Silvia Garelli

Cardiovascular events and mortality in patients with adrenal incidentalomas that are either non-secreting or associated with intermediate phenotype or subclinical Cushing's syndrome: a 15-year retrospective study

BACKGROUNDnIncidental discovery of adrenal masses has increased over the past few years. Mild alterations in cortisol secretion without clinical signs of overt hypercortisolism (subclinical Cushings syndrome) are a common finding in patients with these tumours. Although metabolic alterations and increased cardiovascular risk have been noted in patients with subclinical Cushings syndrome, incidence of cardiovascular events and mortality in the long term have not been assessed. We aimed to ascertain the frequency of new cardiovascular events and mortality in patients with non-secreting adrenal incidentalomas, tumours of intermediate phenotype, or those causing subclinical Cushings syndrome.nnnMETHODSnFrom January, 1995, to September, 2010, consecutive outpatients with adrenal incidentalomas who were referred to the endocrinology unit of S Orsola-Malpighi Hospital, Bologna, Italy, were enrolled into our study. Individuals were assessed every 18-30 months for the first 5 years (mean follow-up 7·5 [SD 3·2] years, range 26 months to 15 years). Cortisol concentrations after the 1 mg dexamethasone suppression test (DST) were used to define non-secreting (+50 nmol/L) and intermediate phenotype (50-138 nmol/L) adrenal incidentalomas and subclinical Cushings syndrome (+138 nmol/L). At the end of follow-up, patients were reclassified as having either unchanged or worsened secreting patterns from baseline.nnnFINDINGSn198 outpatients were assessed; at the end of follow-up, 114 patients had stable non-secreting adrenal incidentalomas, 61 had either a stable intermediate phenotype or subclinical Cushings syndrome, and 23 had a pattern of secretion that had worsened. By comparison with patients with stable non-secreting adrenal incidentalomas, the incidence of cardiovascular events was higher in individuals with a stable intermediate phenotype or subclinical Cushings syndrome (6·7% vs 16·7%; p=0·04) and in those with worsened secreting patterns (6·7% vs 28·4%; p=0·02). Cardiovascular events were associated independently with a change (from baseline to the end of follow-up) in cortisol concentrations post DST (hazard ratio 1·13, 95% CI 1·05-1·21; p=0·001). Survival rates for all-cause mortality were lower in patients with either stable intermediate phenotype adrenal incidentalomas or subclinical Cushings syndrome compared with those with stable non-secreting masses (57·0% vs 91·2%; p=0·005). Factors associated with mortality were age (hazard ratio 1·06, 95% CI 1·01-1·12; p=0·03) and mean concentrations of cortisol post DST (1·10, 1·01-1·19; p=0·04). Compared with patients with stable non-secreting adrenal incidentalomas, unadjusted survival for cardiovascular-specific mortality was lower in patients with either a stable intermediate phenotype or subclinical Cushings syndrome (97·5% vs 78·4%; p=0·02) and in those with worsened secreting patterns (97·5% vs 60·0%; p=0·01). Cancer mortality did not differ between groups.nnnINTERPRETATIONnEven when clinical signs of overt hypercortisolism are not present, patients with adrenal incidentalomas and mild hypercortisolism have an increased risk of cardiovascular events and mortality.nnnFUNDINGnNone.

Cortisol, energy intake, and food frequency in overweight/obese women.

OBJECTIVEnThis retrospective study investigated the relation between daily urinary free cortisol excretion rate, as a marker of cortisol production rate, to daily caloric intake, food choice, body mass index (BMI), and waist circumference.nnnMETHODSnOne hundred twenty-seven overweight/obese women and 21 normal-weight subjects were enrolled in the study. Fasting blood samples for metabolic parameters were taken from each subject, followed by an oral glucose tolerance test. Cortisol excretion rate was assessed on 24-h urine collection (UFC/24 h). In obese patients, the daily caloric intake was calculated, and a weekly food-frequency questionnaire was assessed. Analysis of variance was used to assess the differences between groups. The relations between parameters were investigated by simple and multiple regressions.nnnRESULTSnObese women had significantly higher UFC/24 h than the normal-weight women (P < 0.001). The obese subjects had an unbalanced diet, particularly rich in saturated lipids, and weekly food choice showed a preference for highly caloric foods. UFC/24 h values and waist circumference were significantly correlated (P < 0.001), regardless of BMI. In the obese group, after adjustment for BMI, the UFC/24 h values were also significantly and positively correlated to daily carbohydrate and lipid intake and to weekly starchy food consumption.nnnCONCLUSIONnWe demonstrated a significant association between higher UFC/24 h and energy intake, fats, and consumption of starchy foods, and that these relations were independent of BMI.

