Biomedical subjects

E Arvat

Publications and source records attributed to E Arvat.

At least 19 recordsLinked to original sources

PubMed2005

Hormonal and metabolic responses to acute ghrelin administration in patients with bulimia nervosa.

Ghrelin is generally influenced by energy balance status and is inversely associated with body mass index (BMI), being reduced in simple obesity, notable exception being Prader Willi syndrome, and elevated in several conditions of undernutrition, including anorexia nervosa (AN). Interestingly, ghrelin levels have also been found elevated in patients with bulimia nervosa (BN) in spite of normal BMI. In humans, intravenous (iv) ghrelin administration induces endocrine (increase in GH, PRL, ACTH and cortisol) and metabolic (increase in glucose and decrease in insulin) effects as well as an increase in appetite and food intake. In AN, ghrelin administration surprisingly leads to a decreased GH response and absence of glycemic variations but normal PRL, ACTH and insulin response. This pattern would reflect a decrease in sensitivity to ghrelin or, alternatively, the metabolic status of AN. To further clarify the function of ghrelin in eating disorders, the endocrine and metabolic response to acute iv ghrelin (1.0 microg/kg) was studied in seven young women with purging BN (BW, BMI, mean+/-SEM: 20.3+/-0.5 kg/m2). Circulating total ghrelin levels were also measured. The results in BW were compared to those recorded in a group of nine healthy women (HW; BMI 22.3+/-2.5 kg/m2). The GH response to ghrelin in BW overlapped with that in HW. Ghrelin administration also led to a similar increase in PRL, ACTH, cortisol and glucose levels in the two groups. Insulin levels were not significantly modified by ghrelin administration in either group. The overlapping endocrine and metabolic response to ghrelin in the two groups occurred with regard to circulating total ghrelin levels which were higher in BW than in HW. In conclusion, BN, a condition of ghrelin hypersecretion, is connoted by a normal endocrine and metabolic response to exogenous ghrelin administration.

Adrenocorticotropic Hormone↗

PubMed2005

Ghrelin: more than a natural GH secretagogue and/or an orexigenic factor.

Ghrelin, an acylated peptide produced predominantly by the stomach, has been discovered to be a natural ligand of the growth hormone secretagogue receptor type 1a (GHS-R1a). Ghrelin has recently attracted considerable interest as a new orexigenic factor. However, ghrelin exerts several other neuroendocrine, metabolic and also nonendocrine actions that are explained by the widespread distribution of ghrelin and GHS-R expression. The likely existence of GHS-R subtypes and evidence that the neuroendocrine actions, but not all the other actions, of ghrelin depend on its acylation in serine-3 revealed a system whose complexity had not been completely explored by studying synthetic GHS. Ghrelin secretion is mainly regulated by metabolic signals and, in turn, the modulatory action of ghrelin on the control of food intake and energy metabolism seems to be among its most important biological actions. However, according to a recent study, ghrelin-null mice are neither anorectics nor dwarfs and this evidence clearly depicts a remarkable difference from leptin null mice. Nevertheless, the original and fascinating story of ghrelin, as well as its potential pathophysiological implications in endocrinology and internal medicine, is not definitively cancelled by these data as GHS-R1a null aged mice show significant alterations in body composition and growth, in glucose metabolism, cardiac function and contextual memory. Besides potential clinical implications for natural or synthetic ghrelin analogues acting as agonists or antagonists, there are several open questions awaiting an answer. How many ghrelin receptor subtypes exist? Is ghrelin 'the' or just 'a' GHS-R ligand? That is, are there other natural GHS-R ligands? Is there a functional balance between acylated and unacylated ghrelin forms, potentially with different actions? Within the next few years suitable answers to these questions will probably be found, making it possible to gain a better knowledge of ghrelin's potential clinical perspectives.

Animals↗

PubMed2005

Somatopause reflects age-related changes in the neural control of GH/IGF-I axis.

