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Emanuela Arvat

Publications and source records attributed to Emanuela Arvat.

At least 19 recordsLinked to original sources
PubMed2006

Neuroendocrine effects of citalopram infusion in anorexia nervosa.

Because of the role of serotonin (5HT) in regulating food intake and mood, several studies have focused their attention on the assessment of serotonergic activity in eating disorders, and in particular in anorexia nervosa, but the results have been inconsistent. Citalopram, a highly selective 5HT reuptake inhibitor, has been recently reported as a neuroendocrine probe to assess the serotonergic function in physiological and pathological conditions. We evaluated the adrenocorticotropic hormone (ACTH), cortisol, prolactin (PRL) and growth hormone (GH) secretion during placebo or citalopram IV infusion (20 mg over 120 min), in six women with anorexia nervosa restricter type, and in six healthy women, in order to test the hypothesis that this neurotransmitter system is abnormal in this group of patients. ACTH and PRL secretion was higher during citalopram infusion compared to placebo (p<0.05) in both groups, while cortisol secretion was higher during citalopram infusion only in healthy controls (p<0.05), but not in anorexic patients. GH levels were unaffected by citalopram in both groups. These results demonstrate that serotonergic activation by citalopram affects corticotroph and lactotroph but not somatotroph secretion in anorexic as well as in normal subjects. Our preliminary findings do not support the existence of remarkable alterations in the serotonergic control of anterior pituitary function in anorexia nervosa, while there seems to be an impairment of the adrenal function in this group of patients.

Adrenocorticotropic Hormone↗
PubMed2006

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.

Feedback↗
PubMed2006

Dehydroepiandrosterone sulfate (DHEA-S) and Alzheimer's dementia in older subjects.

OBJECTIVES AND METHODS: We investigated the association of serum dehydroepiandrosterone sulfate (DHEA-S) levels with dementia of Alzheimer's type (DAT) and impairment in selected cognitive domains (memory, language, attention and working memory) in 158 patients (75.5+/-6.7 years, 46 men) with first-diagnosed probable DAT and in 158 age- and sex-matched controls. As secondary goal, we evaluated whether DHEA-S baseline levels were associated with cumulative 6-year mortality. RESULTS: A negative correlation between DHEA-S levels and age was observed (R=-0.25, p<0.001). Age-stratified analysis did not show significant differences of DHEA-S levels between DAT patients and controls. No significant association was found between DHEA-S levels and impairment in selected cognitive domains. Cox regression analysis showed that baseline DHEA-S levels were not associated with cumulative 6-year mortality. CONCLUSIONS: In a sample of newly-diagnosed DAT patients, we did not find significant association between presence of DAT or impairment in cognitive domains and DHEA-S levels; baseline DHEA-S levels are not associated with cumulative mortality in patients and controls.

Age Factors↗
PubMed2006

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

OBJECTIVE: Cushing's 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 (PPARgamma) 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. DESIGN: Ten patients with Cushing's disease were treated with 4-16 mg rosiglitazone p.o. daily for 1-8 months (median 3 months) and plasma ACTH and cortisol, urinary free cortisol (UFC), as well as parameters of insulin sensitivity, were recorded. An acute challenge with 8 mg rosiglitazone for 2 days preceded long-term rosiglitazone administration. RESULTS: The acute challenge with rosiglitazone did not significantly modify plasma ACTH and cortisol levels. During protracted treatment with rosiglitazone, four patients showed a persistent reduction in UFC levels (up to 24% of pretreatment values), achieving normalization in three. In the others, UFC as well as plasma ACTH and cortisol decrements were inscribed within wide, random oscillations indicating that disease activity was substantially unchanged. Insulin sensitivity was ameliorated in most patients, without relation to ACTH or cortisol secretion. Untoward effects, such as weight gain, oedema and worsening of ecchymoses, were reported in several patients. CONCLUSIONS: Although effective in a subset of patients, protracted rosiglitazone administration did not consistently restrain ACTH and cortisol secretion in patients with Cushing's disease. Further investigations are needed to fully define the therapeutic potential of PPARgamma agonists in this disorder.

Adrenocorticotropic Hormone↗
PubMed2006

Endocrine function is altered in chronic migraine patients with medication-overuse.

