS: The present GL provides recommendations about the role of both pharmacological and surgical treatment for the clinical management of the adult patient population with BMI > 27 kg/m2 and < 40 kg/m2 associated with weight-related metabolic comorbidities, resistant to lifestyle changes. The panel: suggests the timely implementation of therapeutic interventions in addition to diet and physical activity; recommends the use of semaglutide 2.4 mg/week and suggests liraglutide 3 mg/day in patients with obesity or overweight also affected by diabetes or pre-diabetes; recommends semaglutide 2.4 mg/week in patients with obesity or overweight also affected by non-alcoholic fatty liver disease; recommends semaglutide 2.4 mg/week as first-line drug in patients with obesity or overweight that require a larger weight loss to reduce comorbidities; suggests the use of orlistat in patients with obesity or overweight also affected by hypertriglyceridemia that assume high-calorie and high-fat diet; suggests the use of naltrexone/bupropion combination in patients with obesity or overweight, with emotional eating; recommends surgical intervention (sleeve gastrectomy, Roux-en-Y gastric bypass, or metabolic gastric bypass/gastric bypass with single anastomosis/gastric mini bypass in patients with BMI ≥ 35 kg/m2 who are suitable for metabolic surgery; and suggests gastric banding as a possible, though less effective, surgical alternative. CONCLUSION: The present GL is directed to all physicians addressing people with obesity-working in hospitals, territorial services or private practice-and to general practitioners and patients. The recommendations should also consider the patient's preferences and the available resources and expertise.

What factors have impact on glucocorticoid replacement in adrenal insufficiency: a real-life study.

PURPOSE: The impact of patient's characteristics on glucocorticoid (GC) replacement therapy in adrenal insufficiency (AI) is poorly evaluated. Aims of this study were to assess the influence of sex and body weight on GC dosing and to describe the choice of GC in AI of different etiologies. METHODS: We retrospectively evaluated hydrocortisone (HC) equivalent total daily dose (HC-TDD) and per-kg-daily dose (HC-KDD) in 203 patients (104 primary AI [pAI], 99 secondary AI [sAI]) followed up for ≥ 12 months. They were treated with HC, modified-release HC (MRHC) or cortisone acetate (CA) and fludrocortisone acetate (FCA) in pAI. RESULTS: At baseline, CA was preferred both in pAI and sAI; at last visit, MRHC was most used in pAI (49%) and CA in sAI (73.7%). Comparing the last visit with baseline, in pAI, HC-TDD and HC-KDD were significantly lower (p = 0.04 and p = 0.006, respectively), while FCA doses increased during follow-up (p = 0.02). The reduction of HC-TDD and HC-KDD was particularly relevant for pAI women (p = 0.04 and p = 0.002, respectively). In sAI patients, no change of HC-KDD and HC-TDD was observed, and we found a correlation between weight and HC-TDD in males (r 0.35, p = 0.02). CONCLUSIONS: Our real-life study demonstrated the influence of etiology of AI on the type of GC used, a weight-based tailoring in sAI, a likely overdosage of GC treatment in pAI women at the start of treatment and the possibility to successfully increase FCA avoiding GC over-treatment. These observations could inform the usual clinical practice.

Clinical presentation and management of patients with primary hyperparathyroidism in Italy.

