Roberta Giordano

Biologic activities of growth hormone secretagogues in humans

Growth hormone secretagogues (GHSs) are synthetic peptidyl and nonpeptidyl molecules with strong, dose-dependent, and reproducible growth hormone (GH)-releasing activity even after oral administration. GHSs release GH via actions on specific receptors (GHS-R) at the pituitary and, mainly, at the hypothalamic levels. GHSs likely act as functional somatostatin antagonists and meantime enhance the activity of GH-releasing hormone (GHRH)-secreting neurons. The GH-releasing effect of GHSs is independent of gender but undergoes marked age-related variations. Estrogens play a major role in enhancing the GH response to GHSs at puberty, which GHRH hypoactivity, somatostatinergic hyperactivity and impaired activity of the putative GHS-like ligand and receptors probably explain the reduced GH-releasing effect of GHSs in aging. The activity of GHSs is not fully specific for GH. Their slight prolactin-releasing activity probably comes from direct pituitary action. In physiological conditions, the ACTH-releasing activity of GHSs is dependent on central actions; a direct action on GHS-R in pituitary ACTH-secreting tumors likely explains the peculiar ACTH and cortisol hyperresponsiveness to GHSs in Cushing disease. GHSs have specific receptor subtypes in other central and peripheral endocrine and nonendocrine tissues mediating GH-independent biologic activities. GHSs influence sleep pattern, stimulated food intake, and have cardiovascular activities. GHs have specific binding in normal and neoplastic follicular derived human thyroid tissue and inhibit the proliferation of follicular-derived neoplastic cell lines. The discovery of ghrelin, a 28 amino acid peptide synthesized in the stomach but also in other tissues, has opened new fascinating perspectives of research in this field.

Effect of protracted treatment with rosiglitazone, a PPARgamma agonist, in patients with Cushing's disease.

Objective  Cushings disease, hypercortisolism due to a pituitary ACTH‐secreting tumour, is a highly morbid illness as yet without effective medical therapy. Recent studies have demonstrated that peroxisome proliferator‐activated receptor gamma (PPARγ) agonists effectively suppress ACTH secretion in a murine tumoral corticotroph cell line, but the few studies conducted so far in patients with ACTH‐secreting pituitary adenomas have yielded variable results.

Long-term follow-up in adrenal incidentalomas: an Italian multicenter study

CONTEXT The long-term consequences of subclinical hypercortisolism (SH) in patients with adrenal incidentalomas (AIs) are unknown. SETTING AND PATIENTS In this retrospective multicentric study, 206 AI patients with a ≥5-year follow-up (median, 72.3 mo; range, 60-186 mo) were enrolled. INTERVENTION AND MAIN OUTCOME MEASURES Adrenocortical function, adenoma size, metabolic changes, and incident cardiovascular events (CVEs) were assessed. We diagnosed SH in 11.6% of patients in the presence of cortisol after a 1 mg-dexamethasone suppression test >5 μg/dL (138 nmol/L) or at least two of the following: low ACTH, increased urinary free cortisol, and 1 mg-dexamethasone suppression test >3 μg/dL (83 nmol/L). RESULTS At baseline, age and the prevalence of CVEs and type 2 diabetes mellitus were higher in patients with SH than in patients without SH (62.2 ± 11 y vs 58.5 ± 10 y; 20.5 vs 6%; and 33.3 vs 16.8%, respectively; P < .05). SH and type 2 diabetes mellitus were associated with prevalent CVEs (odds ratio [OR], 3.1; 95% confidence interval [CI], 1.1-9.0; and OR, 2.0; 95% CI, 1.2-3.3, respectively), regardless of age. At the end of the follow-up, SH was diagnosed in 15 patients who were without SH at baseline. An adenoma size >2.4 cm was associated with the risk of developing SH (sensitivity, 73.3%; specificity, 60.5%; P = .014). Weight, glycemic, lipidic, and blood pressure control worsened in 26, 25, 13, and 34% of patients, respectively. A new CVE occurred in 22 patients. SH was associated with the worsening of at least two metabolic parameters (OR, 3.32; 95% CI, 1.6-6.9) and with incident CVEs (OR, 2.7; 95% CI, 1.0-7.1), regardless of age and follow-up. CONCLUSION SH is associated with the risk of incident CVEs. Besides the clinical follow-up, in patients with an AI >2.4 cm, a long-term biochemical follow-up is also required because of the risk of SH development.

