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C Dieguez

Publications and source records attributed to C Dieguez.

At least 55 records · Page 3Linked to original sources
PubMed2001

Effect of acute pharmacological modulation of plasma free fatty acids on GH secretion in acromegalic patients.

OBJECTIVES: In acromegaly GH secretion is markedly increased due in most cases to a GH secreting pituitary adenoma. GH secretion is modulated by variations in the levels of free fatty acids (FFA). Recent studies in different clinical situations, have shown that reduction in FFA with acipimox (A) modifies somatotroph cell responsiveness. The aim of the present study was to evaluate the effect of acute pharmacological reduction of plasma FFA on both basal GH levels and GHRH-mediated GH secretion in acromegalic patients. PATIENTS: Six acromegalic patients (four female, two male) aged 57 +/- 4 years., with active disease due to pituitary adenomas were studied. Four of the patients had been treated previously by surgery and/or radiotherapy. The diagnosis of active acromegaly was established by clinical assessment, increased serum IGF-I and impaired GH suppression after oral glucose. MEASUREMENTS: Four tests were performed: placebo, A (250 mg, orally, - 210 minutes and - 60 minutes), GHRH (100 microg, iv, 0 minutes) and GHRH plus A. The different tests on each subject were performed in random order one week apart, each subject served as their own control. Serum GH was measured by RIA at appropriate intervals. The area under the curve (AUC) was calculated by the trapezoidal METHOD: Statistical analysis was performed by Wilcoxon test. P < 0.05 was considered significant. RESULTS: The administration of A induced a FFA reduction during the entire test both when administered with placebo and with GHRH: AUC (mmol/l x 90 minutes): placebo plus placebo: 88.2 +/- 7.3. Placebo plus A: 23.2 +/- 4.6 (P < 0.05). Placebo plus GHRH: 85.4 +/- 6.9. A plus GHRH: 21.8 +/- 3.8 (P < 0.05). Mean peak GH level (microg/l) after placebo plus placebo was 5.0 +/- 1.8 not significantly different than after placebo plus A with a mean peak of 6.2 +/- 2 (P = ns). Mean peak GHRH-induced GH secretion was 26.0 +/- 15.4 and was not modified by previous A administration with mean peak of 24.4 +/- 11.8 (P = ns). CONCLUSIONS: In acromegalic patients acute pharmacological reduction of FFA with acipimox did not modify basal GH levels or GHRH-induced GH secretion, suggesting that the adenomatous somatotroph cell is unresponsive to physiological signals such as FFA which act at a pituitary level. These data support the hypothesis of an intrinsic neoplastic pituitary defect for the pathogenesis of acromegaly.

Acromegaly↗
PubMed2001

Developmental and hormonal regulation of leptin receptor (Ob-R) messenger ribonucleic acid expression in rat testis.

In target tissues, leptin receptor (Ob-R) gene expression results in an array of alternatively spliced isoforms (Ob-Ra to Ob-Rf) with different functional features. Recent evidence has pointed to a direct role of leptin in the control of testicular function. However, complete elucidation of the pattern of Ob-R gene expression in the male gonad is still pending. The focus of this study was to characterize in detail the developmental pattern of expression and hormonal regulation of Ob-R gene in rat testis. To this end, the overall expression of Ob-R mRNA was compared to that of the fully functional, long Ob-Rb isoform in different experimental settings, using semiquantitative reverse transcription-polymerase chain reaction. Expression of Ob-R mRNA was detected in testes from 15-, 30-, 45-, and 75-day-old rats at rather constant relative levels. In contrast, testicular expression of Ob-Rb mRNA was higher in pubertal testes (15- to 30-day-old rats) and declined in adulthood. In testes from 30-day-old animals, analysis of isoform distribution revealed that, in addition to abundant Ob-Rb mRNA levels, expression of Ob-Ra, Ob-Rf, and, to a lesser extent, Ob-Rc and Ob-Re messages is detected. Testicular Ob-R mRNA expression appeared sensitive to neonatal imprinting as neonatal treatment with estradiol benzoate (500 microg/rat; Day 1 postpartum) resulted in a persistent increase (P: < 0.01) in the relative expression level of Ob-R mRNA, a phenomenon only partially mimicked by neonatal suppression of serum gonadotropins by means of LHRH-antagonist administration. In addition, neonatal estrogenization differentially altered the pattern of expression of Ob-R isoforms in adult rat testis, as expression of Ob-Rb mRNA was decreased to undetectable levels, whereas that of Ob-Rc remained unaltered, and Ob-Ra, Ob-Rf, and, to a lesser extent, Ob-Re mRNA levels were significantly increased (P: < 0.01) by neonatal exposure to estrogen. Finally, down-regulation of testicular Ob-R gene expression by homologous and heterologous signals was demonstrated as relative levels of Ob-R and Ob-Rb mRNAs were significantly decreased (P: < 0.01), in a coordinate manner, in rat testis after exposure to human recombinant leptin in vitro, and after stimulation with hCG and FSH in vivo. In conclusion, our results indicate that testicular Ob-R gene expression is developmentally regulated, imprinted by the neonatal endocrine milieu, and sensitive to regulation by leptin and gonadotropins. The ability of pivotal signals in testicular function to regulate Ob-R gene expression further supports the contention of a direct role of leptin in functional control of the rat testis.

