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Emanuela Arvat,
Laura Gianotti,
Roberta Giordano,
Fabio Broglio,
Mauro Maccario,
Fabio Lanfranco,
Giampiero Muccioli,
Mauro Papotti,
Andrea Grazian, Ezio Ghigo,
Romano Deghenghi
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ABSTRACT: Growth hormone-releasing hormone (GHRH) and somatostatin are the most important hypothalamic neurohormones controlling growth
hormone (GH) secretion. Several neurotransmitters and neuropeptides also play an important role in the control of GH secretion,
mainly acting via modulation of GHRH and somatostatin. In the past two decades, particular attention has been given to a new
family of substances showing a strong GH-releasing effect: GH secretagogues (GHSs). GHSs increase GH secretion in a dose-and
age-related manner after iv and even oral administration. The endocrine effects of GHSs, are not fully specific for GH; they
show, in fact, prolactin- (PRL), adenocorticotropic hormone- and cortisol-releasing effects. Specific GHS receptors are present
in both the central nervous system and peripheral tissues, where they mediate several extraendocrine effects of GHSs. The
isolation of these “orphan” receptors suggested the existence of an endogenous GHS-like ligand that could be represented by
a recently discovered gastric peptide, named ghrelin. The interaction between GHSs and GHRH at the central level and in the
pituitary gland, but not at peripheral level, has clearly been shown. Because GHRH and GHS receptors share the same localization
in some peripheral tissues, they may have some interactions even at this level.
Endocrine 04/2012; 14(1):35-43. · 1.42 Impact Factor
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ABSTRACT: Growth hormone releasing peptides (GHRPs) are synthetic molecules endowed with potent neuroendocrine activities mediated by
specific receptors in the pituitary and in the central nervous system. GHRPs receptors have been reported even in perpheral
tissues, particularly in the myocardium, where they probably mediate growth hormone (GH)-independent activities. We studied
in humans the cardiac effects of hexarelin administration in 7 normal adults, in 7 severe GH-deficient patients, and in 12
patients with severe dilated cardiomyopathy. Left ventricular ejection fraction (LVEF), mean blood pressure (MBP), heart rate
(HR), and GH levels were evaluated at baseline and every 15 min up to 60 min after acute 2.0 μg/kg iv hexarelin administration.
Basal LVEF in dilated cardiomyopathy was impaired and lower (p<0.001) than in GH deficiency, in turn lower (p<0.001) than in normal subjects. Hexarelin significantly (p<0.05) increased LVEF in normal and in GH-deficient subjects, but not in dilated cardiomyopathy, without significant variations
in MBP and HR. Hexeralin significantly (p<0.05) increased GH levels in normal subjects and in dilated cardiomyopathy but not in GH deficiency. These findings suggest
that, in humans, the acute administration of hexarelin exerts a GH-independent positive inotropic effect likely mediated by
specific GHRPs myocardial receptors.
Endocrine 04/2012; 14(1):105-108. · 1.42 Impact Factor
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ABSTRACT: Ghrelin has been discovered as a natural ligand of the receptor specific for synthetic GH secretagogues (GHS). Ghrelin as
well as synthetic GHS not only possess a remarkable GH-releasing activity but are also endowed with other endocrine and nonendocrine
activities including orexigenic action, influence on gastro-enteropancreatic functions, and cardiovascular and anti-proliferative
effects. Based on these data, particular effort has been focused on the isolation of new putative natural ligands of the GHS-receptors
(GHS-R) and on the identification of synthetic compounds endowed with agonistic or antagonistic activity. For instance, ghrelin
analogs acting as agonists or antagonists would be able to enhance or reduce appetite and food intake; these molecules would
receive obvious interest for treatment of eating disorders and obesity, respectively. Ghrelin and its orally active, agonistic
analogs could have prespectives for diagnosis and treatment of GH insufficiency. In this context, EP1572, a selective, orally
active, peptidomimetic GHS as well as cortistatin, another putative, natural ligand of the GHS-R, and its analogs, are currently
under investigation.