OBJECTIVE: To evaluate the effects of analgesic overuse on endocrine function in patients with chronic migraine and medication-overuse headache (CM-MOH). BACKGROUND: Chronic migraine is frequently associated with an overuse of symptomatic medications. Drugs currently used in acute migraine attacks are associated with several endocrine effects. At present, the endocrine effects of medication overuse in chronic migraine patients are unknown. METHODS: Eighteen patients with CM-MOH, diagnosed according to the ICHD-II criteria, and 18 healthy controls received an intravenous administration of GHRH, hCRH, and TRH. Plasma concentrations of GH, TSH, ACTH, and cortisol were measured for a 90-minute period after administration of the specific releasing hormones. RESULTS: Hormonal basal concentrations were similar in both groups. GH response to GHRH was significantly reduced in patients with CM-MOH in comparison with controls. TRH induced a reduction of TSH concentrations only at the end of the test. After hCRH administration, ACTH and cortisol concentrations were significantly higher in cases than in controls. A significant correlation between duration of the disease and altered hormonal response was found. CONCLUSIONS: Our study shows that both corticotropic and somatotropic functions are significantly impaired in CM-MOH patients and suggests a role for hormones in the development of chronic migraine.

Adrenocorticotropic Hormone↗
PubMed2006

Effects of free fatty acids on ACTH and cortisol secretion in anorexia nervosa.

OBJECTIVE: Free fatty acids (FFAs) exert a stimulatory effect on the hypothalamic-pituitary-adrenal (HPA) axis in animals and inhibit spontaneous ACTH and cortisol secretion in humans. Patients with anorexia nervosa display concomitant HPA axis hyperactivity and increased lipolysis. We studied the effects of a lipid load on ACTH and cortisol secretion in patients with anorexia nervosa in comparison with normal subjects. DESIGN: Eight women with anorexia nervosa (ANW; means +/- s.e.m.: 23.9 +/- 2.3 years of age; body mass index (BMI): 14.9 +/- 0.6 kg/m2) and seven normal women (NW; 25.6 +/- 2.3 years of age; BMI: 22.8 +/- 1.9 kg/m2) had FFA, ACTH, cortisol, glucose and insulin levels measured in the morning every 30 min for 180 min during i.v. saline or lipid-heparin emulsion (LHE) infusion. RESULTS: During saline infusion, ACTH and cortisol levels decreased spontaneously in both groups, ACTH and cortisol levels in ANW being higher than in NW. LHE infusion led to increased FFA levels in both groups (P < 0.005). The ACTH and cortisol decrease in NW was more marked than during saline infusion (P < 0.05). LHE infusion in ANW was associated with a more pronounced decrease in ACTH levels than during saline infusion (P < 0.05), while cortisol levels were unchanged. At the end of the LHE infusion, a progressive decrease in FFA levels was associated with an increase in ACTH and cortisol concentrations in NW (P < 0.05) but not in ANW in whom FFA levels decreased to a lesser extent (P < 0.05). CONCLUSIONS: This study showed that corticotroph sensitivity to the inhibitory effect of an FFA load is preserved in patients with anorexia nervosa, in spite of persistent adrenal hyperactivity.

Adrenocortical Hyperfunction↗
PubMed2006

Corticotrope hypersecretion coupled with cortisol hypo-responsiveness to stimuli is present in patients with autoimmune endocrine diseases: evidence for subclinical primary hypoadrenalism?

OBJECTIVE: In autoimmune polyglandular syndrome types 1, 2, and 4 primary adrenal insufficiency is present, but its diagnosis is often late. We investigated the function of the hypothalamic-pituitary-adrenal axis in a group of patients with autoimmune diseases (AP) without any symptoms and signs of hypoadrenalism. DESIGN: In 10 AP and 12 normal subjects (NS), we studied cortisol (F), aldosterone (A), and DHEA responses to 0.06 microg adrenocorticotropin (ACTH) (1-24) followed by 250 microg, ACTH and F responses to human corticotropin-releasing hormone (hCRH; 100 microg) and insulin tolerance test (ITT) (0.1 UI/kg). RESULTS: Basal F, A, DHEA, as well as urinary free cortisol and plasma renin activity levels in AP and NS were similar, whereas ACTH levels in AP were higher (P<0.05) than in NS. NS showed F, A, and DHEA response to both consecutive ACTH doses. In AP, the F, A, and DHEA responses to 250 microg ACTH were similar to those in NS, whereas the 0.06 microg ACTH dose did not elicit any significant response. The ACTH responses to hCRH and ITT in AP were higher (P<0.05) than in NS. The F response to hCRH in AP was lower (P<0.05) than in NS, whereas the F response to ITT in AP did not significantly differ from NS. CONCLUSIONS: Enhancement of both basal and stimulated corticotrope secretion coupled with reduced adrenal sensitivity to low ACTH dose is present in AP patients without symptoms and signs of hypoadrenalism. This functional picture suggests that normal adrenal secretion is maintained due to corticotrope hyperfunction, suggesting the existence of some subclinical primary hypoadrenalism.