PURPOSE: Evaluation of the phenotype of primary hyperparathyroidism (PHPT), adherence to International Guidelines for parathyroidectomy (PTx), and rate of surgical cure. METHOD: From January 2014-January 2016, we performed a prospective, multicenter study in patients with newly diagnosed PHPT. Biochemical and instrumental data were collected at baseline and during 1-year follow-up. RESULTS: Over the first year we enrolled 604 patients (age 61 ± 14 years), mostly women (83%), referred for further evaluation and treatment advice. Five hundred sixty-six patients had sporadic PHPT (93.7%, age 63 ± 13  years), the remaining 38 (6.3%, age 41 ± 17  years) had familial PHPT. The majority of patients (59%) were asymptomatic. Surgery was advised in 281 (46.5%). Follow-up data were available in 345 patients. Eighty-seven of 158 (55.1%) symptomatic patients underwent PTx. Sixty-five (53.7%) of 121 asymptomatic patients with at least one criterion for surgery underwent PTx and 56 (46.3%) were followed without surgery. Negative parathyroid imaging studies predicted a conservative approach [symptomatic PHPT: OR 18.0 (95% CI 4.2-81.0) P < 0.001; asymptomatic PHPT: OR 10.8, (95% CI 3.1-37.15) P < 0.001). PTx was also performed in 16 of 66 (25.7%) asymptomatic patients without surgical criteria. Young age, serum calcium concentration, 24 h urinary calcium, positive parathyroid imaging (either ultrasound or MIBI scan positive in 75% vs. 16.7%, P = 0.001) were predictors of parathyroid surgery. Almost all (94%) of patients were cured by PTx. CONCLUSIONS: Italian endocrinologists do not follow guidelines for the management of PHPT. Negative parathyroid imaging studies are strong predictors of a non-surgical approach. PTx is successful in almost all patients.

Mild primary hyperparathyroidism as defined in the Italian Society of Endocrinology's Consensus Statement: prevalence and clinical features.

BACKGROUND: Mild primary hyperparathyroidism (PHPT) was recently clearly defined for the first time. Our study was thus aimed to pinpoint proportion and clinical characteristics of this kind of patients. DESIGN AND PATIENTS: We retrospectively evaluated our series of 360 consecutive patients with PHPT, selecting those with all features allowing a correct classification (serum total and ionized calcium, phosphate, creatinine, PTH, 25OHD, urinary calcium, renal and neck ultrasound, MIBI scintiscan, and DEXA at lumbar spine, femoral neck, and distal third of radius). Patients were defined asymptomatic (aPHPT) when bone or kidney was not involved and no hypercalcemic symptom occurred; mild PHPT was defined as aPHPT not meeting updated surgical criteria. RESULTS: Seventy-five patients among 172 classified as aPHPT had all available data required for surgical evaluation and could be evaluated. Sixty/75 met surgical criteria and the remaining 15 were classified as mild. Mild PHPT patients had lower total and ionized calcium, urinary calcium, and PTH levels than aPHPT meeting surgical criteria, while vitamin D levels and BMD were similar. CONCLUSIONS: Mild PHPT strictly defined according to the last consensus represents a small subgroup with a less active form of the disease.

Prevalence and characteristics of metabolic syndrome in primary hyperparathyroidism.

AIMS: Primary hyperparathyroidism (pHPT) is characterized by an increased frequency of glucose tolerance abnormalities associated with insulin resistance. Few studies evaluated the prevalence of metabolic syndrome (MetS) in pHPT and whether there are differences between asymptomatic pHPT patients and symptomatic ones. Thus, we sought to investigate the prevalence of MetS in pHPT patients in comparison to the prevalence of MetS in Italian population. SUBJECTS AND METHODS: We conducted a retrospective chart review of 294 pHPT patients, of these 154 [age (mean ± SD) 58.7 ± 13.3 yr, body mass index 25.6 ± 4.8 kg/m(2); serum calcium (11.3 ± 1.2 mg/dl) 2.8 ± 0.3 mmol/l; PTH 234.8 ± 224.3 ng/l] met the inclusion criteria. A modified National Cholesterol Educational Program (NCEP)/Adult Treatment Panel III (ATP III) definition of the MetS was used. Prevalence of MetS was compared with that reported for the Italian population (Progetto Cuore Study). RESULTS: The prevalence of the MetS (34/154, 22.1%) was similar to that reported in the general Italian population. Asymptomatic pHPT patients were older (62.1 ± 12.7 vs 56.4 ± 13.2 yr, p<0.008) and showed higher prevalence of MetS than symptomatic ones (30.2% vs 16.5%, p<0.045). Moreover the prevalence of nephrolitiasis or overt bone disease was not different between patients MetS+pHPT compared to MetS-pHPT, whereas femoral bone mineral density (BMD) was higher in MetS+pHPT (p<0.003). In the logistic regression model age and femoral BMD were independent predictors of MetS. CONCLUSIONS: The prevalence of MetS in pHPT is not increased in comparison to the general population, thus, its diagnosis is not an appropriate tool to identify the additional cardiovascular risk related to pHPT. Difference in age affects the increased prevalence of MetS in asymptomatic pHPT patients.

