Biomedical subjects

E Ghigo

Publications and source records attributed to E Ghigo.

At least 73 records · Page 4Linked to original sources

PubMed2003

Neuroendocrine and metabolic effects of acute ghrelin administration in human obesity.

Ghrelin stimulates appetite and plays a role in the neuroendocrine response to energy balance variations. Ghrelin levels are inversely associated with body mass index (BMI), increased by fasting and decreased by food intake, glucose load, insulin, and somatostatin. Ghrelin levels are reduced in obesity, a condition of hyperinsulinism, reduced GH secretion, and hypothalamus-pituitary-adrenal axis hyperactivity. We studied the endocrine and metabolic response to acute ghrelin administration (1.0 microg/kg i.v.) in nine obese women [OB; BMI (mean +/- SD) 36.3 +/- 2.3 kg/m(2)] and seven normal women (NW; BMI 20.3 +/- 1.7 kg/m(2)). Basal ghrelin levels in NW were higher than in OB (P < 0.05). In NW, ghrelin increased (P < 0.05) GH, prolactin (PRL), ACTH, cortisol, and glucose levels but did not modify insulin. In OB, ghrelin increased (P < 0.01) GH, PRL, ACTH, and cortisol levels. The GH response to ghrelin in OB was 55% lower (P < 0.02) than in NW, whereas the PRL, ACTH, and cortisol responses were similar. In OB, ghrelin increased glucose and reduced insulin (P < 0.05). Thus, obesity shows remarkable reduction of the somatotroph responsiveness to ghrelin, suggesting that ghrelin hyposecretion unlikely explains the impairment of somatotroph function in obesity. On the other hand, in obesity ghrelin shows preserved influence on PRL, ACTH, and insulin secretion as well as in glucose levels.

Adrenocorticotropic Hormone↗

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↗

PubMed2003

Hormonal diagnosis of GH hypersecretory states.

GH hypersecretory states include organic and functional causes. Among functional GH hypersecretory states, enhanced somatotroph secretion physiologically occurs at birth associated with reduced IGF-I levels reflecting the still immature sensitivity of liver to circulating GH levels; this may also occur in women exposed to oral extrogens. Pathophysiological conditions of GH hypersecretion are generally associated with congenital or acquired/functional conditions of peripheral GH insensitivity. Genetic alterations of the GH receptor lead to the so called Laron's syndrome. On the other hand, a relevant number of clinical conditions (malnutrition, malabsorption, anorexia nervosa, liver cirrhosis, renal failure, Type 1 diabetes mellitus) are associated with acquired GH insensitivity and a more or less pronounced GH hypersecretion. Both organic and acquired conditions of GH insensitivity show low IGF-I synthesis and release and therefore lack the negative IGF-I feedback action on somatotroph function. GH hypersecretion may be associated with renal failure; however, in this case, the alteration in the metabolic clearance rate of GH would also have a role; moreover, IGF-I levels are generally normal in this condition. Hyperthyroidism is another condition connoted by elevated GH levels that reflects a true GH hypersecretory state and is, in fact, associated with high-normal IGF-I levels; this peculiar condition is likely to be reflecting the stimulatory effect of thyroid hormones on both GH and IGF-I secretion and is promptly reversed by treatment-induced euthyroidism. Apart from these "functional" hypersecretory state, the classic organic GH hypersecretory state is represented by acromegaly or giantism. In these conditions GH hypersecretion is generally sustained by a pituitary adenoma hypersecreting GH alone or together with another pituitary hormone, mostly PRL; less frequently GH hypersecretion may be due to ectopic GHRH hypersection. Exaggerated GH secretion elicits exaggerated IGF-I synthesis and secretion that is, in turn, responsible for the large majority of endocrine signs and symptoms. In the appropriate clinical context of acromegalic features, evidence of concomitant marked GH and IGF-I hypersecretion at baseline demonstrates active acromegaly or giantism and indicates the need for magnetic resonance imaging in order to verify the presence of a pituitary tumor. However, as random measurement of basal GH levels is not reliable for definite diagnosis of acromegaly, it is considered mandatory to rely on the lack of GH suppression below 1 microg/l during oral glucose tolerance test (OGTT) coupled with elevated IGF-I levels. The same criteria are assumed, at present, to define true cure of the disease after (or under) treatment. There is consensus about the assumption that concomitant normalization or persistent abnormality of both OGTT-induced GH nadir and IGF-I levels define a successfully or a poorly controlled disease status, respectively. On the other hand, acromegalic patients with GH nadir above 1 microg/l or IGF-I levels persistently elevated are inadequately controlled and their disease should not be considered inactive. It has been clearly demonstrated that an extended exposure to GH and IGF-I excess level, even if slight, has a very harmful effect on patients; therefore early diagnosis of acromegaly and appropriate definition of its cure are of fundamental extreme in order to plan a prompt and appropriate therapeutic intervention(s) guaranteed also by the continuous improvement in the therapeutic tools available to treat this systemic disease.