Adrenal Insufficiency↗
PubMed2005

Hypothalamus-pituitary-adrenal hyperactivity in human aging is partially refractory to stimulation by mineralocorticoid receptor blockade.

CONTEXT: The hypothalamus-pituitary-adrenal (HPA) axis is mainly regulated by CRH, arginine vasopressin, and glucocorticoid feedback. Hippocampal mineralocorticoid receptors mediate proactive glucocorticoid feedback and mineralocorticoid antagonists, accordingly, stimulate HPA axis. Age-related HPA hyperactivity reflects impaired glucocorticoid feedback at the suprapituitary level. DESIGN: ACTH, cortisol, and dehydroepiandrosterone (DHEA) secretion were studied in eight healthy elderly (75.1 +/- 3.2 yr) and eight young (25.0 +/- 4.6 yr) subjects during placebo or canrenoate (CAN) administration (200 mg i.v. bolus followed by 200 mg infused over 4 h). RESULTS: During placebo administration, ACTH and cortisol areas under the curve (AUCs) in elderly subjects were higher than in young subjects (P < or = 0.01); conversely, DHEA AUCs in elderly subjects were lower than in young subjects (P = 0.002). CAN increased ACTH, cortisol, and DHEA levels in both groups. In young subjects, ACTH, cortisol, and DHEA levels at the end of CAN infusion were higher (P < or = 0.05) than after placebo. In elderly subjects, at the end of CAN infusion, ACTH, cortisol, and DHEA levels were higher (P = 0.01) than after placebo. Under CAN, ACTH and cortisol AUCs were persistently higher (P < or = 0.01) and DHEA AUCs lower (P = 0.006) in elderly than in young subjects. Cortisol AUCs after CAN in young subjects did not become significantly different from those in elderly subjects after placebo. CONCLUSIONS: 1) Evening-time ACTH and cortisol secretion in elderly subjects is higher than in young subjects; 2) ACTH and cortisol secretion in elderly subjects is enhanced by CAN but less than that in young subjects; and 3) DHEA hyposecretion in elderly subjects is partially restored by mineralocorticoid antagonism. Age-related variations of HPA activity may be determined by some derangement in mineralocorticoid receptors function at the hippocampal level.

Adrenocorticotropic Hormone↗
PubMed2005

The negative association between total ghrelin levels, body mass and insulin secretion is lost in hypercortisolemic patients with Cushing's disease.

OBJECTIVE: Ghrelin exerts a wide spectrum of endocrine and non-endocrine actions. The stomach is the major source of circulating ghrelin levels that are negatively associated with body mass, insulin and glucose levels. The role of glucocorticoids in ghrelin secretion and action is still unclear. DESIGN: In 8 patients with Cushing's disease (CD, BMI 29.8 +/- 1.6 kg/m(2)), 7 normal (NS) and 6 obese subjects (OB, BMI 32.9 +/- 1.1 kg/m(2)) we studied: a) total ghrelin levels (every 15 min over 3 h) and their correlation with BMI, insulin, glucose, homeostatic model assessment (HOMA) index, ACTH and cortisol levels; b) GH, ACTH, cortisol, insulin and glucose responses to acylated ghrelin administration (1.0 mug/kg i.v. at 0 min). RESULTS: CD patients had BMI, insulin and glucose levels as well as HOMA index higher than those in NS (P < 0.05) but similar to those in OB. Despite this, total ghrelin levels in CD were similar to those in NS and both were higher (P < 0.05) than those in OB. No correlation was found among total ghrelin and BMI, insulin, glucose, ACTH and cortisol levels in CD patients. The GH responses to ghrelin in CD and OB were similar and both were lower (P < 0.002) than those in NS. In CD ghrelin induced exaggerated ACTH and cortisol responses clearly higher (P < 0.005) than in OB and NS. Ghrelin administration increased glucose in all groups; insulin levels showed slight decrease that was significant (P < 0.05) in OB only. CONCLUSIONS: Hypercortisolism in humans is associated with impaired ghrelin secretion and action. In fact, total ghrelin secretion in CD is not reduced despite increased BMI, insulin and glucose levels, while the GH and ACTH responses to acylated ghrelin are clearly reduced and enhanced, respectively.