This paper will focus on the hypofunction of GH/IGF-I axis in aging, as the most impressive example of decreased activity as function of age-related changes in the neural control of somatotroph cells. GH secretion undergoes clear age-related variations that are generally mirrored by IGF-I levels, the best marker of GH status. Given the well known positive influence of GH/IGF-I on body composition, structure functions and metabolism, this paper discusses the potential clinical implications, also taking into account evidence showing that, at least in animals, deficiency in GH/IGF-I is somewhat associated to prolonged life. Although somatopause is likely to contribute to age-related changes in body composition, structure functions and metabolism, we are now in front of the paradox of lifelong GH/IGF-I deficiency or resistance resulting in prolonged life expectancy and GH replacement at advanced age, probably exerting anti-aging effects. This evidence questions whether GH deficiency is or not a beneficial adaptation to aging. By answering this question one is not simply finding new phylosophical paradigm but also the rational basis for anti-aging drug interventions.

Aging↗

PubMed2004

The adrenal sensitivity to ACTH stimulation is preserved in anorexia nervosa.

Hyperactivity of hypothalamus-pituitary-adrenal (HPA) axis in anorexia nervosa (AN) has been demonstrated and is likely to reflect a central nervous system (CNS)-mediated effect of starvation. Alterations in the adrenal response to ACTH in AN have also been reported by some authors. In order to define the adrenal sensitivity to ACTH in this condition, we studied cortisol (F), aldosterone (A) and DHEA responses to the sequential administration of low and supramaximal ACTH 1-24 doses (0.06 microg/m2 ACTH 1-24 iv at 0 min and 250 microg ACTH 1-24 iv at +60 min, respectively) in 10 young women with AN [ANW, age 21.2 +/- 0.9 yr, body mass index (BMI) 15.7 +/- 0.6 kg/m2]. The results in this group were compared with those recorded in 10 healthy normal women (HW, 23.4 +/- 1.1 yr, 21.9 +/- 0.9 kg/m2). In ANW urinary F levels were similar to those in HW. Basal serum F, A and DHEA levels in ANW were not significantly different from those in HW. In HW the lowest ACTH dose induced a significant (p<0.05) increase of F, A and DHEA. The maximal ACTH dose induced F, A and DHEA increases greater (p<0.05) than those induced by the lowest ACTH dose. In ANW both ACTH doses induced significant (p<0.05) F and DHEA increases which were not significantly different from those in HW, though a trend toward a lower cortisol response after ACTH 0.06 microg/m2 in ANW was present. Like in HW, in ANW the maximal ACTH dose induced F and DHEA increases greater (p<0.01) than those induced by the lowest dose. Unlike HW, in ANW A levels did not increase after the lowest ACTH dose while they increased after the maximal one overlapping the response in HW. In conclusion, the cortisol and DHEA responses to a very low and a supra-maximal ACTH dose in patients with AN were similar to those in healthy subjects, indicating that the sensitivity to ACTH of the fasciculata and reticularis adrenal zones is preserved in this condition. On the other hand, a reduced sensitivity to ACTH of the glomerularis adrenal zone in patients with AN is suggested by the lack of aldosterone response to the lowest corticotropin dose.

Adolescent↗

PubMed2004

Adrenal sensitivity to adrenocorticotropin 1-24 is reduced in patients with autoimmune polyglandular syndrome.

