Ettore Ciro degli Uberti

Evaluation of Hormonal Function in a Series of Incidentally Discovered Adrenal Masses

The discovery of an asymptomatic adrenal mass (incidentaloma) during the investigation of an unrelated condition is relatively common. In this study, we report the clinical, radiologic, and endocrine evaluation of 38 patients (22 women and 16 men aged 24 to 84 years) with adrenal incidentaloma (size, 1 to 12 cm). The patients underwent basal and dynamic evaluation of the hypothalamic-pituitary-adrenal (HPA) axis, renin-angiotensin-aldosterone system, and adrenomedullary function. Moreover, computed tomograpy (CT) scan and 131I-6beta-iodomethyl-19-norcholest-5(10)-en-3beta-ol(NP-59) and/or 131I-metaiodobenzylguanidine (MIBG) scintigraphy were performed. The endocrine evaluation indicated two cases of pheochromocytoma and four cases of preclinical Cushings syndrome, three of which underwent surgery with histologic diagnosis of two adrenocortical adenomas and one carcinoma. Low levels of serum dehydroepiandrosterone sulfate (DHEA-S), associated with a markedly increased 17-hydroxyprogesterone (17-OHP) response to a corticotropin (ACTH) test, were found in patients with incidentaloma. On the basis of endocrine and morphologic data, 13 patients underwent surgical treatment: five adrenocortical adenomas (two functioning), two pheochromocytomas, two ganglioneuromas, one cortisol-secreting adrenal carcinoma, one lymphangiomatous cyst, one myelolipoma, and one hemorrhage were found. Careful diagnostic assessment of incidentally discovered adrenal masses must be performed to exclude the presence of malignant and/or functioning lesions and to verify the possibility that patients with incidentaloma have a genetic or acquired deficit of adrenal steroidogenic activity.

BRAF mutation positive papillary thyroid carcinoma is less advanced when Hashimoto's thyroiditis lymphocytic infiltration is present

Concomitant papillary thyroid cancer (PTC) and Hashimotos thyroiditis (HT) is a frequent occurrence. Whether these two conditions are linked and whether PTC with concurrent HT has distinct clinicopathological characteristics are still debated issues. Lymphocytic infiltration is abundant in HT and might be relevant in the pathogenesis and progression of PTC. BRAFV600E mutation is associated with a more advanced PTC at diagnosis; however, its role in the clinicopathological characteristics of PTC with concurrent HT is unknown.

Magmas, a gene newly identified as overexpressed in human and mouse ACTH-secreting pituitary adenomas, protects pituitary cells from apoptotic stimuli.

Pituitary tumors are mostly benign, being locally invasive in 5-35% of cases. Deregulation of several genes has been suggested as a possible alteration underlying the development and progression of pituitary tumors. We here report the identification of a cDNA, corresponding to Magmas gene (mitochondria-associated protein involved in granulocyte-macrophage colony-stimulating factor signal transduction), which is highly expressed in two different ACTH-secreting mouse pituitary adenoma cell lines as compared with normal pituitary as well as in two thirds of 64 examined pituitary adenomas as compared with human normal pituitary. Tim 16, the mitochondrial protein encoded by Magmas, was indeed expressed in a mouse ACTH-secreting pituitary adenoma cell line, AtT-20 D16v-F2 cells, in a subcellular compartment likely corresponding to mitochondria. Magmas silencing determined a reduced rate of DNA synthesis, an accumulation in G1 phase, and a concomitant decrease in S phase in At-T20 D16v-F2 cells. Moreover, Magmas-silenced cells displayed basal caspase 3/7 activity and DNA fragmentation levels similar to control cells, which both increased under proapoptotic stimuli. Our data demonstrate that Magmas is overexpressed in mouse and human ACTH-secreting pituitary adenomas. Moreover, our results show that Magmas protects pituitary cells from apoptosis, suggesting its possible involvement in neoplastic transformation.

Stimulatory Effect of Dermorphin, a New Synthetic Potent Opiate-Like Peptide, on Human Growth Hormone Secretion

Two new related heptapeptides (dermorphins) with potent central and peripheral opiate-like activity have been isolated from the skin of South American frogs, and have been chemically characterized as H-Tyr-D-Ala-Phe-Gly-Tyr-Pro-Ser-NH2 (dermorphin) and H-Tyr-D-Ala-Phe-Gly-Tyr-Hyp-Ser-NH2 (Hyp6-dermorphin). The response of GH to infusion of a synthetic dermorphin (5.5 micrograms/kg/min for 30 min) was studied in 9 healthy men. Dermorphin (D) significantly increased plasma growth hormone (GH) concentrations. The GH response to D was blunted by prior administration of naloxone, suggesting that D interacts with mu-type opiate receptors. However, the evaluation of the physiological significance of D-induced GH release in humans requires further study.