Animals↗
PubMed2001

Involvement of nitric oxide in the regulation of growth hormone secretion in dogs.

Nitric oxide (NO) is a highly reactive gas that has been suggested to function as a neurotransmitter in the neuroendocrine system. In this work, we have evaluated the role of NO pathways in growth hormone (GH) secretion by assessing the effect of L-arginine infusion, a precursor of NO formation, and L-NAME, a nitric oxide synthase (NOS) inhibitor. The experiments were carried out on 7 adult beagle dogs. A saline infusion was carried out on all the dogs as a control test. L-arginine (infusion i.v. 10 g in 100 ml of saline, from t = 0 to 30 min) and L-nitro-arginine-methyl ester, L-NAME (infusion of 300 microg/kg in 120 ml of saline, from t = -30 to 45 min) were administered alone and together with growth hormone-releasing hormone (GHRH) (i.v. bolus at 0 min, at a dose of 100 microg), the synthetic GH secretagogue GHRP-6 (i.v. bolus at 0 min, at a dose of 90 microg), and the 5-HT1D serotonin receptor agonist sumatriptan, SUM (s.c. injection at the dose of 3 mg). Plasma cGH was determined by RIA. Results were evaluated by one-way analysis of variance, followed by the Newman-Keuls test for multiple comparisons. L-arginine administration resulted in a slight increase in plasma cGH in comparison with saline controls. Combined administration of L-arginine and GHRH enhanced cGH release in comparison with GHRH alone. L-NAME alone did not modify baseline cGH levels, but completely suppressed the GH release induced by GHRH or GHRP-6. It also strongly reduced, but did not abolish the effect of the two peptides (GHRH plus GHRP-6) administered together. Finally, administration of the 5-HT1D agonist SUM induced a significant cGH secretion in all dogs, a response which was not modified when L-NAME was administered in combination with SUM. In conclusion, our data show that inhibition of NO blunts both GHRH or GHRP-6-induced cGH release, and are compatible with the hypothesis that it acts by decreasing hypothalamic somatostatin release.

Animals↗
PubMed2001

Hormonal control of growth hormone secretion.