Interplay between serum osteocalcin and insulin sensitivity in primary hyperparathyroidism.

Osteocalcin (OC) has been proposed as a regulator of insulin sensitivity in both humans and other animals. Primary hyperparathyroidism (PHPT) is characterized by high OC levels and insulin resistance. The aim of this study was to evaluate whether in PHPT the link between OC levels and blood markers of insulin resistance was maintained. In a consecutive series of 219 adult PHPT patients, serum OC as well as fasting insulin and glucose levels were measured. Insulin sensitivity was estimated by homeostatic model assessment (HOMA2-S%). The same parameters were evaluated in a subgroup of 45 patients after parathyroidectomy (PTX). PHPT patients were characterized by markedly high OC levels. After subdividing them according to glucose tolerance, it was found that OC was similar in subjects with normal glucose tolerance (NGT) and impaired glucose tolerance (IGT), while diabetic subjects had lower serum OC than those with NGT (P < 0.02) or IGT (P < 0.04). OC was negatively associated with fasting glucose and positively associated with HOMA2-S%. OC independently predicted HOMA2-S% in a multivariate analysis. In the subgroup of surgically cured PHPT patients, OC levels significantly decreased after PTX, while HOMA2-S% did not change. Our findings indicate that in PHPT there is a positive relationship between OC and glucose metabolism, OC being one of the predictors of insulin sensitivity. However, data in surgically cured patients, showing OC normalization in spite of unchanged HOMA2-S%, suggest that OC does not likely play a major role in affecting insulin sensitivity in PHPT.

Insulin resistance is not coupled with defective insulin secretion in primary hyperparathyroidism.

AIMS: An increased frequency of both impaired glucose tolerance and Type 2 diabetes mellitus (DM) has been reported in primary hyperparathyroidism (pHPT), thus we sought to investigate insulin sensitivity and insulin secretion in a large series of pHPT patients. SUBJECTS AND METHODS: One hundred and twenty-two consecutive pHPT patients without known DM were investigated [age (mean +/- sd) 59.3 +/- 13.6 years, body mass index (BMI) 25.7 +/- 4.2 kg/m(2); serum calcium 2.8 +/- 0.25 mmol/l; PTH 203.2 +/- 145.4 ng/l]. Sixty-one control subjects were matched, according to the degree of glucose tolerance, in a 2 : 1 patient:control ratio. Fasting- and oral glucose tolerance test-derived estimates of insulin sensitivity and secretion were determined by means of the quantitative insulin sensitivity check index (QUICKI) and the insulin sensitivity index (ISI) composite. RESULTS: Both the QUICKI and ISI composite were lower in pHPT patients than control subjects (P < 0.03 and P < 0.05, respectively) after adjusting for age, systolic blood pressure and BMI. Conversely, all insulin secretion estimates were significantly increased in pHPT patients than in control subjects (P < 0.04 and P < 0.03, respectively) and after adjusting for age, systolic blood pressure and BMI. Log serum calcium levels were negatively associated with the QUICKI and log ISI composite (R = -0.30, P = 0.001; R = -0.23, P = 0.020, respectively) in pHPT patients. Serum calcium levels significantly and independently contributed to impaired insulin sensitivity in multivariate analysis (QUICKI as dependent variable: beta = -0.31, P = 0.004, R(2) = 0.15; log ISI composite as dependent variable: beta = -0.29, P = 0.005, R(2) = 0.16). CONCLUSIONS: Our study confirms a reduction in both basal and stimulated insulin sensitivity in primary hyperparathyroidism, in spite of increased insulin secretion. Moreover, our data show for the first time a significant relationship between hypercalcaemia and insulin sensitivity in this condition.