Autoimmune polyglandular syndromes are fairly common diseases that are classified into four constellations based on the clinical clustering of the various component diseases. In types 1, 2, and 4, primary adrenal insufficiency due to an autoimmune process is usually present, but its diagnosis is often delayed because it is difficult to detect in a subclinical phase. It is widely accepted that the classical dose of 250 microg ACTH(1-24) is supramaximal, whereas 0.06 microg has been shown to be one of the lowest ACTH doses that is able to stimulate adrenal secretion in normal young subjects. The aim of this study was to clarify the sensitivity and maximal secretory response of the adrenal gland to ACTH in a group of patients with at least two autoimmune diseases, without clinical signs and symptoms of overt or subclinical hypocortisolism. Cortisol (F), aldosterone (A), and dehydroepiandrosterone (DHEA) responses to the sequential administration of very low and supramaximal ACTH(1-24) doses [0.06 microg followed by 250 microg ACTH(1-24) i.v. at 0 and +60 min] were studied in 18 patients with at least two autoimmune diseases (AP; age, 20-40 yr; body mass index, 22-26 kg/m(2)). The results in the patients were compared with the results recorded in 12 normal age-matched control subjects (CS; age, 22-34 yr; body mass index, 20-25 kg/m(2)). At baseline, ACTH levels in AP were within the normal range but higher (P < 0.05) than in CS, whereas F, A, DHEA, urinary-free F, and plasma renin activity were similar in both groups. F, A, and DHEA responses to ACTH were dose dependent in both groups. However, in AP, F, A, and DHEA levels showed no response to the 0.06- micro g ACTH dose, which, in turn, elicited clear responses (P < 0.01) in CS. On the other hand, F, A, and DHEA responses to 250 microg ACTH in AP were not different from those in CS. In conclusion, patients with autoimmune diseases who displayed a normal basal adrenal function showed a loss of F, A, and DHEA response to the very low ACTH dose, although they were normal responders to the high ACTH dose. These data are likely to indicate that a reduced sensitivity to ACTH in all adrenal zones occurs in patients with different types of autoimmune disease.

Adrenal Cortex Function Tests↗

PubMed2003

Hypopituitaric patients with corticotropin insufficiency show marked impairment of the cortisol response to ACTH (1-24) independently of the duration of the disease.

It is widely accepted that the classical dose of 250.0 microg ACTH (1-24) (tetracosactin) is clearly supra-maximal while 1.0 and 0.03 microg have been shown as the maximal and the lowest stimulatory ACTH doses for cortisol (F) secretion in normal young subjects. Testing with low ACTH dose would better evaluate adrenal sensitivity to corticotropin. The aims of the present study were: a) to clarify the adrenal sensitivity to ACTH in patients with different duration of corticotroph insufficiency by testing with low and very low tetracosactin doses; and b) to evaluate diagnostic implication regarding the ability of ACTH tests to distinguish patients with corticotroph insufficiency from normal subjects. In 24 hypopituitaric patients (HYPOPIT, 15 male and 9 female, age 22-50 yr, BMI: 22-26 kg/m2) with corticotrophin deficiency we studied the F, DHEA and aldosterone (A) responses to challenges with low ACTH doses (0.06 or 0.5 microg iv at 0 min) followed by 250 microg iv (at +60 min). The results in HYPOPIT were compared with those recorded in 12 normal controls (NS, 6 male and 6 female, age 22-34 yr, BMI: 20-25 kg/m2). Basal F and DHEA levels in HYPOPIT were lower than in NS, while A levels were similar in both groups. The F responses to ACTH in HYPOPIT were dose-independent and markedly lower (p < 0.0001) than in NS. After the 0.06 and 0.5 microg ACTH dose, 16% of HYPOPIT patients showed AF peak within the range of normal response. No HYPOPIT showed AF peak within the normal range after 250 microg ACTH. The DHEA responses to ACTH in HYPOPIT were dose-independent and markedly lower than in NS (p < 0.0001). Overlap between individual DHEA responses in HYPOPIT and NS was present after 0.06 microg and 0.5 microg but not after 250 microg tetracosactin. The A responses in HYPOPIT were dose-dependent and overlapped with those in NS. The adrenal responses to ACTH in HYPOPIT were not associated with the duration of the disease. In conclusion, the present study shows that the mean F and DHEA but not the A responses to ACTH (1-24) are markedly impaired in hypopituitaric patients with corticotroph insufficiency independently of the duration of the disease. The impaired F and DHEA response to ACTH is also independent of the dose, suggesting the existence of relatively enhanced sensitivity of the fasciculata and reticularis adrenal zone to ACTH but meantime remarkable impairment of the adrenal function due to corticotrophin deficiency. In the present study, testing with submaximal ACTH doses did not distinguish patients with secondary adrenal insufficiency from normal subjects.

Adrenal Insufficiency↗

PubMed2003

Non-acylated ghrelin does not possess the pituitaric and pancreatic endocrine activity of acylated ghrelin in humans.