Growth hormone secretion by the somatotroph cells depends upon the interaction between hypothalamic regulatory peptides, target gland hormones and a variety of growth factors acting in a paracrine or autocrine fashion. This review will be focused on recent data regarding the mechanism by which growth hormone-releasing hormone (GHRH) influences somatotroph cell function and the physiological role played by Ghrelin and leptin in the regulation of growth hormone (GH) secretion. It is well established that binding of GHRH to its receptor leads to activation of protein kinase A (PKA). More recently, it was found that GHRH can also activate mitogen-activated protein (MAP) kinase both in pituitary cells and in a cell line overexpressing the GHRH receptor. Whether somatotroph adenomas, either with or without a GS-alpha mutation, have alterations in some of the components of the activation of the MAP kinase pathway remains to be known. The recent isolation of Ghrelin, the endogenous ligand of the growth hormone secretagogue receptor, can be considered a landmark in the GH field, which opens up the possibility of gaining greater insight into our understanding of the mechanisms involved in the regulation of GH secretion and somatic growth. Indeed, preliminary evidences indicate that this peptide exerts a marked stimulatory effect on plasma GH levels in both rats and humans. Finally, it is well known that GH secretion is markedly influenced by nutritional status. Leptin has emerged as an important adipose tissue-generated signal that is involved in the regulation of GH secretion, thus providing an integrated regulatory system of growth and metabolism. Although the effects of leptin on GH secretion in humans remain to be clarified, indirect evidences indicate that it may play an inhibitory role.

Ghrelin↗
PubMed2001

Ghrelin, a novel placental-derived hormone.

Ghrelin, a GH-releasing acylated peptide, has been recently identified from the rat stomach. The purified peptide consists of 28 amino acids in which the serine 3 residue is n-octanoylated. Here we show that ghrelin messenger RNA and ghrelin peptide are present in the human as well as in rat placentae. In human placenta, ghrelin was detected by PCR at both first trimester and after delivery. While ghrelin was not detected by immunohistochemistry in human placenta at term, it was easily identified by immunohistochemistry at first trimester being mainly expressed in cytotrophoblast cells and scarcely in syncytiotrophoblast ones. Ghrelin was also identified in a human choriocarcinoma cell line, the BeWo cells. Ghrelin was found, by immunohistochemistry, in the cytoplasm of labyrinth trophoblast of rat placenta, whereas other placental cell types seems to be negative for ghrelin immunostaining. Moreover, placental ghrelin messenger RNA, in pregnant rats, showed a characteristic profile of expression being practically undetectable during early pregnancy, with a sharp peak of expression at day 16 and decreasing in the latest stages of gestation. In conclusion, ghrelin has been detected in human and rat placenta showing a pregnancy-related time course of expression. Whether placenta-derived ghrelin is involved in the modulation of GH release, or placental cell growth and differentiation remains to be established.

Animals↗
PubMed2001

Endocrine activities of ghrelin, a natural growth hormone secretagogue (GHS), in humans: comparison and interactions with hexarelin, a nonnatural peptidyl GHS, and GH-releasing hormone.

An endogenous ligand for the GH secretagogue-receptor (GHS-receptor) has recently been isolated, from both the rat and the human stomach, and named ghrelin. It is a 28-amino-acid peptide showing a unique structure with an n-octanoyl ester at its third serine residue, which is essential for its potent stimulatory activity on somatotroph secretion. In fact, it has been demonstrated that ghrelin specifically stimulates GH secretion from both rat pituitary cells in culture and rats in vivo. The aim of the present study was to test the GH-releasing activity of ghrelin in humans and to compare it with that of GHRH and hexarelin (HEX), a nonnatural peptidyl GHS, which possesses strong GH-releasing activity but also significantly stimulates PRL, ACTH, and cortisol secretion. To clarify the mechanisms of action underlying the GH-releasing activity of ghrelin in humans, its interaction with GHRH and HEX was also studied. Seven normal young volunteers (7 men; 24-32 yr old; body mass index, 20-24 kg/m(2)) were studied. All subjects underwent the administration of ghrelin, HEX, and GHRH-29 (1.0 microg/kg i.v. at 0 min) as well as placebo (2 mL isotonic saline i.v. at 0 min). Six subjects also underwent the combined administration of ghrelin and GHRH or HEX. Blood samples were taken every 15 min from -15 up to +180 min. GH levels were assayed at each time point in all sessions; PRL, ACTH, cortisol, and aldosterone levels were also assayed after administration of ghrelin and/or HEX. Ghrelin administration induced a prompt and marked increase in circulating GH levels (Cmax, mean +/- SEM, 92.1 +/- 16.7 microg/L; area under the curve, 1894.9 +/- 347.8 microg/L.h). The GH response to ghrelin was clearly higher (P < 0.01) than the one recorded after GHRH (26.7 +/- 8.7 microg/L; 619.6 +/- 174.4 microg/L.h) and even significantly higher (P < 0.05) than after HEX (68.4 +/- 14.7 microg/L; 1546.9 +/- 380.0 microg/L x h). Ghrelin administration also induced an increase in PRL, ACTH, and cortisol levels; these responses were higher (P < 0.05) than those elicited by HEX. A significant increase in aldosterone levels was recorded after ghrelin but not after HEX. The endocrine responses to ghrelin were not modified by the coadministration of HEX. On the other hand, the coadministration of ghrelin and GHRH had a real synergistical effect (P < 0.05) on GH secretion (133.6 +/- 22.5 microg/L; 3374.3 +/- 617.3 microg/L x h). In conclusion, ghrelin, a natural ligand of GHS-receptor, exerts a strong stimulatory effect on GH secretion in humans, releasing more GH than GHRH and even more than a nonnatural GHS such as HEX. Ghrelin, as well as HEX, also stimulates lactotroph and corticotroph secretion. Ghrelin shows no interaction with HEX, whereas it has a synergistical effect with GHRH on GH secretion. Thus, ghrelin is a new hormone playing a major role in the control of somatotroph secretion in humans, and its effects are imitated by nonnatural GHS.