Effects of extra virgin olive oil supplementation at two different low doses on lipid profile in mild hypercholesterolemic subjects: a randomised clinical trial.

Olive oil, the principal fat of Mediterranean Diet, is known to improve several cardiovascular risk factors at relatively high doses together with intensive modifications of dietary habits. Since this is hard to obtain in the long term, an intervention with encapsulated oil supplements might be more feasible. Aim of this preliminary study was to investigate the effects of the supplementation of a moderate amount of encapsulated extra virgin olive oil vs a lower dose in mildly hypercholesterolemic subjects, as part of their established diet, on blood lipid profile. A prospective randomized study was performed. Thirty-four mildly hypercholesterolemic subjects [age, mean+/-SD: 46+/-7 yr; total cholesterol (TC): 235+/-28 mg/dl] were randomly assigned to receive 2 g (group A) or 4 g (group B) per os of extra-virgin olive oil for 3 months. TC, triglycerides (TG), LDL cholesterol, HDL cholesterol, apolipoprotein A1 (Apo-AI), apolipoprotein B (Apo-B), and atherogenic index of plasma (AIP) were evaluated at the beginning and at the end of the study. In group B, but not in group A, a significant reduction of Apo-B values (7%) was observed; TG concentrations showed a trend towards reduction and Apo-A1 values a trend towards increase (9%). A significant decrease in Apo-B/Apo-A1 ratio (p<0.01) was also observed in group B. Extra virgin olive oil supplementation significantly decreased AIP from baseline in group B (p<0.05). The results of the present study seem to suggest that the daily supplementation, on top of the normal diet, of at least 4 g of extra virgin olive oil, in mildly hypercholesterolemic subjects, is associated to favorable modifications of the plasmatic lipid profile.

B-type natriuretic peptide levels and insulin resistance in patients with severe ischemic myocardial dysfunction.

B-type natriuretic peptide (BNP) is an important clinical parameter of severity in congestive heart failure (CHF). Recent findings suggest a close relation between lipid and glucose metabolism and the natriuretic peptide axis, even if conflicting data exist on the relationship between natriuretic peptide levels and insulin resistance (IR). Thus, we sought to investigate potential relations between BNP level and IR in 134 patients with severe ischemic myocardial dysfunction [mean+/-SD: age =64.8+/-9.6 yr, male/female =104/30; body mass index (BMI) =25.5+/-4.05 kg/m2, 26.1% diabetics; ejection fraction (EF) = 30.2+/-7.7%]. In univariate analysis, an inverse relationship between BNP levels and EF% was observed (R=-0.43, p=0.0006). Moreover, we found an inverse association between BNP levels and BMI (R=-0.27, p=0.036), and also between BNP and homeostasis model assessment of insulin resistance (HOMA-IR) (R=-0.27, p=0.039). In multivariate analysis, EF% and HOMA-IR were significantly and independently associated with logarithmically transformed BNP levels (beta=-0.40, p=0.019 and beta=-0.26, p=0.042, respectively; R2=0.36). In conclusion, in patients with severe ischemic myocardial dysfunction EF and IR are independently associated with BNP levels explaining about 1/3 of the variability of this parameter. Multiple potential mechanisms may underlie this association, but it seems now clinically important to take into account also metabolic features when interpreting plasma natriuretic peptide concentrations obtained for diagnostic or prognostic purposes.

Dopamine D2 receptor gene polymorphisms and response to cabergoline therapy in patients with prolactin-secreting pituitary adenomas.