Ghrelin, a 28-amino acid peptide predominantly produced by the stomach, displays strong GH-releasing activity mediated by the GH secretagogue (GHS)-receptor (GHS-R) type 1a at the hypothalamus-pituitary level. Ghrelin and synthetic GHS also possess other GH-independent peripheral endocrine and non-endocrine activities via the activation of peripheral GHS-R subtypes. In rats in vivo non-acylated ghrelin has been reported devoid of any endocrine activity; however, in vitro, it has been shown as effective as ghrelin in exerting anti-proliferative activity on tumor cell lines. The aim of the present study was to clarify whether non-acylated human ghrelin shares some of the endocrine activities of its acylated form in humans. To this goal, the effects of acylated or non-acylated ghrelin (1.0 microg/kg i.v. at 0 min) on GH, PRL, ACTH, F, insulin and glucose levels were studied in two different testing sessions in 7 normal young volunteers (age [mean +/- SE]: 24.3 +/- 1.7 yr; BMI: 21.5 +/- 0.9 kg/m2). The effects of placebo administration were also studied. The administration of acylated ghrelin induced prompt and marked increase in circulating GH levels (AUC: 5452.4 +/- 904.9 microg*min/l; p < 0.01 vs placebo) and significant increase in PRL (1273.5 +/- 199.7 microg*min/l; p < 0.01 vs placebo), ACTH (4482.7 +/- 954.4 pg*min/ml; p < 0.01 vs placebo) and F levels (15985.0 +/- 1141.9 microg*min/l; p < 0.01 vs placebo). Its administration was also followed by decrease in insulin levels (1448.67 +/- 137.9 mU*min/l; p < 0.05 vs placebo) that was coupled with an increase in plasma glucose levels (10974.2 +/- 852.5 mg*min/dl; p < 0.05 vs placebo). The administration of non-acylated ghrelin and that of placebo did not induce any change in the hormonal parameters or in glucose levels. In conclusion, this study shows that in humans nonacylated ghrelin does not possess the pituitaric and pancreatic endocrine activities of human ghrelin octanoylated in Serine 3.

Acylation↗

PubMed2003

Prolonged treatment with glycerophosphocholine, an acetylcholine precursor, does not disclose the potentiating effect of cholinesterase inhibitors on GHRH-induced somatotroph secretion in anorexia nervosa.

Unlike normal subjects, in patients with anorexia nervosa (AN) the GH response to GHRH is refractory to the increasing and inhibitory effect of cholinergic agonists and antagonists, respectively. This cholinergic impairment could reflect malnutrition-induced exhaustion of acetylcholine (Ach) precursors. We studied whether treatment with glycerophosphocholine (GLY), an Ach precursor, could disclose the potentiating effect of pyridostigmine (PD) on the GH response to GHRH in AN. In 6 young women with AN (AW) we studied the GH response to iv GHRH (1.0 microg/kg) alone and combined with oral PD (120 mg) before and after 1 month of oral treatment with GLY (400 mg thrice daily). Eight age-matched normal women (NW) were studied as controls. Before GLY, basal GH levels in AW were higher (p < 0.05) than in NW. The GH response to GHRH in AW was higher (p < 0.05) than in NW. PD failed to modify the GHRH-induced GH rise in AW, while it enhanced it in NW (p < 0.05). One month treatment with GLY in AW did not modify the GH response to GHRH either alone or combined with PD. This study shows the existence of a derangement in the cholinergic control of somatotroph function in AN and indicates that treatment with Ach precursors does not exert any effect on this impairment. This could reflect primary alterations of cholinergic neurons, though the effectiveness of more prolonged treatment and/or higher doses of cholinergic precursors needs to be verified.

Acetylcholine↗

PubMed2003

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 rhlGF-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, rhlGF-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.

Adult↗

PubMed2003

Suppression and recovery of LH secretion by a potent and selective GnRH-receptor antagonist peptide in healthy early follicular-phase women are mediated via selective control of LH secretory burst mass.