Effect of deltorphin on behavior and hippocampal electrical activity in rabbits

To clarify the role of delta-opioid receptors on modulation of hippocampal electrical activity and behavior, deltorphin (DT), a naturally occurring heptapeptide that selectively binds to delta-opioid receptors, was intravenously (IV) administered to rabbits. For this purpose, at 8-day intervals, the effects of IV administration of normal saline and IV infusion of synthetic DT (1 mg/kg b.wt. for 2 min) on the spontaneous behavior in neutral environment, both in absence of any external stimulus and after the introduction of a stuffed predator, were examined in seven adult male rabbits, on separate and successive occasions. During each session of experimental procedure, hippocampal EEG was also recorded by telemetry. Behavioral activity showed an increase in alert and reactive immobility after the peptide injection in comparison with that observed during control period (saline administration). Under DT treatment the frequency of hippocampal electrical activity decreased, and a reduction in rhythmicity of electrical pattern was also observed in presence of stressful stimulus. These findings show that DT may affect neural and behavioral elements related to the control of attentional and emotional processes, suggesting a modulating role of delta-opioid receptors.

Interrelationships between calcitonin gene-related peptide and sympathoadrenomedullary system: Effects of administration of epinephrine and norepinephrine in healthy man

To investigate the influence of the sympathoadrenomedullary system on the modulation of the circulating levels of calcitonin gene-related peptide (CGRP), the effects of epinephrine (E) and norepinephrine (NE) were studied in 8 normal subjects (4 females and 4 males). The mean basal levels of CGRP in normal subjects were 10.2 +/- 1 pmol/l. After the infusion of E (20 ng/kg per min for 30 min), a significant rise (P < 0.005) in plasma CGRP levels was observed with the expected increases in systolic blood pressure (BP), heart rate (HR) and plasma renin activity (PRA), and decrease in diastolic BP, whereas plasma aldosterone (PA) levels did not significantly change. The infusion of NE (40 ng/kg per min for 30 min) induced an increase in systolic and diastolic BPs, whereas it failed to modify CGRP, HR, PA and PRA. Our data demonstrate that the sympathoadrenomedullary system may modulate CGRP release in man perhaps via the beta-adrenergic pathway. It is likely that the modifications of plasma CGRP levels may be part of the acute vasal response to E.

∂-Opioid receptors and the secretion of growth hormone in man : effect of opioid ∂-receptor agonist deltorphin on GH responses to GH-releasing hormone and insulin-induced hypoglycemia

To investigate the role of ∂-opioid receptors in the modulation of growth hormone (GH) secretion, we compared in normal subjects the effect of the highly selective ∂-opioid receptor agonist Deltorphin (DT) on the GH secretion responses to pituitary (GH-releasing hormone, GHRH)- and hypothalamic (insulin-induced hypoglycemia, ΠH)-mediated stimuli. DT blunted the GH response to IIH, whereas it had no effect on the GH response to GHRH. It is concluded that in man DT-induced activation of ∂-opioid receptors exerts an inhibitory action on hypoglycemia-stimulated GH secretion. Based on the lack of an effect of DT on the GH response to GHRH, we suggest that DT may modulate the secretion of GH through suprapituitary mechanisms.

Differential effects of deltorphin on arginine and galanin-induced growth hormone secretion in healthy man.

Recently we demonstrated the inhibitory action on Growth Hormone (GH) secretion of an opioid heptapeptide, deltorphin (DT), that is highly selective in binding delta-opioid receptors. To investigate the possible mechanism leading to the decrease in GH secretion by specific activation of delta-opioidergic pathway in man, we compared, in normal subjects, the effect of DT on GH secretion responses to two different GH secretagogues, namely arginine (ARG) and galanin (GAL). DT completely blunted the GH response to ARG, whereas it attenuated the GH response to GAL, but not at a statistically significant level. We suggest that the specific activation of delta-opioid receptors in man may exert an inhibitory influence on GH secretion principally by modulating endogenous hypothalamic somatostatin (SRIH) release.

Ipopituitarismo e trauma cranico

RiassuntoIl trauma cranico o cranio-encefalico (TCE) è stato finora indicato come una delle cause più frequenti di diabete insipido, attribuendosi invece uno scarso rilievo patogenetico al TCE nel determinismo dell’insufficienza dell’ipofisi anteriore, se non in rari casi di trauma particolarmente grave. La ricerca accurata di alterazioni della secrezione degli ormoni ipofisari in pazienti dimessi da strutture di neurochirurgia ha dimostrato non solo una elevata frequenza (28–69%) di deficit funzionali anteroipofisari (isolati o variamente combinati), ma anche una prevalenza di diabete insipido meno rilevante di quanto ritenuto in passato. D’altro canto, le numerose segnalazioni di casi di ipopituitarismo, altrimenti definibile come idiopatico, ma correlato a pregresso TCE, confermano la necessità di un’accurata inchiesta anamnestica in tutti i pazienti con storia di TCE di qualsiasi entità esso sia e che presentino segni aspecifici o biochimici di ipopituitarismo. È auspicabile inoltre l’introduzione sempre più ampia di protocolli per la valutazione precoce della funzione ipofisaria e programmi di follow-up a lungo termine per tutti i pazienti con TCE, per identificare ed eventualmente trattare i difetti di funzione ipofisaria al fine di migliorare la prognosi e la qualità di vita di tali pazienti.