Acromegaly↗

PubMed2002

Activity of GH/IGF-1 axis in burn patients: comparison with normal subjects and patients with GH deficiency.

The aim of this study was to clarify the activity of GH/IGF-1 axis as well as the variations of nutritional parameters following a thermal injury in man. To this goal, in 22 patients with burn [BURN, age (mean+/-SE): 46.5+/-3.4 yr, BMI: 25.0+/-0.8 kg/m2, % burn surface area: 26.0+/-3.0%, ROI score: 0.22+/-0.1] we evaluated IGF-1, IGF binding protein (IGFBP-3), GH, GH binding protein (GHBP), pre-albumin (pre-A), albumin (A) and transferrin (TRA) levels on days 1, 3, 7, 14 and 28 after intensive care unit (ICU) admission. IGF-1, IGFBP-3, GH and GHBP levels were also assayed basally in 29 normal subjects (Ns) (Ns, age: 47.5+/-2.8 yr, BMI: 22.0+/-1.4 kg/m2) and in 34 panhypopituitary patients with severe GH deficiency (GHD, age: 42.7+/-2.5 yr, BMI: 25.6+/-0.8 kg/m2). On ICU day 1, IGF-1 and IGFBP-3 in BURN were higher than those in GHD (p<0.05 for both, respectively) and lower than those in Ns (p<0.05) while GH levels in BURN did not differ from those in Ns and higher than GHD (p<0.01). In BURN, IGF-I and IGFBP-3 levels showed a progressive decline (p<0.05) with nadir on day 14, when they overlapped those in GHD, and then an increase on day 28, though persisting lower than in Ns, while GH levels did not vary during ICU stay. IGF-I levels were associated neither to burn extension nor to ROI score. On ICU day 1 pre-A, A and TRA levels were similar to those in Ns, but underwent a progressive decrease with nadir on day 7 (p<0.001) for pre-A and TRA, and later, on day 14 (p<0.05) for A; pre-A and TRA but not A showed a rebound increase (p<0.01) on day 14, though persistingly lower than in Ns. In conclusion, our present data firstly show the time course variation of IGF-I levels in burn patients as function of nutritional and hormonal variables. It has to be emphasized that in the most critical phase after burn injuries, IGF-1 levels are as low as in hypopituitary patients with severe GHD. The physiological basis which leads to the impairment of this endogenous anabolic drive in this phase is, however, not clear yet.

Adult↗

PubMed2002

Activity of GH/IGF-I axis in trauma and septic patients during artificial nutrition: different behavior patterns?

The aim of this study was to compare several parameters of GH/IGF-I axis activity in septic and trauma patients during Intensive Care Unit (ICU) stay. To this goal, 13 patients with sepsis (SEP) and 16 with trauma (TRA) were studied. Thirty-three adult subjects (AS) were studied as controls. Serum IGF-I and -II, IGFBP-1, -2 and -3, GH and GHBP levels were studied on day 1, 3, 5 and 7 after ICU admission, during comparable artificial nutrition in SEP and TRA and basally in AS. In 5 patients with SEP and 6 with TRA, the GH response to GHRH was evaluated on day 3. On ICU day 1, IGF-I and -II and IGFBP-3 in SEP were lower (p<0.05) than in TRA which, in turn, were lower (p<0.01) than in AS. IGF-I increased (p<0.05) both in SEP and TRA, but, on ICU day 7, those in SEP persisted lower than in TRA, which became similar to those in AS. IGF-II levels increased (p<0.05) in SEP only, persisting lower (p<0.05) than in TRA. On ICU day 1, GH in SEP and TRA were similar and did not vary until day 7, overlapping those in AS. The GH response to GHRH in SEP and TRA was similar and lower (p<0.01) than in AS. These findings indicate that IGF-I activity is impaired more in septic than in trauma patients. Reduced IGF-I activity probably reflects peripheral GH resistance though basal and GHRH-induced GH levels were not increased in these conditions.