AIM: GnRH antagonists are competitive inhibitors of GnRH receptors. Their administration induces prompt suppression of the gonadal axis. In animals, GnRH antagonists upregulate the activity of GnRH-secreting neurones, which could cause gonadotrophin rebound following inhibition. The aim of this study was to evaluate the effects of a potent GnRH antagonist, Teverelix (TEV), on the gonadal axis in healthy young women. SUBJECTS AND MEASUREMENTS: In nine women [20-35 years old, body mass index (BMI) 19-25 kg/m2] in the early follicular phase, serum LH and FSH levels were evaluated every 10 min from 08.00 to 12.00 h before, and 24 h and 96 h after TEV injection (2.5 mg in 1 ml subcutaneously on day 0). Serum gonadotrophin and oestradiol levels were also evaluated at baseline and at 6, 8, 12, 48, 72 h after TEV. RESULTS: The antagonist reduced both serum LH and FSH concentrations; LH levels were significantly and promptly reduced at +6 h (nadir at +8 h) until +48 h and recovered at +72 h, while FSH levels were reduced (P<0.05) 24 h after the antagonist and normalized at +48 h. LH (but not FSH) concentrations at +96 h exceeded baseline (P<0.05). TEV suppressed oestradiol concentrations (P<0.05) with a nadir at +24 h, comparable reduction at +48 h and recovery to baseline at +72 h. Deconvolution analysis showed that the antagonist peptide suppressed (P<0.02) the pulsatile production rate, burst mass and amplitude of LH on day 1. Pulsatile FSH secretion also fell at this time (P<0.05). LH and FSH pulse frequency were not modified by TEV. At +96 h, LH pulsatility did not significantly differ from that at baseline. Suppression of mean LH or FSH concentrations did not affect the relative pattern regularity (approximate entropy) of LH and FSH secretion. CONCLUSIONS: This study demonstrates that the acute administration of a potent GnRH antagonist induces prompt inhibition of the gonadal axis lasting for 2 days in women due to mechanistically specific suppression of LH secretory burst mass and the mean FSH secretion rate. The trend toward rebound release of LH following the end of the pharmacological effect of the antagonist could reflect a rise in endogenous GnRH activity.

Adult↗

PubMed2003

Abnormal 5-HT1D receptor function in cluster headache: a neuroendocrine study with sumatriptan.

The purpose of this study was to assess the sensitivity of 5-HT(1D) receptors in patients with episodic cluster headache using sumatriptan as a pharmacological probe. The drug, a selective 5-HT(1B/1D) agonist, stimulates the secretion of growth hormone and inhibits the release of prolactin, adrenocorticotropic hormone (ACTH) and cortisol. These effects may be used to explore the function of serotonergic systems in vivo. We administered subcutaneous sumatriptan and placebo to 20 patients with cluster headache (10 in the active phase and 10 in the remission period) and to 12 controls. The sumatriptan-induced increase of growth hormone concentrations was significantly (P < 0.05) blunted in patients with active cluster headache. Prolactin and ACTH responses to the drug were significantly (P < 0.05) reduced in patients with cluster headache, both in the active and in the remission period. Our results suggest that cerebral serotonergic functions mediated by 5-HT(1D) receptors are altered in patients with episodic cluster headache.

Adult↗

PubMed2003

Ghrelin main action on the regulation of growth hormone release is exerted at hypothalamic level.

Ghrelin, a recently isolated hormone, seems to participate in the physiological regulation of GH secretion. Exogenously administered ghrelin stimulates GH discharge in all species so far tested including man, but whether this action is exerted at pituitary or alternatively at hypothalamic level is not known at present. To understand the point of ghrelin action a group of patients with organic lesion mainly in the hypothalamic area and matched controls were studied. Patients showed a severe GH deficiency after hypothalamic stimulation (ITT), but partial response after GHRH administration. Cases and controls were tested on three separate days by either ghrelin; GHRH; and ghrelin plus GHRH; always at 1 micro g/Kg iv. The mean GH peak after stimulation in the patients were: 0.4 +/- 0.1 micro g/L by ITT; 3.1 +/- 0.5 micro g/L after GHRH; 2.0 +/- 0.8 micro g/L after ghrelin; and 9.6 +/- 2.9 micro g/L after the combination of GHRH plus ghrelin. In the controls GHRH induced a GH peak of 21.2 +/- 7.5 micro g/L, and 75.1 +/- 16.0 micro g/L after ghrelin with a peak after GHRH + ghrelin of 103.5 +/- 26.4 micro g/L. These data indicate that when hypothalamic structures are not operative ghrelin, either alone or in combination with GHRH, is not able to significantly release GH. In addition to postulating a hypothalamic point of action for the ghrelin-induced GH secretion, these results suggests that ghrelin will not have significant clinical utility in patients with GH deficiency due to organic lesion.