Adrenocorticotropic Hormone↗
PubMed2001

Growth hormone secretagogues as diagnostic tools in disease states.

One of the most active topics in the growth hormone-IGF-1 field is that of the so-called growth hormone secretagogues (GHS). At a time when the isolation of GHRH had not occurred, the GHS were developed as artificial tools to release GH. The interest in these groups of compounds was rekindled when it was realized that they were not surrogates of GHRH nor were they acting through the modulation of the release of either GHRH or somatostatin. With the subsequent cloning of the specific receptor of GHS, and today of the natural ligand for that receptor, named ghrelin, it soon become clear that GHS and the GHS-receptor were part of a new physiological system involved in GH regulation. The dual control of GH secretion became a trinity. GHS releases GH when administered by any route--oral, iv, sc, and even transdermally-with a surprising potency and reproductivity. In addition, GHS when administered together with GHRH exert a synergistic action on GH secretion and that combined administration is the most potent GH releaser to date. Clinical studies have demonstrated that the GHS-GHRH administration may be considered the new "gold standard" test of GH reserve in humans, as the GH secretion so elicited is not altered by gender, adiposity, or age. The combined administration of GHRH plus GHS is able to discriminate between healthy subjects and patients with adult GH deficiency, suggesting a considerable utility in the clinical setting.

Adult↗
PubMed2001

Physiology and possible pathology of growth hormone secretagogues.

Growth hormone segretagogues (GHS) are artificial molecules able to stimulate growth hormone (GH) secretion. They were discovered before the hypothalamic growth hormone-releasing hormone (GHRH). These molecules had a structure devoid of opiate activity, and GHRP-6 is the most representative compound. These compounds identified a new physiological system involved in GH regulation, and their action is independent of GHRH or somatostatin. Recently an endogenous ligand for the GHS receptor, ghrelin, was discovered, suggesting that this may be the third factor in the control of GH secretion. This peptide was isolated from the stomach and is characterized by the presence of an acylated group representing a new type of molecular hormonal structure; it is able to stimulate GH secretion in vitro and in vivo in the rat. As observed for the majority of GHS, ghrelin's action is not fully specific for GH release; the acute administration of ghrelin stimulates the release of significant amounts of PRL, ACTH and cortisol. Moreover, the presence of ghrelin in rat and human placenta has been reported, suggesting a possible role of this peptide in the local modulation of GH release and in maternal and fetal pituitary secretion. Ghrelin stimulates gastric acid secretion, is able to induce adiposity by activating a central mechanism for increasing food intake and decreasing fat utilization, and ghrelin mRNA and peptide are expressed in normal and adenomatous human pituitary tissue. Possible therapeutic applications of ghrelin remain to be assessed.