Adult↗

PubMed2002

Impairment of GH secretion in adults with primary empty sella.

Primary empty sella (PES) is generally not associated with overt endocrine abnormalities, although mild hyperprolactinemia and, in children, deficient GH secretion have been reported. The aim of this multi-center collaborative study was to evaluate basal and stimulated GH secretion in a large series of adult PES patients. The study group consisted of 51 patients [41 women and 10 men, age range: 20-78 yr; (mean+/-SD) 47+/-11 yr]; results were compared with those in normal subjects (Ns) (Ns: no.=110, 55 women, age: 20-50 yr, 37+/-14 yr), and in hypopituitaric patients (HYP) with GH deficiency (HYP: no.=44,17 women, age: 20-72, 49+/-16 yr). Baseline IGF-I levels and GH responses to insulin-induced hypoglycemia (insulin tolerance test, ITT) and/or GHRH+arginine (ARG) stimulation tests were evaluated. PES patients were also subdivided according to BMI in lean (BMI <28 kg/M2 no.=22) or obese (BMI >28 kg/m2 no.=29). PES patients had serum total IGF-I concentrations (mean+/-SE: 142.2+/-9.6 ng/ml) higher than HYP patients (77.4+/-6.4 ng/ml, p<0.001), but lower than Ns (213.3+/-17.2 ng/ml, p<0.005), with no differences between lean and obese PES subjects. The increase in serum GH concentrations following ITT and/or GHRH+ARG stimulation tests, although higher than that observed in HYP patients, was markedly reduced with respect to Ns. No difference was observed in the GH response to provocative tests between lean and obese PES patients. When individual GH responses to ITT or GHRH+ARG were taken into account, a large proportion of PES patients (52% after ITT, 61% after GHRH+ARG) showed a GH peak increase below the 1st centile of normal limits. Serum IGF-I levels in PES patients with blunted GH responses to provocative tests were significantly (p<0.001) lower in PES patients with normal GH responses, and a positive correlation was observed between IGF-I levels and serum GH peak concentrations after GHRH+ARG. In conclusion, the results of the present study provide evidence that adult PES patients often have an impairment of GH secretion, as indicated by the blunted GH response to ITT and GHRH+ARG provocative tests, and by the reduction in serum IGF-I levels. These changes are independent of body mass.

Adult↗

PubMed2002

Cortistatin-14 inhibits cell proliferation of human thyroid carcinoma cell lines of both follicular and parafollicular origin.

Cortistatin (CST-14, Pro-c[Cys-Lys-Asn-Phe-Phe-Trp-Lys-Thr-Phe-Ser-Ser-Cys]-Lys-NH2), a neuropeptide member of the SRIH family, binds to all 5 SRIH receptor (sst) subtypes, but also possesses a significant binding affinity to GH secretagogue receptors (GHS-R), which have been reported to mediate the antiproliferative activity of GHS on thyroid cancer cells. The effect of CST-14 on cell proliferation was studied in 3 different human thyroid carcinoma cell lines of follicular origin (N-PAP, WRO, ARO) and in one thyroid medullary carcinoma cell line (TT). CST-14 1 pM determined a significant inhibition of cell proliferation in TT, N-PAP and WRO cells and this effect was dose-dependent and more pronounced than that displayed by SRIH-14 (Ala-Gly-c[Cys-Lys-Asn-Phe-Phe-Trp-Lys-Thr-Phe-Thr-Ser-Cys]-OH) treatment. To a minor extent, CST-14, but not SRIH-14, also temporary inhibited ARO cell proliferation. By immunofluorescence, sst2, sst3 and sst5 have been demonstrated in TT cells, whereas types 3 and 5 only were expressed in N-PAP and WRO cells, and no sst subtype was found in ARO cells. The presence of both GHS-Rla and lb mRNA has been studied and demonstrated in the TT medullary carcinoma cell line, whereas follicular derived cell lines were already known to express GHS binding sites. Addition of EP-80874 (D-Mrp-c[D-Cyspyridilalanyl3-D-Trp-Lys-Val-Cys]-Mrp-NH2), a synthetic peptide that binds to SRIH and GHS-R, completely abolished the antiproliferative effects of CST-14 or SRIH-14 on sst/GHS-R positive thyroid carcinoma cell lines (WRO, N-PAP and TT). EP-80874 was also able to antagonize the inhibitory activity of CST-14 on the growth of cells (ARO) expressing GHS-R but not sst. Taken together, these data firstly demonstrate that EP-80874 has a mixed SRIH/CST antagonist activity and suggest that the oncostatic effect of CST-14 on thyroid cancer cells could be mediated by both sst and/or GHS-R.