Adult↗

PubMed2003

Natural and synthetic growth hormone secretagogues: do they have therapeutic potential?

Ghrelin, a 28 amino acid-acylated peptide predominantly produced by the stomach, displays strong growth hormone (GH)-releasing activity. It is mediated by the hypothalamic-pituitary GH secretagogue (GHS) receptors, which are specific to a family of synthetic, orally active molecules known as GHSs. However, despite their potent and reproducible GH-releasing activity, the potential clinical use of GHSs as orally active growth-promoting agents or anabolic anti-aging drugs has not been confirmed. Ghrelin and GHSs also exert other actions mediated through central and peripheral receptors, including stimulation of adrenocorticotrophic hormone and prolactin secretion, influence on insulin secretion and glucose metabolism, orexigenic effects and modulatory activity on the neuroendocrine and metabolic response to starvation, influence on exocrine gastro-entero-pancreatic functions, cardiovascular effects and modulation of cell proliferation and apoptosis. The discovery of ghrelin and the characterization of these GH-independent biological activities has widened the knowledge of some critical aspects of neuroendocrinology and suggests possible roles for GHSs and ghrelin in the treatment of pathophysiological conditions, including those unrelated to disorders of GH secretion.

Animals↗

PubMed2003

[Endocrine abnormalities in anorexia nervosa].

Anorexia nervosa is a syndrome with multifactorial etiology in which several genetic, biologic, psychological and social factors are involved. Patients affected by anorexia nervosa (AN) may develop multiple endocrine abnormalities, e.g. amenorrhea, hypothalamus-pituitary-adrenal axis hyperactivity, low T3 syndrome and peculiar changes of somatotroph axis function. These endocrine abnormalities are also found after prolonged starvation and may represent an adaptive response developed in order to save energy and proteins. It is still a matter of debate whether these endocrine changes are etiologic or secondary. In fact, several evidences suggest the existence in AN of hypothalamus functional alterations, which may be involved in the development and maintenance of the food intake disorder; on the other hand, the increased CRH secretion seems to be secondary to malnutrition as well as GH hypersecretion coupled to low IGF-I levels; the latter is a common finding in AN, as well as in other undernutrition and malabsorption conditions, type 1 diabetes mellitus, liver cirrhosis and catabolic states. Hypothalamic amenorrhea, which is one of the diagnostic criteria for AN, is not linked only to the reduction of body weight but reflects also deep alterations of gonadotropin secretory pattern. Low T3 syndrome is frequently found in AN; on the other hand, an iodide-induced hypothyroidism is quite uncommon. T3 reduction in AN seems to be an adaptive response to prolonged starvation; however the presence of a simultaneous central dysregulation cannot be excluded. Finally, AN patients frequently show defects in urinary concentration or dilution with inappropriate secretion of antidiuretic hormone, which may be due to intrinsic defects in the neurohypophysis or to abnormalities of its regulatory afferent neurons.

Animals↗

PubMed2002

Alprazolam, a benzodiazepine, does not modify the ACTH and cortisol response to hCRH and AVP, but blunts the cortisol response to ACTH in humans.