Endocrine 04/2012; 22(1):13-18. · 1.42 Impact Factor
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Ezio Ghigo,
Emanuela Arvat,
Roberta Giordano,
Fabio Broglio,
Laura Gianotti,
Mauro Maccario,
Gianni Bisi,
Andrea Graziani,
Mauro Papotti,
Giampiero Muccioli,
Romano Deghenghi,
Franco Camanni
[show abstract]
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ABSTRACT: Growth hormone secretagogues (GHSs) are synthetic peptidyl and nonpeptidyl molecules with strong, dose-dependent, and reproducible
growth hormone (GH)-releasing activity even after oral administration. GHSs release GH via actions on specific receptors (GHS-R)
at the pituitary and, mainly, at the hypothalamic levels. GHSs likely act as functional somatostatin antagonists and meantime
enhance the activity of GH-releasing hormone (GHRH)-secreting neurons. The GH-releasing effect of GHSs is independent of gender
but undergoes marked age-related variations. Estrogens play a major role in enhancing the GH response to GHSs at puberty,
which GHRH hypoactivity, somatostatinergic hyperactivity and impaired activity of the putative GHS-like ligand and receptors
probably explain the reduced GH-releasing effect of GHSs in aging. The activity of GHSs is not fully specific for GH. Their
slight prolactin-releasing activity probably comes from direct pituitary action. In physiological conditions, the ACTH-releasing
activity of GHSs is dependent on central actions; a direct action on GHS-R in pituitary ACTH-secreting tumors likely explains
the peculiar ACTH and cortisol hyperresponsiveness to GHSs in Cushing disease. GHSs have specific receptor subtypes in other
central and peripheral endocrine and nonendocrine tissues mediating GH-independent biologic activities. GHSs influence sleep
pattern, stimulated food intake, and have cardiovascular activities. GHs have specific binding in normal and neoplastic follicular
derived human thyroid tissue and inhibit the proliferation of follicular-derived neoplastic cell lines. The discovery of ghrelin,
a 28 amino acid peptide synthesized in the stomach but also in other tissues, has opened new fascinating perspectives of research
in this field.
Endocrine 04/2012; 14(1):87-93. · 1.42 Impact Factor
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ABSTRACT: This clinical review will summarize the available data regarding the effect of either physiological or increased glucocorticoid concentrations on glucose metabolism and insulin-sensitivity, in order to clarify the role, if any, of subclinical Cushing's syndrome (SCS), a status of altered hypothalamic-pituitary-adrenal axis secretion in the absence of the classical signs or symptoms of overt cortisol excess, in patients with adrenal incidentalomas (AI) and diabetes mellitus type 2. Focusing on patients with SCS associated to AI, while there is convincing evidence in the literature that even a mild hyper cortisolemia is associated with alterations of glucose metabolism, evidence is insufficient to conclude that the simple correction of chronic, even mild, hypercortisolism can completely revert metabolic, mainly glycemic alterations. At the same time, considering the variability of the prevalence of Cushing's syndrome in patients with diabetes mellitus type 2 reported in the literature, no agreement does exist whether screening for CS can be useful and recommended in those patients.
Endocrine 03/2012; 41(3):415-23. · 1.42 Impact Factor
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Riccarda Granata,
Fabio Settanni,
Michel Julien,
Rita Nano,
Gabriele Togliatto,
Antonella Trombetta,
Davide Gallo,
Lorenzo Piemonti,
Maria Felice Brizzi,
Thierry Abribat,
Aart-Jan van Der Lely, Ezio Ghigo
[show abstract]
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ABSTRACT: Des-acyl ghrelin, although devoid of binding to ghrelin receptor (GRLN), exerts many biological effects, including regulation of glucose and lipid metabolism. Indeed, des-acyl ghrelin promotes pancreatic β-cell and human islet cell survival and prevents diabetes in streptozotocin (STZ) treated rats. We investigated whether des-acyl ghrelin fragments excluding serine(3), which is essential for binding to GRLN, would display similar actions. Among the different compounds tested, des-acyl ghrelin((6-13)) and des-acyl ghrelin((6-13)) with alanine substitutions or cyclization, but not with d-amino acid substitutions, showed the best survival effect, similar to des-acyl ghrelin. Des-acyl ghrelin((6-13)) even prevented diabetes in STZ-treated rats and protected human circulating angiogenic cells from oxidative stress and senescence, similar to des-acyl ghrelin. These results suggest that not only full-length des-acyl ghrelin but also short des-acyl ghrelin fragments have clear beneficial effects on several tissues in vitro and in vivo.