Adenocarcinoma, Follicular↗

PubMed2002

Circulating ghrelin levels as function of gender, pubertal status and adiposity in childhood.

Ghrelin, a natural GH secretagogue, exerts remarkable endocrine and non-endocrine activities such as orexigenic effect and modulation of the endocrine and metabolic response to variations in energy balance. Ghrelin levels have been reported to be negatively associated to insulin secretion, enhanced in anorexia and reduced in obesity. Ghrelin levels in childhood have never been evaluated. We measured morning ghrelin levels after overnight fasting in 29 healthy lean children (NC) and in 36 obese children (OBC). The results were compared with those recorded twice in 3 different sessions in healthy lean adults (NA). In NA ghrelin levels showed good within-subject reproducibility without gender-related differences. Ghrelin levels in NC [(median; 25 degrees -75 degrees centile): 426.0; 183.0-618.0 pg/ml] were similar to those in NA (380.5; 257.7-551.7 pg/ml). Ghrelin levels in OBC (229.5; 162.5-339.5 pg/ml) were lower (p<0.03) than in NC (426.0; 183.0-618.0 pg/ml). Both in NC and in OBC, ghrelin levels were independent of gender and pubertal status. In all children, ghrelin levels were negatively associated (p<0.05) to weight excess (r=-0.24), insulin (r=-0.28) and IGF-I (r=-0.4) levels. In conclusion, these findings demonstrate that morning ghrelin levels after overnight fasting show good within-subject reproducibility, and are similar in both sexes and do not vary from childhood to adulthood. In childhood, circulating ghrelin levels are reduced in obese subjects being negatively correlated to overweight and insulin secretion.

Adult↗

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

Short children with familial short stature show enhancement of somatotroph secretion but normal IGF-I levels.

The aim of the present study was to evaluate the GH status in children with familial, idiopathic short stature (FSS). To this goal we evaluated the GH response to GHRH (1 microg/kg iv) + arginine (ARG) (0.5 g/kg iv) test which is one of the most potent and reproducible provocative tests of somatotroph secretion, in 67 children with FSS [50 boys and 17 girls, age 10.8+/-0.4 yr, pubertal stages I-III, height between -3.6 and -1.6 standard deviation score (SDS), target height <10 degrees centile, normality of both spontaneous and stimulated GH secretion as well as of IGF-I levels]. The results in FSS were compared with those in groups of children of normal height (NHC) (42 NHC, 35 boys and 7 girls, age 12.0+/-0.5 yr, pubertal stages I-III, height between -1.3 and 1.4 SDS, height velocity standard deviation score (HVSDS)>25 degrees centile, GH peak >20 microg/l after GHRH+ARG test, mean GH concentration [mGHc]>3 microg/l) and children with organic GH deficiency (GHD) (38 GHD, 29 boys and 9 girls, age 11.2+/-3.7 yr, pubertal stages I-III, height between -5.7 and -1.3 SDS, GH peak <20 microg/l after GHRH +ARG test, mGHc <3 mg/l). Basal IGF-I levels and mGHc were also evaluated in each group over 8 nocturnal hours. IGF-I levels in FSS (209.2+/-15.6 microg/l) were similar to those in NHC (237.2+/-17.2 microg/l) and both were higher (p<0.0001) than those in GHD (72.0+/-4.0 microg/l). The GH response to GHRH +ARG test in FSS (peak: 66.4+/-5.6 microg/l) was very marked and higher (p<0.01) than that in NHC (53.3+/-4.5 microg/l) which, in turn, was higher (p<0.01) than in GHD (8.2+/-0.8 microg/l). Similarly, the mGHc in FSS was higher than in NHC (6.7+/-0.5 microg/l vs 5.1+/-0.7 microg/l, p<0.05) which, in turn, was higher than in GHD (1.5+/-0.2 microg/l, p<0.0001). In conclusion, our present study demonstrates that short children with FSS show enhancement of both basal and stimulated GH secretion but normal IGF-I levels. These findings suggest that increased somatotroph function would be devoted to maintain normal IGF-I levels thus reflecting a slight impairment of peripheral GH sensitivity in FSS.