Ghrelin↗
PubMed2000

GH-releasing hormone and GH-releasing peptide-6 for diagnostic testing in GH-deficient adults.

BACKGROUND: The diagnosis of growth hormone (GH) deficiency in adults is based on provocative testing of GH secretion. The insulin tolerance test (ITT), currently the favoured test for this diagnosis, has been criticised for poor reproducibility and inconvenience. Since the combined administration of GH-releasing hormone (GHRH) plus GH-releasing peptide-6 (GHRP-6) is the most potent stimulus of GH secretion, we did a multicentre study comparing GH peaks elicited by ITT with those elicited by the GHRH/GHRP-6 test in healthy controls and GH-deficient individuals (cases). METHODS: 125 adult patients with organic pituitary disease and 125 healthy individuals were studied. All cases and controls were given GHRH 1 microg per kg bodyweight intravenously plus GHRP-6 1 microg per kg intravenously at 0 min and blood samples were obtained during a subsequent 120 min period. 27 controls and all cases had an ITT. Inclusion criteria were severe GH deficiency--ie, a GH peak after ITT of < or = 3 microg/L. Results of the GHRH/GHRP-6 test were analysed by receiver-operating characteristic curve methodology. FINDINGS: GH peaks seen after the GHRH/GHRP-6 test did not result in any side-effects and were not affected by age, sex, amount of adipose tissue, or by the GH assay system used. The GH mean peak after the GHRH/GHRP-6 test was 59.2 microg/L (SD 2.2) for controls and 4.1 microg/L (0.3) for cases, whereas after ITT the mean peak was 14.3 microg/L (1.7) and 0.5 microg/L (0.06), respectively. The differential peak responses of controls and cases was greater (p<0.001), for GHRH/GHRP-6 test than for ITT. When individually analysed GH peaks were a continuum, from 139.0 microg/L to 0.01 microg/L, with a cut-off point of 15.0 microg/L. The GHRH/GHRP-6 test performed well under the ROC curve analysis. For clinical utility, it is then proposed that values > or = 20.00 microg/L be considered normal and < or = 10.00 microg/L as GH deficient. INTERPRETATION: The GHRH/GHRP-6 test is a convenient, safe and reliable test for adult GH deficiency and is not confounded by clinical factors known to alter GH secretory patterns. An evoked GH concentration of > or = 15.0 microg/L accurately distinguishes between healthy and GH-deficient adults.

Adolescent↗
PubMed2000

Regulation of in vivo TSH secretion by leptin.

Leptin, the product of the ob gene, is a hormone secreted by adipocytes that regulates food intake and energy expenditure. The hypothalamus-pituitary-thyroid axis is markedly influenced by the metabolic status, being suppressed during food deprivation. The aim of the present study was to assess whether leptin can act as a metabolic signal connecting the adipose tissue with the pituitary-thyroid axis. We studied the effect of leptin administration (10 microg, i.c.v.) on spontaneous TSH secretion and TSH responses to TRH in euthyroid and hypothyroid food-deprived rats. Spontaneous TSH secretion was assessed over 6 h with samples taken every 7 min. Administration of leptin to food-deprived euthyroid rats led to a reversal of the inhibitory effect exerted by fasting on spontaneous TSH secretion. This stimulatory effect of leptin on spontaneous TSH appears to be dependent on the thyroid status since it could not be observed in hypothyroid rats. This data suggests that blunted spontaneous TSH secretion in food-deprived rats is a functional and reversible state, and that the decreased leptin concentrations could be the primary event responsible for the suppression of the hypothalamic-pituitary-thyroid-axis in food-deprived rats.

Animals↗
PubMed2000

Preliminary evidence that Ghrelin, the natural GH secretagogue (GHS)-receptor ligand, strongly stimulates GH secretion in humans.