Journal of Medicinal Chemistry 03/2012; 55(6):2585-96. · 4.80 Impact Factor
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ABSTRACT: Aim of this review is to highlight how and when Traumatic Brain Injury (TBI) as well as Subarachnoid Haemorrhage (SAH) and primary Brain Tumours (pBT) of the Central Nervous System (CNS) can induce hypopituitarism, an under-diagnosed clinical problem. Moreover, this review aims to clarify, on the basis of the recent evidences, how these patients have to be tested for pituitary-function. Both retrospective and prospective studies recommended that patients with more severe form of Brain Injuries (BI) and in particular, those with fractures of the base of the skull or early diabetes insipidus, have to be closely monitored for signs and symptoms of endocrine dysfunction. Further studies will be crucial to raise awareness and remind physicians on the prevalence of hypopituitarism in patients with BI and to elucidate any incremental benefits these patients may receive from hormone replacement.
Pituitary 03/2012; 15(1):20-4. · 1.83 Impact Factor
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ABSTRACT: To clarify the metabolic effects of an overnight i.v. infusion of unacylated ghrelin (UAG) in humans. UAG exerts relevant metabolic actions, likely mediated by a still unknown ghrelin receptor subtype, including effects on β-cell viability and function, insulin secretion and sensitivity, and glucose and lipid metabolism.
We studied the effects of a 16-h infusion (from 2100 to 1300 h) of UAG (1.0 μg/kg per h) or saline in eight normal subjects (age (mean±s.e.m.), 29.6±2.4 years; body mass index (BMI), 22.4±1.7 kg/m(2)), who were served, at 2100 and 0800 h respectively, with isocaloric balanced dinner and breakfast. Glucose, insulin, and free fatty acid (FFA) levels were measured every 20 min.
In comparison with saline, UAG induced significant (P<0.05) changes in glucose, insulin, and FFA profiles. UAG infusion decreased glucose area under the curve (AUC) values by 10% (UAG(0 - 960 min): 79.0±1.7×10(3) mg/dl per min vs saline(0- 960 min): 87.5±3.8×10(3) mg/dl per min) and the AUC at night by 14% (UAG(180)(-)(660 min): 28.4±0.5×10(3) mg/dl per min vs saline(180 - 660 min): 33.2±1.1×10(3) mg/dl per min). The overall insulin AUC was not significantly modified by UAG infusion; however, insulin AUC observed after meals was significantly increased under the exposure to UAG with respect to saline at either dinner or breakfast. The FFA AUC values were decreased by 52% under the exposure to UAG in comparison with saline (UAG(0 - 960 min): 0.3±0.02×10(3) mEq/l per min vs saline(0 - 960 min): 0.6±0.05×10(3) mEq/l per min).
Exposure to the i.v. administration of UAG improves glucose metabolism and inhibits lipolysis in healthy volunteers. Thus, in contrast to the diabetogenic action of AG, UAG displays hypoglycemic properties.