Arginine↗

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

Glucagon administration elicits blunted GH but exaggerated ACTH response in obesity.

Reduction in both spontaneous and stimulated GH secretion in obesity has been clearly demonstrated. Mild hyperactivity of hypothalamus-pituitary-adrenal (HPA) axis has been also reported. Glucagon, at least after im administration, induces clear increase in either GH or ACTH and F levels but its effect on somatotroph and corticotroph secretion in obesity has never been studied. In 7 patients with abdominal obesity (OB, aged 24-42 yr, BMI: 29.1-43.9 kg/m2, waist/hip ratio [WHR]: 0.86-1.00) we studied the GH, ACTH and F responses to the im administration of glucagon (0.017 mg/kg at 0 min). The results in OB were compared with those in a group of 6 age-matched controls normal subjects (Ns aged 26-32 yr, BMI 19.7-22.5 kg/m2). In Ns glucagon administration induced clear increase in GH (peak vs baseline, mean+/-SE: 11.6+/-3.4 vs 3.3+/-0.7 microg/l, p<0.02), and ACTH (52.9+/-15.2 vs 19.0+/-1.5 pg/ml, p<0.02) levels which peaked at +150 and +165 min, respectively. Increase in F levels (222.3+/-23.8 vs 158.3+/-7.0 ng/ml, p<0.05) was also recorded but peaked at +180 min. In OB glucagon administration induced GH response (7.4+/-2.3 vs 0.8+/-0.6 microg/l) lower (p<0.05) than that recorded in Ns; when the GH responses were evaluated by co-variance analysis, a significant difference between the 2 groups was recorded in term of peaks but not of AUCs. On the other hand, the ACTH response to glucagon in OB was higher than that in Ns (11452.6+/-2447.7 vs 4892.2+/-719.4 pg/ml x min, p<0.05). The F response to glucagon in OB and Ns was, however, similar (24057.9+/-4109.1 vs 29835.9+/-1566.0 ng/ml x min). In conclusion, this study demonstrates that in obese patients the im administration of glucagon elicits blunted GH response but exaggerated ACTH increase which is uncoupled with the adrenal response. These findings agree with the existence of concomitant GH insufficiency and altered corticotroph function in obesity.

Adrenocorticotropic Hormone↗

PubMed2002

GH-independent cardiotropic activities of hexarelin in patients with severe left ventricular dysfunction due to dilated and ischemic cardiomyopathy.

AIM: To investigate acute cardiotropic activities of hexarelin in patients with severe left ventricular dysfunction due to ischemic (iCMP) and dilated cardiomyopathy (dCMP). METHODS AND RESULTS: We studied the effect of intravenous hexarelin administration on growth hormone (GH) levels and left ventricular ejection fraction (LVEF) evaluated by radionuclide angiography in eight patients with dCMP (age 53.0+/-2.8, LVEF 16.7+/-2.1%) and five patients with iCMP (age 52.0+/-2.8 years, LVEF 22.6+/-2.1). Results were compared with a group of seven normal subjects (age 37.4+/-3.4 years, LVEF 64.0+/-1.5%) and seven patients with severe growth-hormone deficiency (GHD; age 42.0+/-4.4 years, LVEF 50.0+/-1.9%) previously studied with the same methodology. In dCMP and iCMP patients hexarelin induced a similar significant (P<0.05) increase in GH levels. In iCMP patients hexarelin induced a LVEF increase (peak LVEF 26.2+/-2.5%, P<0.05) as observed in normals and GHD, while in dCMP LVEF was unchanged (peak LVEF 17.7+/-1.7, P=NS). In all groups other hemodynamic parameters were unchanged. CONCLUSIONS: Acute hexarelin administration increases LVEF in iCMP patients (as in normals and GHD) but not in dCMP patients in spite of a similar GH releasing effect and basal LVEF. A possible explanation of the positive inotropic effect of hexarelin in iCMP could be a direct stimulation on viable myocardium or myocardial contractile reserve.