An endogenous ligand for the GH secretagogue-receptor (GHS-R) has been recently purified from rat and human stomach and named Ghrelin. It has been demonstrated that Ghrelin specifically stimulates GH secretion from rat pituitary cells in culture as well as in rats in vivo. In this preliminary study, in 4 normal adults [age (mean+/-SE): 28.6+/-3.5 yr; body mass index (BMI): 22.3+/-2.1 kg/m2] we administered 1.0 microg/kg Ghrelin or GHRH-29 to compare their GH-releasing activities in humans. In all subjects Ghrelin induced a prompt, marked and long-lasting increase in circulating GH levels (peak: 107.9+/-26.1 microg/l; AUC: 6503.1+/-1632.7 microg/l/h). The GH response to Ghrelin was clearly higher (p<0.05) than that after GHRH (peak: 22.3+/-4.5 microg/l; AUC: 1517.5+/-338.4 microg/l/h). In conclusion, this preliminary study shows that Ghrelin exerts a strong stimulatory effect on GH secretion in humans releasing more GH than GHRH.

Adult↗
PubMed2000

Regulation of somatotroph cell function by the adipose tissue.

Obese subjects exhibit a marked decrease in plasma growth hormone (GH) levels. However, the mechanisms by which increased adiposity leads to an impairment of GH secretion are poorly understood. Recent evidence suggests that the adipose tissue can markedly influence GH secretion via two different signals, namely free fatty acids (FFA) and leptin. FFA appear to inhibit GH secretion mainly by acting directly at pituitary level. Interestingly, reduction in circulating FFA levels in obese subjects led to a marked increase in GH responses to different GH secretagogues. This indicates that FFA exert a tonic inhibitory effect that contributes to blunted GH secretion in obese subjects. Recent data have shown that leptin is a metabolic signal that regulates GH secretion, since the administration of leptin antiserum to adult rats led to a marked decrease in spontaneous GH secretion. However, leptin prevents,the inhibitory effect exerted by fasting on plasma GH levels. The effect of leptin in adult rats appears to be exerted at hypothalamic level by regulating growth hormone releasing hormone (GHRH), somatostatin and neuropeptide Y (NPY)-producing neurones. In addition, during fetal life or following the development of pituitary tumors, leptin can also act directly at the anterior pituitary.

Adipose Tissue↗
PubMed2000

Short-term fasting abolishes the sex-related difference in GH and leptin secretion in humans.

We studied growth hormone (GH) and leptin secretion in eight male (age 29.3 +/- 1.2 yr, body mass index 22.2 +/- 0.5 kg/m(2)) and seven female normal subjects (28.0 +/- 0.8 yr, 20.1 +/- 0.7 kg/m(2)) before and after 36 h of fasting. In the fed state, 8-h mean GH and leptin concentrations were higher in females (P < 0.05 and P < 0. 0001, respectively). Fasting increased GH and decreased leptin in both sexes. There was significant interaction between gender and fasting (P < 0.05 for GH and P < 0.005 for leptin). Females showed a slighter increase in GH but a more marked decrease in leptin, so that there was no significant gender-related difference in GH and leptin after fasting. Fasting did not modify insulin-like growth factor (IGF) I, IGF binding protein (IGFBP)-3, acid-labile subunit, or GH binding protein; increased IGFBP-1 and free fatty acids (P < 0.0001) but decreased glucose (P < 0.001) and insulin levels (P < 0.05). In males, insulin levels were higher (P < 0.05) in the fed state and underwent deeper reduction after fasting (interaction P < 0.03). In conclusion, GH and leptin secretions are higher in women than in men in the fed but not in the fasting condition, which abolishes these gender-related differences in humans.

Adult↗
PubMed2000

Influence of different serotonin receptor subtypes on growth hormone secretion.