Ageing, growth hormone and physical performance.

Human ageing is associated to a declining activity of the GH/IGF-I axis and to several changes in body composition, function and metabolism which show strict similarities with those of younger adults with pathological GH deficiency. The age-related changes of the GH/IGF-I axis activity are mainly dependent on age-related variations in the hypothalamic control of somatotroph function, which is also affected by changes in peripheral hormones and metabolic input. The term “somatopause” indicates the potential link between the age-related decline in GH and IGF-I levels and changes in body composition, structural functions and metabolism which characterise ageing. Physical exercise is an important environmental regulator of the GH/IGF-I axis activity. Increased physical fitness and regular training increase GH production in adults, while the GH response to aerobic or resistance exercise is reduced with age. In older subjects regular exercise has the potential to improve overall fitness and quality of life and is also associated to decreased morbidity and increased longevity. Similar effects are seen following GH therapy in adult deficiency. This assumption led to clinical trials focusing on rhGH and/or rhIGF-I as potential anabolic drug interventions in elderly subjects. To restore the activity of GH/IGF-I axis with anabolic, anti-ageing purposes, attention has been also paid to GH-releasing molecules such as GHRH, orally active synthetic GH-secretagogues (GHS) and, more recently, to the endogenous natural GHS, ghrelin, which exerts several important biological actions, including the regulation of metabolic balance and orexigenic effects. At present, however, there is no definite evidence that “frail” elderly subjects really benefit from restoring GH and IGF-I levels within the young adult range by treatment with rhGH, rhIGF-I, GHRH or GHS. In this article the alteration of the GH/IGF-I axis activity during ageing is revised taking into account the role of physical activity as a regulator of the axis function and considering the effects of the restoration of GH and IGF-I circulating levels on body composition and physical performance. 2003, Editrice Kurtis

Endocrine and Non-Endocrine Activities of Growth Hormone Secretagogues in Humans

Growth hormone (GH) secretagogues (GHS) are synthetic peptidyl and non-peptidyl molecules which possess strong, dose-dependent and reproducible GH releasing effects as well as significant prolactin (PRL) and adrenocorticotropic hormone (ACTH) releasing effects. The neuroendocrine activities of GHS are mediated by specific receptors mainly present at the pituitary and hypothalamic level but also elsewhere in the central nervous system. GHS release GH via actions at the pituitary and (mainly) the hypothalamic level, probably acting on GH releasing hormone (GHRH) secreting neurons and/or as functional somatostatin antagonists. GHS release more GH than GHRH and the coadministration of these peptides has a synergistic effect but these effects need the integrity of the hypothalamo-pituitary unit. The GH releasing effect of GHS is generally gender-independent and undergoes marked age-related variations reflecting age-related changes in the neural control of anterior pituitary function. The PRL releasing activity of GHS probably comes from direct pituitary action, which indeed is slight and independent of both age and gender. The acute stimulatory effect of GHS on ACTH/cortisol secretion is similar to that of corticotropin releasing hormone (CRH) and arginine vasopressin (AVP). In physiological conditions, the ACTH releasing activity of GHS is mediated by central mechanisms, at least partially, independent of both CRH and AVP but probably involving GABAergic mechanisms. The ACTH releasing activity of GHS is gender-independent and undergoes peculiar age-related variations showing a trend towards increase in ageing. GHS possess specific receptors also at the peripheral levels in endocrine and non-endocrine human tissues. Cardiac receptors are specific for peptidyl GHS and probably mediate GH-independent cardiotropic activities both in animals and in humans.

