M. Balbo

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.

Hypothalamus–pituitary–adrenal axis evaluation in patients with hypothalamo–pituitary disorders: comparison of different provocative tests

Background  The insulin tolerance test (ITT) is the gold standard test to evaluate hypothalamic–pituitary–adrenal (HPA) axis in suspected ACTH insufficiency. When contraindicated, alternative tests have been proposed such as metyrapone and ACTH stimulation test. 250 µg ACTH is a supramaximal dose and unreliable in this setting. The diagnostic reliability of 1·0 µg ACTH test is controversial and very low doses have been proposed.

Ghrelin does not mediate the somatotroph and corticotroph responses to the stimulatory effect of glucagon or insulin-induced hypoglycaemia in humans

objective  Acylated ghrelin, a gastric peptide, possesses a potent GH‐ but also significant ACTH/cortisol‐releasing activity mediated by the activation of GH secretagogue receptors (GHS‐R) at the hypothalamus–pituitary level. The physiological role of ghrelin in the control of somatotroph and corticotroph function is, however, largely unclear. Glucagon is known to induce a clear increase of GH, ACTH and cortisol levels in humans, at least after intramuscular administration. In fact, glucagon is considered to be a classical alternative to insulin‐induced hypoglycaemia (ITT) for the combined evaluation of the function of GH and the hypothalamus–pituitary–adrenal (HPA) axis. We aimed to clarify whether ghrelin mediate the GH and corticotroph responses to intramuscular glucagon or ITT, which has recently been reported able to induce a surprising ghrelin decrease.

A study of central serotoninergic activity in healthy subjects and patients with Type 2 diabetes treated by traditional one-to-one care or Group Care

Aim: Central serotoninergic activity may modulate glucose metabolism via neuroendocrine effectors. Group Care is a clinico-pedagogic intervention that improves metabolic control and quality of life in Type 2 diabetes through lifestyle modification and, possibly, central mechanisms. The hypothesis that central serotoninergic activity is modified in patients followed by Group Care was tested by measuring their hypothalamic-pituitary-adrenal response to citalopram, a selective serotonin reuptake inhibitor. Methods and subjects: Ten healthy controls and 17 non-obese, non-insulin-treated patients with Type 2 diabetes received, in random order, iv infusions of either 20 mg citalopram or saline. Nine patients had been long-term on Group Care and 8 had always been on traditional one-to-one care. Circulating glucose, insulin, ACTH, cortisol, DHEA, GH and PRL were measured every 15 min for 240 min. Differences between areas under the curves after citalopram and saline (Δ-AUC) were calculated. Results: Citalopram stimulated ACTH and cortisol secretion in healthy subjects (p=0.026 and p=0.011, respectively) and patients on Group Care (p=0.056 and p=0.038) but not in patients on traditional care. In healthy subjects, basal glucose correlated with growth hormone Δ- AUC (r=0.820; p=0.004) and inversely with insulin Δ-AUC (r=−0.822; p=0.003). The former correlation was preserved in the patients (r=0.637; p=0.026). Conclusions: Diabetes may blunt the response of the hypothalamic-pituitary-adrenal axis to citalopram, but this is preserved in patients followed by a long-term intervention model that improves clinical as well as cognitive and emotional variables.

Neuroendocrine effects of Citalopram, a selective serotonin re-uptake inhibitor, during lifespan in humans

Objective: Serotonergic system contributes to the regulation of hypothalamus-pituitary-adrenal axis. In humans, serotonergic agonists increase PRL, ACTH, and cortisol, while serotonin (5HT) influence on GH is controversial. Central 5HT activity and neuroendocrine function change during lifespan. Design: To clarify the neuroendocrine response to 5HT across lifespan, we assessed ACTH, cortisol, DHEA, PRL, and GH responses to citalopram (CT) in young adults (YA) (no.=12, 29.2±1.7 yr mean±SEM), middle aged (MA) (no.=12, 54.3±0.9 yr), and elderly (ES) (no.=12, 69.3±0.9 yr) males. All the subjects received placebo (saline iv over 120 min) or CT (20 mg iv over 120 min). Blood samples were taken every 15 min up to 240 min. Results: During placebo, ACTH, cortisol, GH, and PRL were similar in all groups while DHEA showed an age-dependent reduction from middle age (p<0.001). During CT, ACTH, and cortisol were higher than during placebo in YA (p<0.05) and even more in MA (p<0.01 vs placebo, p<0.05 vs YA); in ES, the increase of both ACTH and cortisol (p<0.05 vs placebo) was lower than in MA (p<0.05) and higher than in YA (p<0.05 for cortisol only). No changes were observed for DHEA, GH, and PRL in any group. Conclusions: Corticotrope response to CT is age-dependent in normal men, being amplified starting from middle age, suggesting precocious changes in the serotonergic neuroendocrine control during lifespan. CT is a useful tool to evaluate the age-dependent serotonergic function in humans.