The role of serotonin (5-HT) in the regulation of growth hormone (GH) secretion remains unclear due to the existence of many different receptors that mediate the 5-HT actions, and the lack of suitable specific agonist and antagonist drugs. In the present work we have taken advantage of the recent development of new selective 5-HT drugs in order to clarify the role played by different 5-HT receptor types and subtypes on GH secretion. The experiments were carried out on beagle dogs. GH-releasing hormone (GHRH) increased basal canine GH (cGH) levels from 0.8 +/- 0.2 to 8.8 +/- 1.7 microg/l at 15 min. Administration of 5-HT(1D) receptor agonist sumatriptan (SUM) induced a cGH peak at 30 min of 12.9 +/- 2.7 microg/l. The combined administration of GHRH plus SUM strikingly potentiated cGH release with a peak of 36.9 +/- 6 microg/l at 30 min (p < 0.05). Pretreatment with the muscarinic receptor antagonist atropine completely abolished the cGH response to SUM, while the cholinergic agonist pyridostigmine (PYR) did not modify this response (15.3 +/- 5 microg/l PYR plus SUM vs. SUM alone 12.9 +/- 2. 7 microg/l). On the other hand, administration of drugs with activity at 5-HT(2A/C) receptors showed a stimulatory role for the 5-HT(2C) receptor subtype, since LY-53857 (antagonist 5-HT(2A/C)) and DOI agonist (5-HT(2A/C)) both modified the GH response stimulated by GHRH (AUC 88.5 +/- 30.4 and 400 +/- 64.6 vs. 267.3 +/- 52.6 respectively), while ketanserin (antagonist 5-HT(2A)) did not modify this response. The 5-HT(3) antagonist ICS-205-930 failed to modify either basal or GHRH induced GH responses. In conclusion, our data show that 5-HT(1D) receptors play a stimulatory role on GH secretion in the dog, possibly by acting through a decrease in hypothalamic somatostatin release. Similarly, the 5-HT(2C) receptor subtypes also appear to play a stimulatory role. However, 5-HT(2A) and 5-HT(3) receptors do not appear to be involved in the control of basal and GHRH-induced GH secretion.

Amphetamines↗
PubMed2000

Serum leptin levels in patients with acromegaly before and after correction of hypersomatotropism by trans-sphenoidal surgery.

It has been shown that GH excess is associated with decreased leptin levels and decreased body fat mass. Reports regarding the effect of GH on serum leptin levels are inconsistent. We studied leptin secretion in 20 acromegalics before and 2 months after trans-sphenoidal surgery and in 20 gender-, age-, and body mass index (BMI)-matched control subjects. The mean 8-h leptin concentration for each subject was measured from a pool formed of samples collected hourly beginning at 2200 h until 0600 h the next morning. In a subgroup of 10 acromegalics, leptin pulsatility was assessed for the same period of time in 10-min sampling intervals. Basal GH, insulin-like growth factor-I (IGF-I), insulin, glucose, and lipids levels were measured. Area under the curve for insulin (AUCins) during oral glucose tolerance test was calculated. Control subjects and acromegalics had similar BMI, but patients with active acromegaly had significantly lower mean leptin level (mean +/- SEM; in men, 2.6+/-0.4 vs. 7.1+/-1.1 microg/L, P = 0.003; in women, 16.0+/-3.4 vs. 23.5+/-3.1 microg/L; P = 0.036). Mean 8-h leptin correlated with BMI (r = 0.57, P = 0.007, in controls; r = 0.70, P = 0.001, in patients). In stepwise regression analysis with mean 8-h leptin as a dependent variable, BMI (P<0.001) and gender (P = 0.01) in acromegalics entered the equation, whereas in control subjects gender, free fatty acids, insulin, and age accounted for 99.3% in leptin variability. After surgery, BMI did not change significantly; and glucose (P = 0.014), GH (P<0.001), and IGF-I (P<0.001) levels together with AUCins (P = 0.002) decreased, whereas mean leptin concentration rose significantly and attained normal levels (4.1+/-0.8 microg/L, P = 0.028) in acromegalic men and (23.6+/-4.7 microg/L, P = 0.003) in acromegalic women. Correlation between leptin level and BMI was preserved after surgery (r = 0.62, P = 0.005). In stepwise regression analysis, free fatty acids (P = 0.04) contributed to 26.8% of the variance in corrected-leptin (for BMI and gender). Leptin concentration peak height and interpeak nadir level rose significantly (P = 0.033 and P = 0.037) after surgery by Cluster analysis, without significant changes in leptin pulse frequency and incremental peak amplitude. Nocturnal rise of leptin (mathematically described by a cubic curve) was characterized by an acrophase just after midnight, before and after surgery. The amplitude and the average leptin concentration of the cubic fit increased significantly after surgery (P = 0.028 and P< 0.001). In conclusion in acromegalic patients: 1) leptin secretion maintains the pulsatility and nocturnal rise; 2) the gender-based leptin differences are preserved; 3) GH-IGF-I normalization leads to a rise in leptin that is not related to changes in BMI; and 4) the possible role of rise in leptin levels when assessing clinical and metabolic outcome of therapy in acromegalic patients deserves additional studies.