Evaluation of the autoimmune regulator (AIRE) gene mutations in a cohort of Italian patients with autoimmune‐polyendocrinopathy‐candidiasis‐ectodermal‐dystrophy (APECED) and in their relatives

Objective   Autoimmune‐polyendocrinopathy‐candidiasis‐ectodermal‐dystrophy (APECED) is a rare syndrome characterized by chronic candidiasis, chronic hypoparathyroidism and Addisons disease. APECED has been associated with mutations in autoimmune regulator (AIRE) gene. Our aim is to perform a genetic analysis of the AIRE gene in Italian APECED patients and in their relatives.

Neuroregulation of the Hypothalamus-Pituitary-Adrenal (HPA) Axis in Humans: Effects of GABA-, Mineralocorticoid-, and GH-Secretagogue-Receptor Modulation

The hypothalamus-pituitary-adrenal (HPA) axis exerts a variety of effects at both the central and peripheral level. Its activity is mainly regulated by CRH, AVP, and the glucocorticoid-mediated feedback action. Moreover, many neurotransmitters and neuropeptides influence HPA axis activity by acting at the hypothalamic and/or suprahypothalamic level. Among them, GABA and Growth Hormone Secretagogues (GHS)/GHS-receptor systems have been shown to exert a clear inhibitory and stimulatory effect, respectively, on corticotroph secretion. Alprazolam (ALP), a GABA-A receptor agonist, shows the most marked inhibitory effect on both spontaneous and stimulated HPA axis activity, in agreement with its peculiar efficacy in panic disorders and depression where an HPA axis hyperactivation is generally present. Ghrelin and synthetic GHS possess a marked ACTH/cortisol-releasing effect in humans and the ghrelin/GHS-R system is probably involved in the modulation of the HPA response to stress and nutritional/metabolic variations. The glucocorticoid-mediated negative feedback action is mediated by both glucocorticoid (GR) and mineralocorticoid (MR) receptors activation at the central level, mainly in the hippocampus. In agreement with animal studies, MRs seem to play a crucial role in the maintenance of the circadian ACTH and cortisol rhythm, through the modulation of CRH and AVP release. GABA agonists (mainly ALP), ghrelin, as well as MR agonists/antagonists, may represent good tools to explore the activity of the HPA axis in both physiological conditions and pathological states characterized by an impaired control of the corticotroph function.

Long-term morphological, hormonal, and clinical follow-up in a single unit on 118 patients with adrenal incidentalomas.

OBJECTIVE To evaluate long-term morphological, functional, and clinical outcome in adrenal incidentalomas. DESIGN AND METHODS A total of 118 patients (77 F and 47 M; age 62.3+/-1.0 years) with adrenal incidentalomas were evaluated at baseline and followed-up for median 3 years (range 1-10 years) by clinical, biochemical, hormonal, and morphological evaluation. Among them, six patients with diagnosis of subclinical Cushings syndrome (SCS) underwent surgery. RESULTS At entry, 86% (n=102) of tumors were nonfunctioning (NF) and 14% (n=16) showed SCS. Comparing NF with SCS patients, a significantly higher percentage of dyslipidemia was found in the group of SCS patients (50 vs 23%, P=0.033). During follow-up, adrenal function remained normal in all NF patients, none of them developed subclinical or overt endocrine disease. The cumulative risk of mass enlargement was globally low (25%), but progressive up to 8 years. SCS was confirmed in all patients, and none of them shifted to overt Cushings syndrome. The cumulative risk of developing metabolic-cardiovascular abnormalities was globally low (22%), but progressive up to 8 years and new diseases were recorded in the group of NF patients only (three patients with dyslipidemia, four with impaired fasting glucose/impaired glucose tolerance, and three with diabetes mellitus). SCS patients who underwent surgery did not show any significant clinical improvement. CONCLUSIONS The risk of mass enlargement, hormonal, and metabolic impairment over time is globally low. Conservative management seems to be appropriate, but further prospective studies are needed to establish the long-term outcome of such patients, especially for metabolic status, cardiovascular risk profile and their relationship with endocrine function.