Acylation↗
PubMed2004

Ghrelin, hypothalamus-pituitary-adrenal (HPA) axis and Cushing's syndrome.

Ghrelin, a peptide predominantly produced by the stomach, has been discovered as a natural ligand of the GH Secretagogue receptor type 1a (GHS-R1a), known as specific for synthetic GHS. Ghrelin has recently attracted considerable interest as a new orexigenic factor. However, ghrelin exerts pleiotropic actions that are explained by the widespread distribution of ghrelin and GHS-R expression. Besides strong stimulation of GH secretion, the neuroendocrine ghrelin actions also include significant stimulation of both lactotroph and corticotroph secretion; all these actions depend on acylation of ghrelin in serine-3 that allows binding and activation of the GHS-R1a. However, GHS-R subtypes are likely to exist; they also bind unacylated ghrelin that is, in fact, the most abundant circulating form and exerts some biological actions. Ghrelin secretion is mainly regulated by metabolic signals, namely inhibited by feeding, glucose and insulin while stimulated by energy restriction. The role of glucocorticoids on ghrelin synthesis and secretion is still unclear although morning ghrelin levels have been found reduced in some patients with Cushing's syndrome; this, however, would simply reflect its negative association to body mass. Ghrelin, like synthetic GHS, stimulates ACTH and cortisol secretion in normal subjects and this effect is generally sensitive to the negative glucocorticoid feedback. It is remarkable that, despite hypercortisolism, ghrelin as well as synthetic GHS display marked increase in their stimulatory effect on ACTH and cortisol secretion in patients with Cushing's disease. This is even more intriguing considering that the GH response to ghrelin and GHS is markedly reduced by glucocorticoid excess. It has been demonstrated that the ACTH-releasing effect of ghrelin and GHS is purely mediated at the central level in physiological conditions; its enhancement in the presence of ACTH-secreting tumours is, instead, likely to reflect direct action on GHS receptors present on the neoplastic tissues. In fact, peculiar ACTH hyperresponsiveness to ghrelin and GHS has been observed also in ectopic ACTH-secreting tumours.

Adrenocorticotropic Hormone↗
PubMed2004

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. SUBJECTS: To this aim we enrolled six normal young male subjects [age (mean +/- SD): 29.0 +/- 8.0 years, body mass index (BMI) 21.9 +/- 2.5 kg/m(2)]. DESIGN AND MEASUREMENTS: In all the subjects we studied ghrelin, GH, ACTH, cortisol and glucose levels after glucagon (GLU; 0.017 mg/kg intramuscularly), ITT (0.1 IU/kg insulin intravenously) or saline administration. RESULTS: Saline infusion was not followed by any significant variation in ghrelin, GH and glucose levels while ACTH and cortisol showed the expected spontaneous morning trend toward a decrease. GLU administration increased (P < 0.01) circulating GH, ACTH and cortisol as well as insulin and glucose levels. ITT induced an obvious increase (P < 0.01) of GH, ACTH and cortisol levels. The ITT-induced increases in GH and ACTH, but not cortisol, levels were higher (P < 0.01) than those after GLU. Circulating ghrelin levels were not modified by GLU. On the other hand, ghrelin levels underwent a transient reduction (P < 0.01) after insulin-induced hypoglycaemia. CONCLUSIONS: Ghrelin does not mediate the GH and ACTH responses to glucagon or to the ITT. In fact, ghrelin levels are not modified at all by glucagon and transiently decrease during the ITT. These findings support the assumption that ghrelin does not play a major role in the physiological control of somatotroph and corticotroph function.

Adrenocorticotropic Hormone↗
PubMed2004

Ghrelin secretion is inhibited by glucose load and insulin-induced hypoglycaemia but unaffected by glucagon and arginine in humans.

