Micaela Pellegrino

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

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.

Alprazolam (a benzodiazepine activating GABA receptor) reduces the neuroendocrine responses to insulin‐induced hypoglycaemia in humans

objective Alprazolam (ALP), a benzodiazepine‐activating GABAergic receptor, possesses clear centrally mediated inhibitory effects on ACTH and cortisol secretion that could reflect an inhibitory influence on CRH‐ and/or AVP‐secreting neurones. An inhibitory effect of ALP on catecholamine release has also been shown while its effect on GH secretion is unclear. To further clarify the neuroendocrine actions of ALP, we studied the ALP effects on the neurohormonal responses to hypoglycaemia in a group of normal subjects.

Silent renal stones in primary hyperparathyroidism: prevalence and clinical features.

OBJECTIVE (1) To evaluate the prevalence of silent nephrolithiasis in patients with primary hyperparathyroidism (PHPT) compared with controls, and (2) To characterize clinically PHPT patients with silent renal stones. METHODS We reviewed clinical data for 141 patients with PHPT and without symptoms or history of nephrolithiasis in whom renal ultrasonography was performed at diagnosis. A total of 141 sex- and age- matched subjects with abdomen ultrasonography obtained for reasons different from urinary symptoms served as controls. RESULTS Silent nephrolithiasis was more prevalent in PHPT patients than in controls (11.35% vs. 2.13%; P = .003). Among patients with PHPT, those with silent renal stones showed higher serum calcium and parathyroid hormone levels and met surgical criteria, regardless of nephrolithiasis, more frequently than those without renal stones. CONCLUSION The prevalence of silent nephrolithiasis is increased in patients with PHPT as compared with controls. Moreover, it seems likely that silent renal stone disease could identify a subset of PHPT patients with more severe disease. Accordingly, we suggest ultrasonographic screening of nephrolithiasis in all PHPT patients. Further studies are needed to better characterize this clinical entity.

Vitamin D status in primary hyperparathyroidism: a Southern European perspective

Vitamin D deficiency (VDD) is common in patients with primary hyperparathyroidism (pHPT), and this could affect the clinical expression of the disease. However, few North American or North European studies have addressed this issue, showing vitamin D repletion in only about one‐third of the patients.

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/m2; 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.

Neuroblastoma in the Elderly and SIADH: Case Report and Review of the Literature

Objective. To report the rare case of a thymic neuroblastoma, in an elderly woman with SIADH at presentation. Methods. Clinical and biochemical data of the patient are presented and the pertinent literature is reviewed. Results. a 79-year-old woman was admitted into our department with worsening asthenia, severe hyponatremia (114.8 mEq/L), low plasma osmolarity (253 mEq/L), and inappropriate urinary sodium concentration (151 mEq/L). CT scan showed an a large solid inhomogeneous mass in the anterior mediastinum. 18F-FDG-PET/CT showed uptake in the mass. On continuous 3% hypertonic saline infusion, sodium gradually increased without achieving normal values. The patient underwent surgery, followed by full normalization of sodium levels. Tumor cells were positive for neuroendocrine markers. Thymic neuroblastoma with SIADH was diagnosed. Conclusions. Neuroblastoma is an extremely rare tumor in the elderly. Contrary to children and younger adults, neuroblastoma in older adults is typically localized in the anterior mediastinum and is often associated with SIADH. Moreover, it has mainly local aggressiveness in this age group, without metastatic spread; thus radical surgery achieves cure in most cases.

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

BackgroundMild 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 patientsWe 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.ResultsSeventy-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.ConclusionsMild PHPT strictly defined according to the last consensus represents a small subgroup with a less active form of the disease.

Primary hyperaldosteronism is associated with derangement in the regulation of the hypothalamus-pituitary-adrenal axis in humans

Hippocampal mineralocorticoid receptors (MR) play a major role in the control of hypothalamus-pituitary-adrenal (HPA) axis. The functional profile of HPA axis and the impact of MR blockade under chronic exposure to mineralocorticoid excess are unknown. To clarify this issue, ACTH, cortisol, and aldosterone secretions were studied in 6 patients with primary hyperaldosteronism (HA) and 8 controls (IMS) during placebo, placebo+human CRH (hCRH) (2 μg/kg iv bolus at 22:00 h), potassium canrenoate (CAN, 200 mg iv bolus at 20:00 h followed by 200 mg infused over 4 h) or CAN+hCRH. During placebo, both aldosterone and ACTH levels were higher (p<0.01) in HA than in NS, while cortisol levels were not significantly different. Both HA and NS showed significant ACTH and cortisol responses to hCRH (p<0.004), although the hormonal responses in HA were higher (p<0.02) than in NS. CAN infusion did not modify aldosterone levels in both HA and NS. Under CAN infusion, ACTH showed progressive rise in NS (p<0.05) but not in HA, while cortisol levels showed a significant (p<0.05) but less marked and delayed increase in HA compared to NS. CAN enhanced hCRH-induced ACTH and cortisol responses in NS (p<0.05), but not in HA. In conclusion, in humans primary hyperaldosteronism is associated with deranged function of the HPA axis. In fact, hyperaldosteronemic patients show basal and hCRH-stimulated HPA hyperactivity that is, at least partially, refractory to further stimulation by mineralocorticoid blockade with canrenoate. Whether this hormonal alteration can influence the clinical feature of hypertensive patients with primary hyperaldosteronism needs to be clarified.

KDIGO CATEGORIES OF GLOMERULAR FILTRATION RATE AND PARATHYROID HORMONE SECRETION IN PRIMARY HYPERPARATHYROIDISM

OBJECTIVE The recent Fourth Workshop on the Management of Asymptomatic primary hyperparathyroidism (PHPT) maintained the threshold of 60 mL/min for decreased renal function, below which surgery is recommended. This study investigated the relationship between different stages of renal insufficiency and parathyroid hormone (PTH) levels in an updated case series of PHPT patients. METHODS This was a retrospective, cross-sectional study involving 379 consecutive PHPT patients. Biochemical evaluation included total and ionized serum calcium, phosphate, creatinine, immunoreactive intact PTH, and 25-hydroxyvitamin D3 (25[OH]D3) levels in the fasting state. Glomerular filtration rate (GFR) was estimated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation. RESULTS Mean CKD-EPI estimated GFR was 81.9 ± 20.3 mL/min/1.73 m(2), and median GFR was 84.0 mL/min/1.73 m(2) (interquartile range, 26.8 mL/min/1.73 m(2)). The patients were divided into 5 groups according to the Kidney Disease: Improving Global Outcomes 2012 guidelines: group 1 with normal or increased GFR (>90 mL/min/1.73 m(2)); group 2 with mild GFR decrease (60 to 89 mL/min/1.73 m(2)); group 3a with mild to moderate GFR decrease (45 to 59 mL/min/1.73 m(2)); group 3b with moderate to severe GFR decrease (30 to 44 mL/min/1.73 m(2)); and group 4 with severe GFR decrease (<30 mL/min/1.73 m(2)). Among the 5 groups of patients, serum calcium levels were different (P = .025), whereas 25(OH)D3 levels were not (P = .36). PTH levels were comparable across groups 1 through 3a, but they were significantly higher in groups 3b and 4 (P<.0001). CONCLUSION In our series of PHPT patients, PTH levels did not rise as a result of renal impairment until GFR decreased below 45 mL/min/1.73 m(2).