Steroid Profiling by LC-MS/MS in Nonsecreting and Subclinical Cortisol-Secreting Adrenocortical Adenomas

CONTEXTnLong-term follow-up studies revealed that patients with subclinical hypercortisolism (SH) due to adrenocortical adenomas have an increased incidence of cardiovascular diseases and mortality. No studies have yet investigated the steroid profile and its implications in patients with SH.nnnOBJECTIVEnThe objective of the study was to analyze the steroid profile by liquid chromatography-tandem mass spectrometry in sera from patients with unilateral adrenocortical adenomas.nnnDESIGNnThis was a cross-sectional study.nnnSETTINGnThe study was conducted at an outpatient clinic.nnnPARTICIPANTSnPatients with adrenocortical adenomas (nonsecreting, n = 66; SH, n = 28) and 188 age- and sex-matched controls drawn from the general population participated in the study.nnnMAIN OUTCOME MEASURESnCortisol, 21-deoxycortisol, 11-deoxycortisol, 17-hydroxyprogesterone, androstenedione, dehydroepiandrosterone, T, progesterone, 11-deoxycorticosterone, and corticosterone in the basal condition and after a 1-24 ACTH test, and clinical data were measured.nnnRESULTSnPatients with SH showed lower basal and 1-24 ACTH-stimulated levels of dehydroepiandrosterone and androstenedione than those with nonsecreting adenomas and controls. T was also lower in SH females. Receiver-operating characteristic curves showed that androgens had good accuracy in predicting SH (sensitivity and specificity were 71% and 76% for dehydroepiandrosterone and 69% and 61% for androstenedione, respectively). Increased cortisol and reduced dehydroepiandrosterone levels were independently associated with increased waist circumference. Cortisol was also independently associated with increased number of cardiovascular risk factors in SH patients. After 1-24 ACTH stimulation, the SH patients also showed increased production of 21-deoxycortisol and 11-deoxycorticosterone.nnnCONCLUSIONSnLiquid chromatography-tandem mass spectrometry steroid profile performed for the first time in sera from patients with adrenocortical adenomas showed impaired secretion of several steroids in SH patients. This fingerprint can help in better characterizing the functional status of these tumors.

Obesity-related proliferative diseases: the interaction between adipose tissue and estrogens in post-menopausal women

Abstract Epidemiological studies have shown that overweight and cancer are closely related, even though obesity alone does not apparently heighten cancer risk by the same amount. Given the low overall risk of all cancers with obesity, it is unlikely that obesity alone causes cancer, but should instead be considered as a tumor promoter. There are three main hypotheses that could explain how obesity might contribute to cancer development and growth: the inflammatory cytokines from adipose tissue hypothesis, the insulin resistance and hyperinsulinemia hypothesis, and the unopposed estrogen cancer hypothesis. The link between obesity and cancer is that adipocytes constitute a major component of the tumor microenvironment for breast and abdominally metastasizing cancers, promoting tumor growth. This review will mainly focus attention on the relationship between adipose tissue, estrogens, and cancer risk.

Cross-talk between adipose tissue and the HPA axis in obesity and overt hypercortisolemic states.

Abstract In addition to its roles in providing insulation and mechanical support, adipose tissue (AT) has been recognised as the major site for storage of surplus fuel. Since leptin was discovered, white AT (WAT) has been recognised as an endocrine organ and an important source of biologically active substances with local and/or systemic action called adipokines. The metabolic and endocrine activities of AT are under the control of several hormones: a particular role has been played by glucocorticoids (GC), which able to participate, along with other hormones, both in recruitment of progenitor cells and in differentiation and secretive activities. AT is also able to generate cortisol from cortisone through 11β-hydroxysteroid-dehydrogenase (11β-HSD). There are controversial reports in the literature, showing a hyperactivity of 11β-HSD in obesity. It has been postulated that obesity, particularly the visceral body fat distribution (V-BFD), may be considered a maladaptation to stress exposure, thus leading to hyperactivation of the hypothalamic-pituitary-adrenal (HPA) axis, and higher-than-normal cortisol levels. In this review, we will examine the cross-talk between the HPA axis and AT, their relationship under stressful events, depending on steroid hormones and different adipokine secretions.

Food addiction distinguishes an overweight phenotype that can be reversed by low calorie diet

Similarities in neural activation patterns in obese and substance-dependent subjects led to the food addiction concept, but studies exploiting this issue for obesity stratification are missing. We assessed brain activation in response to food cues using 18 F-2-fluoro-2-deoxy-glucose-PET in 36 overweight women, stratified by low or high food addiction groups according to the Yale Food Addiction Scale (YFAS). Assessments were repeated after a 3-month diet. We found greater activation in thalamus, hypothalamus, midbrain, putamen, and occipital cortex (reward), but not in prefrontal and orbitofrontal cortices (control/reward receipt) in the high-YFAS versus low-YFAS group. In high-YFAS subjects, orbitofrontal responsiveness was inversely related to YFAS severity and hunger rating, and positive associations were observed between regional brain activation and lipid intake. A 3-month diet abolished group differences in brain activation. Our data suggest that food addiction distinguishes an overweight phenotype that can be reversed by diet, opening to personalized strategies in obesity treatment.

Treatment: New Drugs

Obesity, a dramatic worldwide medical burden, is a risk factor for the development of cardiovascular diseases, type 2 diabetes mellitus and furthermore is also associated with an elevated risk of cardiovascular mortality. Lifestyle modifications are not always sufficient to limit body weight excess; thus, safe and effective antiobesity drugs are urgently needed to help clinicians treat patients with efficacy; particularly, for those patients who do not meet eligibility criteria for bariatric surgery. This article will focus mainly on United States and Europe approved antiobesity drugs critically discussing their efficacy and emphasizing their safety profile. In detail, clinical trial data generated to obtain approval from agencies will be presented. It is, however, important to keep in mind that not always these types of clinical trials provide strict guidance for clinicians.