Dopamine-agonist cabergoline (CB) reduces prolactin (PRL) secretion and tumor size in 80% of patients with prolactin-secreting adenomas (PRL-omas) by binding type 2 dopamine receptor (DRD2). The mechanisms responsible for resistance to CB remain largely unknown. To assess the association of DRD2 with sensitivity to CB, TaqI-A1/A2, TaqI-B1/B2, HphI-G/T and NcoI-C/T genotypes were determined in a cross-sectional retrospective study, including 203 patients with PRL-oma. DRD2 alleles frequencies did not differ between patients and 212 healthy subjects. Conversely, NcoI-T allele frequency was higher in resistant rather than responsive patients, considering both PRL normalization (56.6 vs 45.3%, P=0.038) and tumor shrinkage (70.4 vs 41.4%, P=0.006). Finally, [TaqI A1-/TaqI B1-/HphI T-/NcoI T-] haplotype was found in 34.5% of patients normalizing PRL with < or =3 mg/week of CB vs 11.3% of resistants (P=0.021). In conclusion, resistance to CB was associated with DRD2 NcoI-T+ allele, consistent with evidence suggesting that this variant may lead to reduction and instability of DRD2 mRNA or protein.

The basal to total insulin ratio in outpatients with diabetes on basal-bolus regimen.

OBJECTIVE: To evaluate the basal/total ratio of daily insulin dose (b/T) in outpatients with diabetes type 1 (DM1) and type 2 (DM2) on basal-bolus regimen, by investigating whether there is a relationship with HbA1c and episodes of hypoglycemia. METHODS: Multicentric, observational, cross-sectional study in Italy. Adult DM1 (n = 476) and DM2 (n = 541) outpatients, with eGFR >30 mL/min/1.73 m2, on a basal-bolus regimen for at least six months, were recruited from 31 Italian Diabetes services between March and September 2016. Clinicaltrials.govID: NCT03489031. RESULTS: Total daily insulin dose was significantly higher in DM2 patients (52.3 ± 22.5 vs. 46 ± 20.9 U/day), but this difference disappeared when insulin doses were normalized for body weight. The b/T ratio was lower than 0.50 in both groups: 0.46 ± 0.14 in DM1 and 0.43 ± 0.15 in DM2 patients (p = 0.0011). The b/T was significantly higher in the patients taking metformin in both groups, and significantly different according to the type of basal insulin (Degludec, 0.48 in DM1 and 0.44 in DM2; Glargine, 0.44 in DM1 and 0.43 in DM2; Detemir, 0.45 in DM1 and 0.39 in DM2). The b/T ratio was not correlated in either group to HbA1c or incidence of hypoglycemia (<40 mg/dL, or requiring caregiver intervention, in the last three months). In the multivariate analysis, metformin use and age were independent predictors of the b/T ratio in both DM1 and DM2 patients, while the type of basal insulin was an independent predictor only in DM1. CONCLUSION: The b/T ratio was independent of glycemic control and incidence of hypoglycemia.

Correction to: The basal to total insulin ratio in outpatients with diabetes on basal-bolus regimen.

[This corrects the article DOI: 10.1007/s40200-018-0358-2.].

High prevalence of colonic polyps in patients with acromegaly. Influence of sex and age.

BACKGROUND: An association between acromegaly and colonic polyps has been reported, although risk factors are still uncertain. METHODS: Full colonoscopy was performed with a fiberoptic colonoscopy on 31 acromegalic patients, 11 men and 20 women aged 27 to 85 years (mean, 52.2 years), and on 236 subjects, 127 men and 109 women aged 23 to 84 years (mean, 50.1 years), referred for hemorrhoids, who were considered controls. The colonoscopic findings were evaluated in relation to demographic, clinical, and hormonal data pertaining to the two groups. RESULTS: The prevalence of either adenomatous or hyperplastic polyps was higher in acromegalic patients than in controls (38% vs 14% and 26% vs 10%, respectively; P < .001, respectively). Acromegalics with and without colonic adenomas did not differ significantly in growth hormone and insulinlike growth factor I levels or duration of acromegalic disease and its status (activity or remission); however, patients with adenoma were younger (median age, 50.5 vs 59 years; range, 27 to 85 years vs 39 to 66 years; P < .05). An opposite age pattern was observed in the control group. Indeed, the prevalence of adenoma in acromegalic patients was much higher than that in controls among those less than 50 years of age (46% vs 7%, P < .001); the difference was less remarkable at older ages. Adenomatous polyps were more frequently found in male subjects, in both patients and controls (45% vs 33% [not significant] and 19% vs 9% [P < .05], respectively). CONCLUSIONS: Acromegaly may carry an increased risk of colonic adenoma, especially in younger patients, who usually display more aggressive disease. A smaller increase in risk was observed in elderly patients, in whom disease is reportedly milder. We suggest that acromegalic patients should undergo screening colonoscopy.