European Journal of Endocrinology 02/2012; 166(5):911-6. · 3.42 Impact Factor
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ABSTRACT: Acylated ghrelin (AG) is a 28 amino acid gastric peptide a natural ligand for the growth hormone secretagogue (GHS) receptor type 1a (GHS-R1a), endowed with GH-secreting and orexigenic properties. Besides, ghrelin exerts several peripheral metabolic actions, including modulation of glucose homeostasis and stimulation of adipogenesis. Notably, AG administration causes hyperglycemia in rodents as in humans. Ghrelin pleiotropy is supported by a widespread expression of the ghrelin gene, of GHS-R1a and other unknown ghrelin binding sites. The existence of alternative receptors for AG, of several natural ligands for GHS-R1a and of acylation-independent ghrelin non-neuroendocrine activities, suggests that there might be a complex 'ghrelin system' not yet completely explored. Moreover, the patho-physiological implications of unacylated ghrelin (UAG), and obestatin (Ob), the other two ghrelin gene-derived peptides, need to be clarified. Within the next few years, we may better understand the 'ghrelin system', where we might envisage clinical applications.
Peptides 10/2011; 32(11):2323-32. · 2.43 Impact Factor
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ABSTRACT: In 1976, small peptide growth hormone secretagogues (GHSs) were discovered and found to promote growth hormone (GH) release from the pituitary. The GHS receptor (GHS-R) was subsequently cloned, and its endogenous ligand ghrelin was later isolated from the stomach. Ghrelin is a 28-amino acid peptide, whose acylation is essential for binding to GHS-R type 1a and for the endocrine functions, including stimulation of GH secretion and subsequent food intake. Unacylated ghrelin, the other ghrelin form, although devoid of GHS-R binding is an active peptide, sharing many peripheral effects with acylated ghrelin (AG). The ghrelin system is broadly expressed in myocardial tissues, where it exerts different functions. Indeed, ghrelin inhibits cardiomyocyte and endothelial cell apoptosis, and improves left ventricular (LV) function during ischemia-reperfusion (I/R) injury. In rats with heart failure (HF), ghrelin improves LV dysfunction and attenuates the development of cardiac cachexia. Similarly, ghrelin exerts vasodilatory effects in humans, improves cardiac function and decreases systemic vascular resistance in patients with chronic HF. Obestatin is a recently identified ghrelin gene peptide. The physiological role of obestatin and its binding to the putative GPR39 receptor are still unclear, although protective effects have been demonstrated in the pancreas and heart. Similarly to AG, the hypothalamic peptide growth hormone-releasing hormone (GHRH) stimulates GH release from the pituitary, through binding to the GHRH-receptor. Besides its proliferative effects in different cell types, at the cardiovascular level GHRH inhibits cardiomyocyte apoptosis, and reduces infarct size in both isolated rat heart after I/R and in vivo after myocardial infarction. Therefore, both ghrelin and GHRH exert cardioprotective effects, which make them candidate targets for therapeutic intervention in cardiovascular dysfunctions.
Experimental Biology and Medicine 05/2011; 236(5):505-14. · 2.64 Impact Factor
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Roberta Giordano,
Andreea Picu,
Elisa Marinazzo,
Valentina D'Angelo,
Rita Berardelli,
Ioannis Karamouzis,
Daniela Forno,
Domenico Zinnà,
Mauro Maccario, Ezio Ghigo,
Emanuela Arvat
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ABSTRACT: Cushing's syndrome is associated with several comorbidities responsible for the increased cardiovascular risk, not only during the active phase but also after disease remission.
In 29 patients with Cushing's syndrome (14 Cushing's diseases and 15 adrenal adenomas), waist circumference, fasting and 2-h glucose after oral glucose tolerance test (OGTT), lipid profile and blood pressure were evaluated during the active disease and 1 year after remission and compared with those in 29 sex-, age- and BMI-matched controls.
During the active disease, waist circumference, 2-h glucose after OGTT, total and LDL cholesterol were higher in patients with Cushing's syndrome than in controls (P < 0·001) but similar in Cushing's disease and adrenal adenomas. The prevalence of impaired glucose tolerance (IGT), diabetes mellitus, dyslipidaemia and hypertension was higher (P < 0·001) in patients with Cushing's syndrome (27%, 24%, 59% and 72%) than in controls (10%, 0%, 21% and 10%), with no significant difference between Cushing's disease and adrenal adenomas. One year following hormonal remission, waist circumference persisted higher than in controls (P < 0·05) in both Cushing's disease and adrenal adenomas. Metabolic and cardiovascular abnormalities were still present in both groups, although with a lower prevalence, as well as with a more marked decrease in adrenal adenomas (P < 0·05 vs active disease for IGT, dyslipidaemia and hypertension).
