Pietro Putignano

Glucocorticoids and neuroendocrine function

Recent experimental evidence supports the role of glucocorticoids in the neuroendocrine control of food intake and energy expenditure. In particular, glucocorticoids promote food consumption directly through stimulation of NPY and inhibition of CRH and melanocortin release. CRH and NPY are also functionally linked by a mutual regulation. CRH is anorexigenic when secreted acutely while it exerts the opposite effect when, upon sustained secretion, it stimulates the hypothalamo–pituitary–adrenal (HPA) axis. The orexigenic effects of glucocorticoids are counteracted by a steroid-induced rise in leptin levels that closes a regulatory loop regarding food consumption. Furthermore, glucocorticoids may alter body fat distribution, increasing truncal adiposity both directly and by inhibition of growth hormone secretion. No clearcut alterations of the HPA function are apparent in obesity as a whole. However, subtle and specific abnormalities may be noted in subsets of obese patients. Indeed, obesity, mostly visceral type, is associated with an increased cortisol clearance and 11-β hydroxysteroid dehydrogenase activity in the omental fat. In the same vein, an increased cortisol rise following a mixed meal has been observed in obese subjects. Finally, it has been proposed that adrenal incidentalomas, often characterized by enhanced cortisol secretion, might be a clinical expression of the X syndrome.

Screening for Cushing’s syndrome in obese women with and without polycystic ovary syndrome

Obesity and insulin resistance, menstrual abnormalities and clinical and biochemical signs of hyperandrogenism are common features in women with polycystic ovary syndrome (PCOS) and Cushing’s syndrome (CS). Further, an overdrive of the pituitary-adrenal axis has been documented in PCOS and this condition is often present in women with CS. For this reason, screening for hypercortisolism is often needed in obese women with polycystic ovaries. The aim of this study was to compare the diagnostic value of different screening tests for CS in a population of obese premenopausal women with PCOS and without PCOS (OB) and in a group of patients with CS. We reviewed retrospectively the case records of 117 obese women of reproductive age (60 PCOS and 57 OB, BMI 25.1–70.1, 13–45 yr) who were screened for CS at our Institution in the years 1995–2001 and turned out to be free of the disease. Data were compared with those of 58 premenopausal obese women with active CS (BMI 25.1–50.2 kg/m2, 18–45 yr). Screening for CS was performed by urinary free cortisol (UFC) (three consecutive 24-h urine collections), cortisol circadian rhythm (blood samples taken at 08:00–17:00–24:00 h), and 1 mg overnight dexamethasone suppression test (DST). A 24:00 h plasma cortisol (MNC) of 207 nmol/l, a UFC of 221 nmol/day and plasma cortisol after DST of 50 nmol/l and 138 nmol/l were taken as cut-off values for the diagnosis of CS. As expected, patients with CS showed elevated basal and post-dexamethasone plasma cortisol and UFC levels (p<0.001 vs OB and PCOS). PCOS had higher UFC (p<0.005) but not MNC and post-DST plasma cortisol levels compared to OB. DST showed the greatest specificity and diagnostic accuracy in differentiating CS from PCOS and OB (both p<0.05 vs MNC and UFC, according to the 138 nmol/l criterion) while MNC and UFC displayed a similar discriminatory value. However, by using a lower threshold (50 nmol/l) as response criterion, there were no diagnostic differences between DST and the other tests. Specificity and diagnostic accuracy of UFC measurement was lower in PCOS than in OB (both p<0.05) whilst there were no differences between groups for DST and MNC. Similarly, the area under the ROC curve relative to DST, giving an estimate of the inherent diagnostic accuracy of the test, was slightly greater than those of MNC and UFC (z=0.694 and z=0.833 for DST vs MNC and UFC, respectively, both p=NS). These results indicate that the 1-mg DST and MNC are unaffected by the presence of PCOS and can be safely used to screen for CS premenopausal obese women with PCOS, while caution should be exercised in interpreting mildly elevated UFC levels in these patients.