Alprazolam (AL), a benzodiazepine which activates gamma-amino butyrric acid (GABA)-ergic receptors, exerts a clear inhibitory effect on the activity of the hypothalamo-pituitary-adrenal (HPA) axis and is able to markedly reduce the ACTH response to metyrapone-induced inhibition of glucocorticoid feedback. It has been suggested that its inhibitory action could be regulated by CRH or AVP mediated mechanisms. However, the effect of benzodiazepines on the HPA response to CRH or AVP is contradictory. It has been shown that benzodiazepines have specific receptors on the adrenal gland but it is unclear if they mediate biological effects in humans. In order to further clarify the mechanisms underlying the inhibitory effect of benzodiazepine on HPA axis in humans, we studied the effect of AL (0.02 mg/kg po at -90 min) or placebo in 7 healthy young volunteers (7 female, age: 26-34 yr; wt: 50-58 kg, BMI 20-22 kg/m2) on: 1) the ACTH and cortisol responses to hCRH (2.0 microg/kg iv at 0 min) or AVP (0.17 U/kg im at 0 min); 2) the cortisol, aldosterone and DHEA responses to ACTH 1-24 (0.06 and 250 microg iv at 0 and 60 min, respectively). After placebo, the ACTH and cortisol responses to hCRH (peaks, mean+/-SE: 29.8+/-4.4 pg/ml and 199.3+/-19.6 microg/l) were similar to those recorded after AVP (31.7+/-6.5 pg/ml and 164.8+/-18.0 microg/l); the cortisol response to 0.06 microg ACTH (190.4+/-11.8 microg/l) was similar to that recorded after hCRH and AVP but lower (p<0.01) than that after 250 microg ACTH (260.6+/-17.4 microg/l). AL did not modify the ACTH response to both hCRH (42.5+/-7.1 pg/ml) and AVP (33.3+/-2.7 pg/ml), which even showed a trend toward increase. AL also failed to significantly modify the cortisol response to both hCRH (156.3+/-12.7 microg/l) and AVP (119.4+/-14.5 microg/l), which, on the other hand, showed a trend toward decrease. The cortisol peaks after 0.06 microg ACTH were significantly reduced (p<0.02) by AL pre-treatment (115.0+/-7.7 microg/l) which, in turn, did not modify the cortisol response to the subsequent ACTH bolus (214.7+/-16.6 microg/l). The DHEA and aldosterone responses to all the ACTH doses were not significantly modified by AL. In conclusion, these data show that the HPA response to AVP as well as to hCRH is refractory to the inhibitory effect of AL which, in turn, blunts the cortisol response to low ACTH dose. These findings suggest that both CRH- and AVP-mediated mechanisms could underlie the CNS-mediated inhibitory effect of AL on HPA axis; in the meantime, these results suggest that benzodiazepines could also act on adrenal gland by blunting the sensitivity of the fasciculata zone to ACTH.

Adrenocorticotropic Hormone↗

PubMed2002

EP1572: a novel peptido-mimetic GH secretagogue with potent and selective GH-releasing activity in man.

EP1572 UMV1843 [Aib-DTrp-DgTrp-CHO]) is a new peptido-mimetic GH secretagogue (GHS) showing binding potency to the GHS-receptor in animal and human tissues similar to that of ghrelin and peptidyl GHS. EP1572 induces marked GH increase after s.c. administration in neonatal rats. Preliminary data in 2 normal young men show that: 1) acute i.v. EP1572 administration (1.0 microg/kg) induces strong and selective increase of GH levels; 2) single oral EP1572 administration strongly and reproducibly increases GH levels even after a dose as low as 0.06 mg/kg. Thus, EP1572 is a new peptido-mimetic GHS with potent and selective GH-releasing activity.

Adult↗

PubMed2002

Benzodiazepines and anterior pituitary function.