Adult↗

PubMed2002

Concomitant impairment of growth hormone secretion and peripheral sensitivity in obese patients with obstructive sleep apnea syndrome.

To clarify the impairment of the GH/IGF-I axis in obstructive sleep apnea syndrome (OSAS), in 13 adult male patients with OSAS (OSA) as well as 15 weight-matched patients with simple obesity (OB) and 10 normal lean male subjects (NS), we studied: 1) the GH response to GHRH (1 micro g/kg iv) plus arginine (30 g iv); and 2) the IGF-I and IGF binding protein-3 responses to a very low dose recombinant human (rh)GH treatment (5.0 microg/kg sc per day for 4 d). The GH response to arginine plus GHRH in OSA was lower than in OB (P < 0.05), which in turn was lower than in NS (P < 0.001). Basal IGF-I levels in OSA were lower than in OB (P < 0.05), which in turn were lower than in NS (P < 0.03). As opposed to OB and NS, in OSA a very low rhGH dose did not affect IGF-I. Adjusting for age and basal values, rhGH-induced IGF-I rise in OSA was lower than in OB (P < 0.01). IGF binding protein-3, glucose, and insulin levels in the three groups were not modified by rhGH. OSA show a more marked impairment of the maximal secretory capacity of somatotroph cells together with reduced IGF-I sensitivity to rhGH stimulation. These findings suggest that OSAS is connoted by a concomitant impairment of GH secretion and sensitivity.

Adult↗

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↗

PubMed2002

GH secretion is impaired in patients with primary hyperparathyroidism.

The activity of the GH/IGF-I axis as a function of parathyroid activity and calcium metabolism in humans has never been assessed. To address this issue, we studied 18 patients (5 men, 13 women; age range, 23-76 yr; mean, 61 yr) with primary hyperparathyroidism (PHP) due to solitary parathyroid adenoma. GH secretion was evaluated by serum IGF-I levels, spontaneous mean GH secretion over two morning hours, and GH response to arginine (ARG) alone or combined with GHRH. In five patients, serum GH concentrations were measured every 20 min for 24 h, and deconvolution analysis was performed. A group of 35 age- and sex-matched normal subjects served as controls. Mean serum IGF-I levels in PHP were lower than in normal controls, and in six PHP patients individual serum IGF-I levels were below the age-related normal range. The mean (+/-SE) peak GH response to ARG alone in PHP patients was significantly lower than in normal subjects (4.0 +/- 1.0 vs. 22.0 +/- 1.3 microg/liter; P < 0.001). Likewise, the mean (+/-SE) peak GH response to ARG plus GHRH was reduced in PHP patients (9.9 +/- 0.9 vs. 38.0 +/- 3.5 microg/liter; P < 0.001). The mean GH concentration over two morning hours in PHP was lower (0.20 +/- 0.05 vs. 1.34 +/- 0.31 microg/liter; P < 0.001). The mean GH concentration over 24 h in five PHP patients was lower than in six normal controls (0.3 +/- 0.1 vs. 0.7+/- 0.1 microg/liter; P < 0.05); the deconvolution analysis showed that 24-h GH production rate (3.0 +/- 1.7 vs. 28.2 +/- 4.7 microg/liter.d; P < 0.05) and mean secretory burst mass (1.2 +/- 0.7 vs. 10.5 +/- 2.6 microg/liter; P < 0.05), but not pulse frequency, were lower in PHP patients than in normal controls. GH half-life and approximate entropy values of 24-h GH profiles were similar in PHP patients and normal controls. No correlation was found between serum-ionized calcium or PTH levels and spontaneous or stimulated GH levels in PHP patients. In conclusion, this study demonstrates that PHP patients have a reduction in both spontaneous and stimulated GH secretion. Accordingly, PHP should be mentioned as a further example of a metabolic condition in which GH secretion in adults is reduced.

Adult↗