Tissue-specific dysregulation of 11β-hydroxysteroid dehydrogenase type 1 and pathogenesis of the metabolic syndrome

Glucocorticoids are important regulators of glucose, lipid and protein metabolism, acting mainly in the liver, adipose tissue and muscle. Chronic glucocorticoid excess is associated with clinical features, such as insulin resistance, visceral obesity, hypertension, and dyslipidemia, which also represent the classical hallmarks of the metabolic syndrome. Elevenß-hydroxysteroid dehydrogenase type 1 (11ß-HSD-1), a key intracellular enzyme which catalyses the conversion of inactive cortisone to active cortisol, has been implicated in the development of the metabolic syndrome. The shift of this reaction towards cortisol generation may lead to tissutal overexposure to glucocorticoids even with normal circulating cortisol levels. The most robust evidence in support of a pathogenetic role of this enzyme in the development of the metabolic syndrome has been reported in experimental animals, whereas results of human studies are less convincing with several case control and cross-sectional studies showing an association between with 11ß-HSD-1 setpoint and individual features of the metabolic syndrome. However, recent data suggest a tissue-specific rather than systemic alteration of this shuttle, with down-regulation in liver but up-regulation in adipose tissue and skeletal muscle of obese subjects. New techniques based on direct tissutal estimates of cortisol/cortisone ratios are clearly needed to precisely assess the role of enzyme in all target tissues. If confirmed, these results would prompt the development of selective and tissuespecific 11ß-HSD-1 inhibitors to decrease insulin resistance and treat the metabolic syndrome, thus contrasting the harmful effects of glucocorticoid excess in peripheral tissues

Effect of small doses of dexamethasone on plasma leptin levels in normal and obese subjects: A dose-response study

To further elucidate the role of glucocorticoids in the regulation of leptin secretion, we studied the effects of overnight small doses of dexamethasone on plasma leptin levels in normal weight controls and in obese patients and correlated the results with indexes of insulin sensitivity and body fat distribution. In 114 subjects (81 obese patients, 49 women and 32 men, BMI 37.4±0.77 kg/m2 and 33 normal-weight subjects, 17 women and 16 men, BMI 22.1±0.41 kg/m2) plasma F and leptin levels were measured at 08:00 h basally and after the administration of different doses of dexamethasone (a fixed dose of 1-mg and 0.0035, 0.007, 0.015-mg/kg bw, given po at 23:00 h the night before). Tests were performed one week apart with bw remaining stable over the study period. Basal leptin levels were significantly higher in obese than in normal subjects (31.9±2.41 vs 7.7±0.93 ng/ml, p<0.0001). In obese patients, leptin levels increased significantly by 1-mg (from 31.9±2.41 to 35.0±2.59 ng/ml, p<0.005) and the 0.015-mg/kg bw dose (from 31.5±2.34 to 33.7±2.44 ng/ml, p<0.05), while they were unaffected by each dose of dexamethasone in normal subjects. However, after splitting subjects by gender, mean leptin levels rose from 39.3±2.97 to 43.3±3.12 ng/ml after the 1-mg dose, p<0.005, from 39.1±2.87 to 43.6±2.91 ng/ml after the 0.015-mg/kg bw dose, p<0.005, from 39.3±2.90 to 42.2±2.90 ng/ml after the 0.007-mg/kg bw dose, p<0.05 and from 38.8±2.66 to 41.1±2.87 ng/ml after the 0.0035-mg/kg bw dose, p=0.055, only in obese women. Conversely, no leptin changes were seen in the other groups and no differences were observed in the leptin response between groups. After the 1-mg dose, in the whole group, the absolute leptin variation was weakly but significantly related to BMI values (r=0.231, p<0.02) while in all sessions the percent leptin changes over baseline were not significantly correlated with age, BMI, waist, WHR, insulin, HOMA index, a marker of insulin sensitivity, plasma dexamethasone concentrations and to the percent cortisol variation following dexamethasone. In conclusion, in obese women but not in obese men and in normal weight subjects, small overnight increases in plasma glucocorticoid concentrations induced gender-related plasma leptin elevations that were unrelated to body fat distribution and insulin sensitivity. A greater sensitivity of female adipose tissue to glucocorticoids probably underlies this sexually dimorphic pattern of leptin response. These findings provide an additional piece of information on the regulation of leptin secretion exerted by glucocorticoids.

Pituitary Tumors, ACTH-Secreting

The chronic exposure to excessive concentrations of circulating glucocorticoids, or hypercortisolism, determines a severe disease named Cushings syndrome (CS). Adrenocorticotropic hormone-secreting pituitary tumors induce adrenal cortisol hypersecretion and represent the most frequent form (around 70%) of endogenous CS. This serious endocrine disorder is known as Cushings disease (CD). This article reviews the clinical features of CD and the diagnostic algorithm to establish the diagnosis of endogenous hypercortisolism, named CS, and, subsequently, to differentiate between pituitary (CD) and non-pituitary (ectopic and adrenal) causes of CS. Finally, currently available therapeutic approaches, including surgery, radiotherapy and medical therapy, are illustrated.