OBJECTIVE: Circulating ghrelin levels are increased by fasting and decreased by feeding, glucose load, insulin and somatostatin. Whether hyperglycaemia and insulin directly inhibit ghrelin secretion still remains matter of debate. The aim of the present study was therefore to investigate further the regulatory effects of glucose and insulin on ghrelin secretion. DESIGN AND SUBJECTS: We studied the effects of glucose [oral glucose tolerance test (OGTT) 100 g orally], insulin-induced hypoglycaemia [ITT, 0.1 IU/kg insulin intravenously (i.v.)], glucagon (1 mg i.v.), arginine (0.5 mg/kg i.v.) and saline on ghrelin, GH, insulin, glucose and glucagon levels in six normal subjects. MEASUREMENTS: In all the sessions, blood samples were collected every 15 min from 0 up to + 120 min. Ghrelin, GH, insulin, glucagon and glucose levels were assayed at each time point. RESULTS: OGTT increased (P < 0.01) glucose and insulin while decreasing (P < 0.01) GH and ghrelin levels. ITT increased (P < 0.01) GH but decreased (P < 0.01) ghrelin levels. Glucagon increased (P < 0.01) glucose and insulin without modifying GH and ghrelin. Arginine increased (P < 0.01) GH, insulin, glucagon and glucose (P < 0.05) but did not affect ghrelin secretion. CONCLUSIONS: Ghrelin secretion in humans is inhibited by OGTT-induced hyperglycaemia and ITT but not by glucagon and arginine, two substances able to increase insulin and glucose levels. These findings question the assumption that glucose and insulin directly regulate ghrelin secretion. On the other hand, ghrelin secretion is not associated with the GH response to ITT or arginine, indicating that the somatotroph response to these stimuli is unlikely to be mediated by ghrelin.

Adult↗
PubMed2004

Acetylcholine regulates ghrelin secretion in humans.

Ghrelin secretion has been reportedly increased by fasting and energy restriction but decreased by food intake, glucose, insulin, and somatostatin. However, its regulation is still far from clarified. The cholinergic system mediates some ghrelin actions, e.g. stimulation of gastric contractility and acid secretion and its orexigenic activity. To clarify whether ghrelin secretion undergoes cholinergic control in humans, we studied the effects of pirenzepine [PZ, 100 mg per os (by mouth)], a muscarinic antagonist, or pyridostigmine (PD, 120 mg per os), an indirect cholinergic agonist, on ghrelin, GH, insulin, and glucose levels in six normal subjects. PD increased (P < 0.05) GH (change in area under curves, mean +/- SEM, 790.9 +/- 229.3 microg(*)min/liter) but did not modify insulin and glucose levels. PZ did not significantly modify GH, insulin, and glucose levels. Circulating ghrelin levels were increased by PD (11290.5 +/- 6688.7 pg(*)min/ml; P < 0.05) and reduced by PZ (-23205.0 +/- 8959.5 pg(*)min/ml; P < 0.01). The PD-induced ghrelin peak did not precede that of GH. In conclusion, circulating ghrelin levels in humans are increased and reduced by cholinergic agonists and antagonists, respectively. Thus, ghrelin secretion is under cholinergic, namely muscarinic, control in humans. The variations in circulating ghrelin levels induced by PD and PZ are unlikely to mediate the cholinergic influence on GH secretion.

Acetylcholine↗
PubMed2004

Free fatty acids exert an inhibitory effect on adrenocorticotropin and cortisol secretion in humans.