Primary hyperparathyroidism and Klinefelter's syndrome in a young man.

UNLABELLED: We report the association of primary hyperparathyroidism (PHPT) and Klinefelter's syndrome (KS) in a 22-year-old male complaining of worsening fatigue. PHPT was asymptomatic at the diagnosis, but the patient had worsening hypercalcemia and osteoporosis, and developed acute renal colic. He then underwent parathyroidectomy with resection of a single adenoma and normalization of calcium and parathyroid hormone levels. Clinical and therapeutic implications of this rare association are discussed. LEARNING POINTS: The coexistence of KS and PHPT is very uncommon.Patients with mild PHPT often have nonspecific symptoms that may be confused and superimposed with those of hypogonadism.KS patients, especially when young and already osteoporotic at diagnosis, should be screened for other causes of secondary osteoporosis, in particular PHPT.

Endocrine evaluation of incidentally discovered adrenal masses (incidentalomas)

Since 1989, 45 patients [pts; 26 females and 19 males, aged 19-79 yr (median, 58)] bearing incidentally discovered adrenal masses were studied. The aim of the study was to verify the prevalence of hormone activity in clinically silent adrenal masses. Endocrine work-up included determination of urinary catecholamines and their metabolites, measurement of PRA and aldosterone levels in clino- and orthostatic posture, and basal and dynamic [dexamethasone (dex) suppression and ovine CRH stimulation] evaluation of hypothalamic-pituitary-adrenal axis. The most frequent finding was the reduction of dehydroepiandrosterone sulfate (DHEA-S) levels below the third percentile of controls in 19 (42%) pts. DHEA-S levels were significantly lower in pts than in controls [68 (range, 5-1000) vs. 208 (34-326) micrograms/dL; 1.8 (0.1-27.1) vs. 5.6 (0.9-8.8) mumol/L; P < 0.001]. Three pts (7%) had high 24-h mean serum cortisol levels, and 6 (14%) had blunted day-night amplitude of cortisol rhythm. Defective dex suppressibility was found in 15% of pts vs. 8% of controls (P < 0.05). ACTH and cortisol responses to ovine CRH did not significantly differ between pts and controls, although blunted ACTH responses were found in 22% of the cases. The above-mentioned endocrine alterations could be accounted for by autonomous cortisol secretion by the adrenal nodule at a rate not sufficient to give clinical expression, but able to inhibit to some extent the hypothalamic-pituitary-adrenal axis. These results indicate that silent cortisol hypersecretion is frequently observed in pts with adrenal incidentaloma even if progression to overt Cushing's syndrome seems unlikely. Indeed, the size of the mass and the hormone pattern remained substantially unchanged in 9 pts followed up for 12 months. From merely a cost/benefit ratio, the evaluation of DHEA-S levels and dex suppression has sufficient sensitivity to identify the occurrence of silent hypercortisolism.

Different patterns of steroid secretion in patients with adrenal incidentaloma.