Acromegaly↗
PubMed2000

Reduction of free fatty acids by acipimox enhances the growth hormone (GH) responses to GH-releasing peptide 2 in elderly men.

GH release is increased by reducing circulating free fatty acids (FFAs). Aging is associated with decreased plasma GH concentrations. We evaluated GH releasing capacity in nine healthy elderly men after administration of GH-releasing peptide 2 (GHRP-2), with or without pretreatment with the antilipolytic drug acipimox, and compared the GHRP-2-induced GH release with the response to GHRH. The area under the curve (AUC) of the GH response after GHRP-2 alone was 4.8 times higher compared with GHRH alone (1834 +/- 255 vs. 382 +/- 78 microg/L.60 min, P: < 0.001). Acipimox, which reduced FFAs from 607 micromol/L to 180 micromol/L, increased the GH AUC to 1087 after GHRH and to 2956 microg/L.60 min after GHRP-2 (P: < 0.01). The AUC after acipimox/GHRP-2 were positively correlated with the AUC after GHRP-2 alone (r = 0.93, P: < 0.01); this was also observed between acipimox/GHRH and GHRH alone (r = 0.73, P: = 0.03). Significant negative correlations were observed between basal FFAs and AUC after GHRH or GHRP-2 after combining the data with and without acipimox (r = 0.58, P: = 0.01 and r = 0.48, P: = 0.04, respectively), and between basal FFAs and GH at t = 0 (r = -0.44, P: = 0.001). Interestingly, GHRP-2 administration was followed by a significant early rise in plasma FFAs by 60% (P = 0.01), indicating an acute lipolytic effect. In conclusion, reduction of circulating FFAs strongly enhances GHRP-2-stimulated GH release in elderly men. The data indicate that the decreased GH release associated with aging can be reversed by acipimox and that the pituitary GH secretory capacity in elderly men is still sufficient.

Aged↗
PubMed2000

Leptin increases in vivo GH responses to GHRH and GH-releasing peptide-6 in food-deprived rats.

BACKGROUND: Leptin has recently been shown to have a stimulatory effect on basal GH secretion. However, the mechanisms by which leptin exert this effect are not yet clear. GHRH and GH-releasing peptide (GHRP)-6 are the two most potent GH secretagogues described to date. OBJECTIVE: To determine if leptin could also enhance in vivo GH responses to a maximal dose of GHRH. DESIGN: Leptin (10microg i.c.v.) or vehicle was administered at random before GHRH (10microg/kg i,v.) or GHRP-6 (50microg/kg i.v.), to freely-moving rats with food available ad libitum and to (48h) food-deprived rats. METHODS: Leptin and GH concentrations were measured by radioimmunoassay. Comparison between the different groups was assessed by the Mann-Whitney test. RESULTS: In comparison with fed rats, food-deprived rats showed a marked decrease in GH responses to GHRH as assessed by the area under the curve (5492+/-190ng/ml in fed rats and 1940+/-128ng/ml in fasted rats; P<0.05) and GHRP-6 (3695+/-450 in fed rats and 1432+/-229 in fasted rats; P<0.05). In comparison with its effects in vehicle-treated rats, leptin administered to food-deprived rats markedly increased GH responses to both GHRH (6625+/-613ng/ml; P<0.05) and GHRP-6 (5862+/-441ng/ml; P<0.05). CONCLUSIONS: These data suggest that the blunted GH response to GHRH and GHRP-6 in food-deprived rats is a functional and reversible state, and that the decreased leptin concentrations could be the primary defect responsible for the altered GH secretion in food-deprived rats.

Animals↗