Free fatty acid (FFA) administration stimulates the hypothalamic-pituitary-adrenal (HPA) axis in rats, suggesting that the HPA axis and lipolysis may be linked by a positive-feedback loop. To clarify the influence of FFA on the HPA axis in humans, we studied the effect of lipid load on both basal and stimulated ACTH and cortisol secretion in normal subjects. In six young female volunteers [(mean +/- SEM) age, 24.4 +/- 2.1 yr; body mass index, 23.1 +/- 1.2 kg/m(2)), ACTH, cortisol, FFA, glucose, and insulin levels were measured every 30 min for 330 min during the following procedures: 1) i.v. saline infusion (from 0 to 330 min); 2) i.v. FFA infusion (Intralipid 10%, from 0 to 210 min) followed by saline infusion (from 210 to 330 min); 3) human CRH (hCRH) administration (2 microg/kg i.v. at 90 min) during saline infusion (from 0 to 330 min); and 4) hCRH administration during FFA infusion (Intralipid 10%, from 0 to 210 min, followed by saline infusion from 210 to 330 min). During saline infusion, ACTH and cortisol levels progressively declined. Lipid-heparin emulsion (LHE) infusion strikingly increased circulating FFA levels and, simultaneously, amplified the ACTH and cortisol decrease (P < 0.05). After LHE withdrawal, FFA decrease was associated with an increase (P < 0.05) in ACTH and cortisol levels (restored to baseline values within 60 min). The ACTH and cortisol responses to hCRH, however, were unaffected by LHE that, concomitantly, induced an increase (P < 0.05) in glucose but not in insulin levels. This study shows that an LHE-induced increase in FFA levels has an inhibitory effect on spontaneous ACTH and cortisol secretion in humans. Lipid load, however, does not affect the ACTH and cortisol responses to hCRH; this evidence would indicate that the negative influence of FFA on the HPA axis in humans takes place at the suprapituitary level.

Adrenocorticotropic Hormone↗
PubMed2004

GHRH and GH secretagogues: clinical perspectives and safety.

The diagnosis and treatment of growth hormone deficiency (GHD), as well as the possibility of counteracting somatopause and age-related changes in body composition, structural functions, and metabolism, prompted interest in potential clinical uses of GH-releasing hormone (GHRH) and GH secretagogues (GHS). GHD often reflects hypothalamic GHRH deficiency and it has been clearly demonstrated that the age-related decline in the function of the GH/IGF-I axis reflects a reduction in hypothalamic function as evidenced by the preservation of the releasable pool of pituitary GH in aged subjects. The effectiveness of recombinant human GH (rhGH) is well established, but it is also recognized that GH replacement does not mimic physiological GH secretion which theoretically would be restored by GHRH and/or GHS. At present, it has been clearly demonstrated that GHRH and/or GHS represent reliable tools for the diagnosis of GHD. On the other hand, neither GHRH nor GHS has been shown to provide effective alternatives to rhGH for the treatment of GHD. Although GHRH and/or GHS represent the most logical approaches for the restoration of the GH/IGF-I axis to a youthful level of activity and for counteracting the somatopause, this hypothesis has never been proven definitively. Conceptually, GHRH replacement would be the most physiological approach and its safety is guaranteed, provided an appropriate dose is used, in order to avoid hyperactivity of the GH/IGF-I axis. However, a long-acting preparation is needed. On the other hand, GHS, e.g., ghrelin analogues, could be considered as a function of their selectivity of action. However, ghrelin has a wide spectrum of endocrine and non-endocrine actions at both central and peripheral levels. Thus, non-selective GHS, although available in orally active forms, could elicit unforeseen side effects. Previous studies with GHRH and/or GHS in aging patients provided encouraging results. However, it still remains to be definitively demonstrated that aged subjects would benefit from chronic treatment with these molecules.

Adult↗
PubMed2003

Acetylcholine does not play a major role in mediating the endocrine responses to ghrelin, a natural ligand of the GH secretagogue receptor, in humans.