These results show that chronic hypercortisolism, independently of its aetiology, contributes to metabolic impairment and increased cardiovascular risk, while these abnormalities mostly persist in patients with previous Cushing's disease after hormonal remission. Pituitary hormonal deficiencies, hormonal replacement treatments and/or incomplete cure from Cushing's disease may account for these findings.
Clinical Endocrinology 03/2011; 75(3):354-60. · 3.17 Impact Factor
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ABSTRACT: Turner's syndrome (TS) is a rare genetic disorder caused by complete or partial X chromosome monosomy in a phenotypic female, and it is associated with increased morbidity and mortality for cardiovascular diseases, impaired glucose tolerance, and dyslipidemia.
In 30 adult TS patients under chronic hormonal replacement therapy (HRT), 17β-estradiol (E(2)), body mass index (BMI), waist circumference, fasting glucose and insulin, homeostatic model assessment (HOMA) index, serum lipids, oral glucose tolerance test (OGTT), 24 h ambulatory blood pressure monitoring (ABPM), and intima-media thickness (IMT) were evaluated and compared with those in 30 age- and sex-matched controls (CS).
No difference was found between TS and CS in E(2) and BMI, whereas waist circumference was higher (P<0.05) in TS (77.7±2.5 cm) than in CS (69.8±1.0 cm). Fasting glucose in TS and in CS was similar, whereas fasting insulin, HOMA index, and 2 h glucose after OGTT were higher (P<0.0005) in TS (13.2±0.8 mUI/l, 2.5±0.2, and 108.9±5.5 mg/dl respectively) than in CS (9.1±0.5 mUI/l, 1.8±0.1, and 94.5 ± 3.8 mg/dl respectively). Total cholesterol was higher (P<0.05) in TS (199.4 ± 6.6 mg/dl) than in CS (173.9±4.6 mg/dl), whereas no significant differences in high-density lipoprotein, low-density lipoprotein, and triglycerides were found between the two groups. In 13% of TS, ABPM showed arterial hypertension, whereas IMT was <0.9 mm in all TS and CS. A negative correlation between insulin levels, HOMA index, or 2 h glucose after OGTT and E(2) was present in TS.
Our results indicate that adult patients with TS under HRT are connoted by higher frequency of central obesity, insulin resistance, hypercholesterolemia, and hypertension.
European Journal of Endocrinology 03/2011; 164(5):819-26. · 3.42 Impact Factor
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ABSTRACT: Glucocorticoids are known to decrease protein synthesis and conduction velocity of muscle fibers. However, the degree of impairment of muscle protein synthesis and conduction slowing in patients with Cushing's disease remains poorly characterized. Our objective was to investigate whether and to what extent chronic endogenous hypercortisolism could decrease the circulating levels of muscle proteins and modify myoelectric indexes of sarcolemmal excitability and fatigability.
A total of ten patients with Cushing's disease and 30 healthy controls matched for age, sex, and body mass index were compared.
Blood sampling and electrophysiological tests on vastus lateralis, vastus medialis, and tibialis anterior muscles were performed.
Serum creatine kinase (CK) and plasma myoglobin were significantly lower in patients with respect to controls (P<0.001 and P<0.05 respectively): the mean relative difference between patients and controls was 48.9% for CK and 21.4% for myoglobin. Muscle fiber conduction velocity (MFCV) and myoelectric manifestations of fatigue were significantly decreased in all muscles of the patients with respect to controls. The mean relative difference in MFCV between patients and controls was 26.0% for vastus lateralis, 22.9% for vastus medialis, and 11.6% for tibialis anterior. These differences contrasted with the paucity of signs suggestive of myopathy that were obtained by needle electromyography in the patients.