Benzodiazepines (BDZ) are one of the most prescribed classes of drugs because of their marked anxiolytic, anticonvulsant, muscle relaxant and hypnotic effects. The pharmacological actions of BDZ depend on the activation of 2 specific receptors. The central BDZ receptor, present in several areas of the central nervous system (CNS), is a component of the GABA-A receptor, the activation of which increases GABAergic neurotransmission and is followed by remarkable neuroendocrine effects. The peripheral benzodiazepine receptors (PBR), structurally and functionally different from the GABA-A receptor, have been shown in peripheral tissues but also in the CNS, in both neurones and glial cells, and in the pituitary gland. BDZ receptors bind to a family of natural peptides called endozepines, firstly isolated from neurons and glial cells in the brain and then in several peripheral tissues as well. Endozepines modulate several central and peripheral biological activities, including some neuroendocrine functions and synthetic BDZ are likely to mimic them, at least partially. BZD, especially alprazolam (AL), possess a clear inhibitory influence on the activity of the HPA axis in both animals and humans. This effect seems to be mediated at the hypothalamic and/or suprahypothalamic level via suppression of CRH. The strong negative influence of AL on hypothalamicpituitary-adrenal (HPA) axis agrees with its peculiar efficacy in the treatment of panic disorders and depression. BZD have also been shown to increase GH secretion via mechanisms mediated at the hypothalamic or supra-hypothalamic level, though a pituitary action cannot be ruled out. Besides the impact on HPA and somatotrope function, BDZ also significantly affect the secretion of other pituitary hormones, such as gonadotropins and PRL, probably acting through GABAergic mediation in the hypothalamus and/or in the pituitary gland. In all, BDZ are likely to represent a useful tool to investigate GABAergic activity and clarify its role in the neuroendocrine control of anterior pituitary function; their usefulness probably overrides what had been supposed before.

Animals↗

PubMed2002

The stimulatory effect of canrenoate, a mineralocorticoid antagonist, on the activity of the hypothalamus-pituitary-adrenal axis is abolished by alprazolam, a benzodiazepine, in humans.

Mineralocorticoid receptors (MR) in the hippocampus play a major role in the control of the hypothalamus-pituitary-adrenal (HPA) axis, mediating the proactive feedback of glucocorticoids in the maintenance of basal activity. Intracerebroventricular and intrahippocampal MR blockade stimulates HPA axis in animals; the systemic administration of mineralocorticoid antagonists enhances spontaneous and CRH-stimulated ACTH and cortisol secretion in humans. Benzodiazepines, namely alprazolam, activate central gamma-aminobutyric acid (GABA)ergic receptors, which are mainly distributed in the hippocampus. Alprazolam has a inhibitory effect on HPA axis either in basal conditions or after central nervous system-mediated stimuli. In humans, alprazolam strongly reduces the corticotroph responsiveness to removal of glucocorticoid feedback by metyrapone. We studied the effect of alprazolam (0.02 mg/kg, orally) on the effect of canrenoate (CAN), an MR antagonist (200 mg as an iv bolus, followed by 200 mg infused in 250 ml saline) or placebo on ACTH, cortisol, and dehydroepiandrosterone (DHEA) secretion in six normal young women (aged 25-32 yr; body mass index, 19-23 kg/m(2)). During placebo, ACTH, cortisol, and DHEA secretion showed a progressive decrease (baseline vs. nadir, mean +/- SEM, from 1830-2400 h, 2.6 +/- 0.3 vs. 1.4 +/- 0.3 pmol/liter, 133.2 +/- 16.4 vs. 46.9 +/- 5.2 nmol/liter, and 22.6 +/- 2.3 vs. 18.6 +/- 2.3 nmol/liter, respectively), although statistical significance was obtained for ACTH and cortisol only (P < 0.05). During CAN treatment, ACTH, cortisol, and DHEA secretion showed a progressive rise, which began at approximately 2100 h and peaked between 2300 and 2400 h (2.9 +/- 0.3 pmol/liter, 172.6 +/- 27.9 nmol/liter, and 45.3 +/- 10.7 nmol/liter, respectively; P < 0.05). Alprazolam abolished the CAN-induced increases in ACTH, cortisol, and DHEA levels (1.8 +/- 0.1 pmol/liter, 59.7 +/- 8.6 nmol/liter, and 19.8 +/- 6.7 nmol/liter; P < 0.05), inducing hormonal peaks overlapping with those recorded after placebo in the absence of any treatment. In conclusion, our study demonstrates that the inhibitory effect of GABAergic activation by alprazolam overrides the stimulatory effect of mineralocorticoid blockade by canrenoate on the HPA axis in humans. These findings emphasize the role of GABA in the control of the HPA axis in humans.

Adrenal Glands↗