OBJECTIVE: Ghrelin is a 28 amino residue peptide produced predominantly by the stomach with substantially lower amounts deriving from other central and peripheral tissues. Ghrelin is a natural ligand of the GH secretagogue (GHS) receptor (GHS-R) and possesses a potent GH-releasing activity for which the acylation in serine 3 is essential. Ghrelin also possesses other endocrine and non-endocrine activities reflecting central and peripheral GHS-R distribution and stimulates PRL, ACTH and cortisol secretion, has been reported able to induce hyperglycaemia and to decrease insulin levels and has orexigenic activity. Moreover, ghrelin stimulates gastric motility and acid secretion and its action is mediated by acetylcholine which, in turn, is known to play a stimulatory influence on GH, ACTH and insulin secretion. SUBJECTS AND METHODS: In order to clarify the influence, if any, of acetylcholine on the endocrine activities of ghrelin, we studied the effects of cholinergic enhancement by pyridostigmine (PD, 120 mg p.o. at -60 minutes) and blockade by pirenzepine (PIR, 100 mg p.o. at -60 minutes) on GH, PRL, cortisol, insulin and glucose responses to human acylated ghrelin (1.0 microg/kg i.v. at 0 minutes) in seven normal young volunteers [age (mean +/- SEM): 28.3 +/- 3.1 years; BMI: 21.9 +/- 0.9 kg/m2]. In the same subjects, the effects of PD and PIR on the GH response to GHRH (1.0 microg/kg i.v. at 0 minutes) have also been studied. RESULTS: The administration of ghrelin induced a prompt increase in circulating GH levels (hAUC: 5452.4 +/- 904.9 microg*min/L) which was markedly higher (P < 0.01) than that elicited by GHRH (966.9 +/- 20.50 microg*min/L). Ghrelin also induced a significant increase in PRL (1273.5 +/- 199.7 microg*min/L) and cortisol levels (15505.1 +/- 796.3 microg*min/L) and a decrease in insulin levels (Delta hAUC: -198.1 +/- 39.2 mU*min/L) which was preceded by an increase in plasma glucose levels (8743.8 +/- 593.0 mg*min/dL). The GH response to GHRH was markedly potentiated by PD (4363.3 +/- 917.3 microg*min/L; P < 0.01 vs. GHRH alone). In turn, PD did not modify either the GH response to ghrelin (6564.2 +/- 1753.5 microg*min/L) or its stimulatory effect on PRL and cortisol as well as its effects on insulin and glucose levels. The GH response to GHRH was inhibited by PIR (171.5 +/- 34.7 microg*min/L, P < 0.01 vs. GHRH alone) which, in turn, did not significantly modify the GH response to ghrelin (4044.0 +/- 948.8 microg*min/L). PIR also did not modify the effects of ghrelin on PRL, cortisol, insulin and glucose levels. CONCLUSIONS: The endocrine activities of ghrelin are not affected significantly by cholinergic enhancement and muscarinic blockade. Thus, acetylcholine does not play a major role in the endocrine actions of ghrelin. Moreover, as the cholinergic system influences GH secretion via modulation of somatostatin release, the present data agree with the assumption that ghrelin is partially refractory to the influence of somatostatin.

Acetylcholine↗
PubMed2003

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. DESIGN: In eight normal subjects [four women and four men, 22-34 years old, body mass index (BMI) 20-25 kg/m2] the ACTH, cortisol, GH, adrenaline (A) and noradrenaline (NA) responses to insulin-induced hypoglycaemia [ITT, 0.1 UI/kg regular insulin intravenously (i.v.) at 0 min] preceded by placebo or ALP (0.02 mg/kg orally at -90 min) were studied in two sessions at least 10 days apart. MEASUREMENTS: Blood samples were taken basely at -90 and 0 min and every 15 min up to +120 min. ACTH, cortisol, GH, A and NA level were assayed at each time point in both sessions. RESULTS: All subjects experienced hypoglycaemia (plasma glucose levels below 2.2 mmol/l). After placebo ITT induced clear-cut increases in ACTH (peak vs. baseline, mean +/- SEM: 27.9 +/- 3.9 vs. 7.1 +/- 1.5 pmol/l), cortisol (438.1 +/- 32.0 vs. 237.7 +/- 19.3 nmol/l) and GH (38.1 +/- 9.7 vs. 5.7 +/- 2.0 micro g/l) levels (P < 0.05). Marked increase in A (6627.2 +/- 116.7 vs. 263.7 +/- 71.4 pmol/l) and NA (3.8 +/- 1.5 vs. 1.6 +/- 1.0 nmol/l) levels were also recorded (P < 0.05). Pretreatment with ALP significantly inhibited the ACTH peak response to ITT (17.8 +/- 5.0 pmol/l, P < 0.05), while the cortisol response showed a non significant reduction (342.1 +/- 38.7 nmol/l). ALP also significantly reduced the GH (21.7 +/- 4.7 micro g/l, P < 0.02) and A (3828.0 +/- 1400.7 pmol/l, P < 0.02) responses to ITT. On the contrary, ALP lowered basal NA levels (P < 0.05) but did not significantly affect its response to ITT (2.2 +/- 1.2 nmol/l). Glucose changes induced by ITT were not modified by ALP. CONCLUSIONS: This study shows that GABAergic activation by alprazolam significantly inhibits the neuroendocrine and adrenomedullary responses to hypoglycaemia.

Adrenocorticotropic Hormone↗