Slowing of muscle fiber conduction and decreased levels of circulating muscle proteins are sensitive markers of impaired muscle function, which are suitable for use in combination with clinical assessment and standard electrodiagnostic tests for accurate identification and follow-up of myopathic patients.
European Journal of Endocrinology 03/2011; 164(6):985-93. · 3.42 Impact Factor
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ABSTRACT: The acylated peptide ghrelin (AG) and its endogenous non-acylated isoform (UAG) protect cardiomyocytes, pancreatic β-cells, and preadipocytes from apoptosis, and induce preadipocytes differentiation into adipocytes. These events are mediated by AG and UAG binding to a still unidentified receptor, which determines the activation of phosphoinositide 3-kinase (PI3K), protein kinase B (AKT), and mitogen-activated protein kinase (MAPK) ERK1/2. AG and UAG also possess antilipolytic activity in vitro, but the underlying mechanism remains unknown. Thus, the objective of the current study was to characterize the molecular events involved in AG/UAG receptor signaling cascade. We treated rat primary visceral adipocytes with isoproterenol (ISO) and forskolin (FSK) to stimulate lipolysis, simultaneously incubating them with or without AG or UAG. Both peptides blocked ISO- and FSK-induced lipolysis. By direct measurement of cAMP intracellular content, we demonstrated that AG/UAG effect was associated to a reduction of ISO-induced cAMP accumulation. Moreover, the cAMP analog 8Br-cAMP abolished AG/UAG effect. As AG and UAG were ineffective against lipolysis induced by db-cAMP, another poorly hydrolyzable cAMP analog, phosphodiesterase (PDE) involvement was hypothesized. Indeed, cilostamide, a specific PDE3B inhibitor, blocked AG/UAG effect on ISO-induced lipolysis. Furthermore, the PI3K inhibitor wortmannin and AKT inhibitor 1,3-dihydro-1-(1-((4-(6-phenyl-1H-imidazo(4,5-g)quinoxalin-7-yl)phenyl)methyl)-4piperidinyl)-2H-benzimidazol-2-one trifluoroacetate also blocked AG/UAG action, suggesting a role in PDE3B activation. In particular, PI3K isoenzyme gamma (PI3Kγ) selective inhibition through the compound AS605240 prevented AG/UAG effect on ISO-stimulated lipolysis, hampering AKT phosphorylation on Ser(473). Taken together, these data demonstrate for the first time that AG/UAG attenuation of ISO-induced lipolysis involves PI3Kγ/AKT and PDE3B.
Biochimica et Biophysica Acta 03/2011; 1811(6):386-96. · 4.66 Impact Factor
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ABSTRACT: Gonadotropin Releasing Hormone (GnRH) antagonists (GnRHa) suppress gonadotropin and sex-steroid secretion. In normal women, acute GnRHa administration induces inhibitory effect on pituitary-gonadal axis, followed by Luteinizing Hormone (LH) rebound. Functional hypothalamic amenorrhea (HA) is characterised by impaired gonadotropin secretion and hypogonadism secondary to blunted GnRH pulsatility.
We studied the effects of a GnRHa, cetrorelix (CTX 3.0 mg), in six women with HA (age 30.7 ± 3.2 years; BMI 21.5 ± 1.7 kg/m(2)) and six control subjects (CS, 28.2 ± 0.6 years; 22.6 ± 0.9 kg/m(2)) on LH, Follicle-Stimulating Hormone (FSH) and oestradiol levels over 4 h (08.00-12.00 am) before, +24 h and +96 h after CTX; LH, FSH, and oestradiol were also evaluated at +6, +8, +12, +48, +72 h after CTX.
CS: CTX reduced (p < 0.05) LH, FSH, and oestradiol (nadir at +12 h, +24 h, and +24 h); LH rebounded at +96 h, FSH and oestradiol recovered at +48 h and +72 h. The 4-h evaluation showed LH and FSH reduction (p < 0.05) at +24 h, with LH rebound at +96 h. HA: CTX reduced (p < 0.05) LH, FSH, and oestradiol, (nadir at +24 h, +48 h, and +48 h, recovery at +48 h, +72 h, and +96 h). The 4-h evaluation showed gonadotropin reduction (p < 0.05) 24 h after CTX, without any rebound effect.