We previously found that a remarkable number of patients with adrenal incidentaloma display partially autonomous cortisol secretion. The amount of hypercortisolism is insufficient to give clinical expression, but enough to inhibit, in some cases, normal adrenal tissue. Other researchers found with high frequency a partial deficiency of 21-hydroxylase. The aim of the present study was to make a combined evaluation of these aspects of adrenal steroidogenesis. Twenty patients (6 men and 14 women, aged 25-74 yr; median, 59 yr) with incidentally discovered adrenal masses were studied. All had an adrenal adenoma histologically proven or diagnosed on the basis of size (< or = 4.0 cm in all but 1) and computed tomography picture (hypodense homogeneous mass with well defined margins). The following parameters were used to evaluate the ACTH-cortisol axis: overnight 1-mg dexamethasone suppression (4 nonsuppressors), ovine CRH stimulation (blunted ACTH-cortisol response in 2 cases), circadian serum cortisol rhythm (blunted night/day ratio in 4 and increased 24-h mean in 1), and 24-h urinary free cortisol excretion (always within the normal range). Three patients had 2 concomitant alterations, and 5 had a single abnormality. Partial deficiency of 21-hydroxylase was assumed in 6 patients who showed an exaggerated 17-hydroxyprogesterone response to ACTH, with a peak value of more than 10 ng/mL (> 30 nmol/L), according to New's nomogram. No abnormalities of the ACTH-cortisol axis were found in these patients, with the exception of low amplitude cortisol rhythm in 1 case. Therefore, 2 distinct patterns, dysregulated and partially autonomous cortisol secretion, on the one hand, and reduced 21-hydroxylase activity, on the other, can be found in a high number of patients bearing an adrenal incidentaloma. They appear mutually exclusive, and the differentiation by endocrine testing is quite clear. Serum dehydroepiandrosterone sulfate was below the third percentile in 13 of 20 patients and could represent a specific marker of cortical adenomas. This finding was evenly distributed among patients with subclinical hypercortisolism or partial enzymatic defect; therefore, low serum dehydroepiandrosterone sulfate is not readily attributable to suppressed ACTH secretion, which actually occurs in only some patients with subclinical hypercortisolism.

Hypopituitarism and growth hormone deficiency (GHD) after traumatic brain injury (TBI).

In adults, hypopituitarism and growth hormone deficiency (GHD) should be suspected and diagnosed within an appropriate clinical context. It has been demonstrated that all patients with primary hypothalamic-pituitary diseases before and after any medical intervention (defined as neurosurgery, radiotherapy and medical therapy) are at obvious risk - more than just at high risk - for hypopituitarism (greater than 80% had severe GHD). The same obvious risk applies to patients diagnosed as having congenital or acquired GHD in childhood (between 30% and 50% of patients with severe GHD after retesting). Taking into account the fragility of the infundibular-hypothalamic structure, patients with other common pathological conditions of the central nervous system (CNS), such as traumatic brain injury (TBI), subarachnoid haemorrhage (SAH) or primary brain tumours (BT) with related medical intervention could be at risk for developing hypopituitarism, including GHD. GHD is the first and most common sign of pituitary impairment. Despite the risk of pituitary dysfunction and the results of some studies that these risks are greater than previously believed, neuroendocrine evaluations are still not routinely included as part of the clinical management plan for patients with TBI and SAH. Preliminary results of a multicenter study performed under the auspices of the Italian Society of Endocrinology underscore the high risk of hypopituitarism and GHD under these clinical conditions. Thus, careful screening of pituitary function should always be performed in patients following TBI and SAH.

Circadian profile of serum melatonin in Cushing's disease and acromegaly.

We evaluated the circadian profiles of serum melatonin (MT) and cortisol in 6 patients with Cushing's disease while those of serum MT and GH were evaluated in 8 patients with acromegaly. The control group consisted of 15 healthy subjects in whom MT, cortisol and GH were determined. The presence of a circadian rhythmicity was validated by the cosinor method, while the diurnal and nocturnal amount of MT secretion were expressed in terms of area under the curve. Gross alterations of MT rhythm were not apparent in Cushing's patients. In acromegalics, we observed a blunted day-night oscillation of MT accounted for by a significant increase of its secretion during the day-time period.