Screening of Cushing's Syndrome in Outpatients with Type 2 Diabetes: Results of a Prospective Multicentric Study in Italy

CONTEXT Cushings syndrome may remain unrecognized among patients referred for metabolic syndrome; thus, a proactive screening has been suggested in certain patient populations with features of the disorder. However, conflicting data have been reported on the prevalence of Cushings syndrome in patients with type 2 diabetes. OBJECTIVE Our aim was to evaluate the prevalence of unsuspected Cushings syndrome among outpatients with type 2 diabetes. DESIGN AND SETTING This was a cross-sectional prospective study in 24 diabetes clinics across Italy. PATIENTS Between June 2006 and April 2008, 813 patients with known type 2 diabetes without clinically overt hypercortisolism were evaluated. Follow-up of the study was closed in September 2010. Patients were not selected for characteristics conferring a higher pretest probability of hypercortisolism. Patients underwent a first screening step with the 1-mg overnight dexamethasone suppression test. RESULTS Forty patients failed to suppress serum cortisol less than 5.0 μg/dl (138 nmol/liter) and underwent a standard 2-d, 2-mg dexamethasone suppression test, after which six patients (0.6% of the overall series) failed to suppress cortisol less than 1.8 μg/dl (50 nmol/liter), receiving a definitive diagnosis of Cushings syndrome that was adrenal dependent in five patients. Four patients were cured, being able to discontinue, or reduce, the glucose-lowering agents. CONCLUSIONS The present data do not support widespread screening of patients with type 2 diabetes for Cushings syndrome; however, the disorder is less rare than previously thought when considering epidemiology of type 2 diabetes. Our results support a case-finding approach in patients with uncontrolled diabetes and hypertension despite appropriate treatment.

Metabolic and cardiovascular profile in patients with Addison’s disease under conventional glucocorticoid replacement

Objective: Although two studies have shown that Addison’s disease (AD) is still a potentially lethal condition for cardiovascular, malignant, and infectious diseases, a recent retrospective study showed a normal overall mortality rate. Differently from secondary hypoadrenalism, scanty data exist on the role of conventional glucocorticoid replacement on metabolic and cardiovascular outcome in AD. Subjects and methods: In 38 AD under conventional glucocorticoid replacement (hydrocortisone 30 mg/day or cortisone 37.5 mg/day) ACTH, plasma renin activity (PRA), DHEAS, fasting glucose and insulin, 2-h glucose after oral glucose tolerance test, serum lipids, 24-h blood pressure and intima-media thickness (IMT) were evaluated and compared with 38 age-, sex- and body mass index (BMI)-matched controls (CS). Results: AD had ACTH and PRA higher and DHEAS lower (p<0.0005) than CS. Mean waist was higher (p<0.05) in AD than in CS. Although no differences were found for mean gluco-lipids levels, a higher percentage of AD compared to CS were IGT (8 vs 0%), hypercholesterolemic (18 vs 8%), and hypertriglyceridemic (18 vs 8%); none of the AD and CS showed either HDL<40 mg/dl or LDL>190 mg/dl. At the multiple regression analysis, in both AD and CS, BMI was the best predictor of 2-h glucose and age of total and LDL cholesterol; in AD, no significant correlation was found between the above mentioned metabolic parameters and either hormone levels or disease duration. In both AD and CS 24-h blood pressure and IMT were normal. Conclusions: Our study shows a higher prevalence of central adiposity, impaired glucose tolerance and dyslipidemia in AD patients.