One single CTX dose still modulates gonadotropin secretion in HA. Its 'paradoxical' stimulatory effect on gonadotropins needs to be verified after prolonged administration.
Gynecological Endocrinology 01/2011; 27(10):753-8. · 1.58 Impact Factor
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ABSTRACT: Ghrelin, a 28 amino acid octanoylated peptide predominantly produced by the stomach, was discovered to be the natural ligand
of the type 1a growth hormone (GH) secretagogue receptor (GHS-R1a). Thus, it was considered as a natural GHS additional to
growth hormone-releasing hormone (GHRH), although later on ghrelin has mostly been considered a major orexigenic factor. Ghrelin
activity at the pituitary level is not fully specific for GH, because it also includes stimulatory effects on both the lactotroph
and corticotroph system. In fact, ghrelin in humans significantly stimulates prolactin (PRL) secretion, independently of both
gender and age and probably involving a direct action on somatomammotroph cells, and possesses an acute stimulatory effect
on the activity of the hypothalamus-pituitary-adrenal axis, which is similar to that of the opioid antagonist naloxone, arginine-vasopressin
(AVP) and even corticotropin-releasing hormone (CRH). Finally, ghrelin plays a relevant role in the modulation of the hypothalamus-pituitary-gonadal
axis function, with a predominantly central nervous system (CNS)-mediated inhibitory effect upon the gonadotropin pulsatility
both in animals and in humans. Overall, ghrelin is a pleiotropic hormone with a wide spectrum of biological actions. Further
studies are required to gain insights into the exact mechanisms involved in ghrelin physiology and pathophysiology and to
define the potential therapeutic roles, if any, of ghrelin and its analogs.
KeywordsGhrelin-Pituitary-GH-PRL-ACTH-LH-FSH
12/2010: pages 17-31;
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ABSTRACT: The insulin-like growth factor (IGF) system plays essential role in the regulation of cell growth, proliferation and survival and affects nearly every organ system in the body. IGF-I, which has a high structural similarity to insulin, exerts growth-promoting effects, influences glucose metabolism and has neuroprotective and cardioprotective effects, partly because of its cell-proliferative and antiapoptotic properties. Aberrations in the IGF system may associate with various pathological conditions, including cancer. Insulin and its synthetic analogs are known to possess IGF-IR binding affinity, and concern has been raised about their mitogenic potential in humans. The present review summarizes the main aspects of the IGF system biology and the interactions among IGF-I, insulin, insulin analogs and their receptors.
Acta Diabetologica 11/2010; 48(1):1-9. · 2.78 Impact Factor
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ABSTRACT: The ghrelin gene peptides include acylated ghrelin (AG), unacylated ghrelin (UAG), and obestatin (Ob). AG, mainly produced by the stomach, exerts its central and peripheral effects through the GH secretagogue receptor type 1a (GHS-R1a). UAG, although devoid of GHS-R1a-binding affinity, is an active peptide, sharing with AG many effects through an unknown receptor. Ob was discovered as the G-protein-coupled receptor 39 (GPR39) ligand; however, its physiological actions remain unclear. The endocrine pancreas is necessary for glucose homeostasis maintenance. AG, UAG, and Ob are expressed in both human and rodent pancreatic islets from fetal to adult life, and the pancreas is the major source of ghrelin in the perinatal period. GHS-R1a and GPR39 expression has been shown in beta-cells and islets, as well as specific binding sites for AG, UAG, and Ob. Ghrelin colocalizes with glucagon in alpha-islet cells, but is also uniquely expressed in epsilon-islet cells, suggesting a role in islet function and development. Indeed, AG, UAG, and Ob regulate insulin secretion in beta-cells and isolated islets, promote beta-cell proliferation and survival, inhibit beta-cell and human islet cell apoptosis, and modulate the expression of genes that are essential in pancreatic islet cell biology. They even induce beta-cell regeneration and prevent diabetes in streptozotocin-treated neonatal rats. The receptor(s) mediating their effects are not fully characterized, and a signaling crosstalk has been suggested. The present review summarizes the newest findings on AG, UAG, and Ob expression in pancreatic islets and the role of these peptides on beta-cell development, survival, and function.
Journal of Molecular Endocrinology 09/2010; 45(3):107-18. · 3.48 Impact Factor
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ABSTRACT: The activation of G protein-coupled receptor 103 (GPR103) by its endogenous peptidic ligands, QRFPs, is involved in the central regulation of feeding by increasing food intake, body weight, and fat mass after intracerebroventricular injection in mice. However, the role of GPR103 in regulating peripheral metabolic pathways has not yet been explored. The present study aimed to investigate the role of GPR103 in adipogenesis and lipid metabolism using 3T3-L1 adipocyte cells. Our results show that differentiated 3T3-L1 cells expressed the GPR103b subtype mRNA and protein, as well as QRFP mRNA. QRFP-43 and -26 induced an increase in triglyceride accumulation of 50 and 41%, respectively, and elicited a dose-dependent increase in fatty acid uptake, by up to approximately 60% at the highest concentration, in 3T3-L1-differentiated cells. QRFP-43 and -26 inhibited isoproterenol (ISO)-induced lipolysis in a dose-dependent manner, with IC(50)s of 2.3 +/- 1.2 and 1.1 +/- 1.0 nm, respectively. The expression of genes involved in lipid uptake (FATP1, CD36, LPL, ACSL1, PPAR-gamma, and C/EBP-alpha), was increased by 2- to 3-fold after treatment with QRFP. The effects of QRFP on ISO-induced lipolysis and fatty acid uptake were abolished when GPR103b was silenced. In a mouse model of diet-induced obesity, the expression of GPR103b in epididymal fat pads was elevated by 16-fold whereas that of QRFP was reduced by 46% compared to lean mice. Furthermore, QRFP was bioactive in omental adipocytes from obese individuals, inhibiting ISO-induced lipolysis in these cells. Our results suggest that GPR103b and QRFP work in an autocrine/paracrine manner to regulate adipogenesis.
Molecular Endocrinology 08/2010; 24(8):1615-25. · 4.54 Impact Factor
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ABSTRACT: Acylated ghrelin (AG) is a diabetogenic and orexigenic gastric polypeptide. These properties are not shared by the most abundant circulating form, which is unacylated (UAG). An altered UAG/AG profile together with an impairment of circulating endothelial progenitor cell (EPC) bioavailability were found in diabetes. Based on previous evidence for the beneficial cardiovascular effects of AG and UAG, we investigated their potential to revert diabetes-associated defects.
Healthy human subjects, individuals with type 2 diabetes, and ob/ob mice were AG or UAG infused. EPC mobilization in patients and mice was evaluated, and the underlying molecular mechanisms were investigated in bone marrow stromal cells. Recovered EPCs were also evaluated for the activity of senescence regulatory pathways and for NADPH oxidase activation by knocking down p47(phox) and Rac1. Finally, UAG modulation of human EPC vasculogenic potential was investigated in an in vivo mouse model.
Neither AG nor UAG had any effect in healthy subjects. However, systemic administration of UAG, but not AG, prevented diabetes-induced EPC damage by modulating the NADPH oxidase regulatory protein Rac1 and improved the vasculogenic potential both in individuals with type 2 diabetes and in ob/ob mice. In addition, unlike AG, UAG facilitated the recovery of bone marrow EPC mobilization. Crucial to EPC mobilization by UAG was the rescue of endothelial NO synthase (eNOS) phosphorylation by Akt, as UAG treatment was ineffective in eNOS knockout mice. Consistently, EPCs expressed specific UAG-binding sites, not recognized by AG.
These data provide the rationale for clinical applications of UAG in pathologic settings where AG fails.
Diabetes 04/2010; 59(4):1016-25. · 8.29 Impact Factor
