leptin and Acromegaly

A case of Berardinelli-Seip syndrome, a congenital generalised lipodystrophy, is reported. Symptoms first appeared when the patient was 20 years old. She showed severe insulin resistance as well as micro- and macro-angiopathic complications, including chronic kidney disease, which required renal replacement therapy with peritoneal dialysis. The patient's clinical course was reviewed since paediatric age (when initial signs of the disease being already evident) to present time. Berardinelli-Seip syndrome is very uncommon, and the present case is particularly rare because it is the only case (at least as reported in the literature) in a patient receiving dialysis.

Topics: Acromegaly; Cardiomyopathy, Hypertrophic; Child; Delayed Diagnosis; Diabetic Nephropathies; Diagnosis, Differential; Exons; Female; Glomerulonephritis, Membranoproliferative; GTP-Binding Protein gamma Subunits; Humans; Insulin Resistance; Leptin; Lipodystrophy, Congenital Generalized; Peritoneal Dialysis, Continuous Ambulatory

Elevated BMI, fat mass and food intake increases leptin whereas ghrelin is reduced. Ghrelin stimulates growth hormone (GH) secretion. This prospective cross-sectional study was performed to investigate the influence of GH excess on leptin and ghrelin levels at baseline and after glucose load in a large group of acromegalic patients.. Leptin, ghrelin, GH, glucose and insulin concentrations were measured during a 3 h OGTT in 17 active, 25 inactive patients without medication (inact) and 8 inactive patients treated successfully with somatostatin analogues (inact-SA). Leptin concentration was measured using an in-house immunofluorometric assay, total serum ghrelin by a commercially available radioimmunoassay. Leptin was corrected for BMI.. During OGTT, no significant difference of baseline, nadir or AUC of leptin/BMI was seen between the groups (baseline leptin/BMI: act: 0.26 microgm(2)/lkg (0.06-0.87); inact: 0.34 microgm(2)/lkg (0.03-1.79); inact-SA: 0.29 microgm(2)/lkg (0.03-1.47). A slight but significant reduction of leptin/BMI occurred in all groups during OGTT (active p<0.001, inact p<0.001, inact-SA p<0.05). Inact had higher ghrelin levels (130 ng/L (69-292) compared to active (102 ng/L (27-232); p=n.s.). Inact-SA had significantly lower ghrelin levels (88 ng/L (72-113)) than inact (p<0.001). There was a significant decline of ghrelin during OGTT in all groups (active p<0.001, inact p<0.001, inact-SA p<0.05).. GH only has a slight influence on leptin secretion. Ghrelin levels are lowered by GH and SA. Nevertheless, the physiological decreasing effect of glucose load on ghrelin secretion is preserved.

Topics: Acromegaly; Adult; Aged; Aged, 80 and over; Body Mass Index; Cross-Sectional Studies; Female; Ghrelin; Glucose Tolerance Test; Humans; Leptin; Male; Middle Aged

Posttreatment assessment of disease activity and definition of cure of acromegaly, using measurement of GH secretion, remains problematic. Furthermore, with our efforts to achieve tight biochemical control of the disease it is foreseeable that a proportion of patients may be rendered GH deficient, thus requiring testing for GH deficiency. The aim of our study was to evaluate residual GH secretion in cured patients with acromegaly.. At baseline, circulating GH, IGF-I, IGFBP-3, leptin and lipid (cholesterol and tri-glycerides) levels were measured in 33 acromegalic patients nine years after treatment with surgery of whom 6 were additionally irradiated. Two tests were performed: the GH suppression test--oral glucose tolerance test (OGTT) and the GH provocation test--ghrelin test (1 microg/kg i.v. bolus) and the results were compared with 11 age- and sex-matched control subjects.. According to the consensus criteria (normal IGF-I levels and post-OGTT GH nadir <1 microg/l), 21 treated acromegalic patients were cured, 6 had discordant IGF-I and GH nadir values during OGTT, while 6 had persistent acromegaly. After the GH provocative test with ghrelin (cut-off for severe GH deficiency is GH <3 microg/l), we detected 9 severely GH deficient patients (GHD) among 21 cured acromegalic patients. Mean GH peak (+/-s.e.m.) response to the ghrelin test in GHD acromegalics was significantly lower compared with acromegalics with sufficient GH secretory capacity and control subjects (1.2 +/- 0.2 microg/l vs 20.1 +/- 2.4 microg/l vs 31.1 +/- 2.5 microg/l respectively, P<0.0001). Mean IGF-I and IGFBP-3 levels were not different between GHD and GH-sufficient cured acromegalics. Leptin levels and body mass index (BMI) were significantly higher in GHD male acromegalics compared with GH-sufficient male acromegalics. GHD female acromegalics tended to have higher BMIs while leptin levels were not different.. The assessment of residual GH secretory capacity by the GH provocation test is necessary in the long-term follow-up of successfully treated acromegalics since a large proportion of these patients are rendered GH deficient.

Topics: Acromegaly; Adult; Age Factors; Aged; Diagnostic Techniques, Endocrine; Female; Ghrelin; Glucose Tolerance Test; Human Growth Hormone; Humans; Insulin-Like Growth Factor Binding Protein 3; Insulin-Like Growth Factor I; Leptin; Lipids; Magnetic Resonance Imaging; Male; Middle Aged; Obesity; Peptide Hormones; Pituitary Gland; Postoperative Complications

In humans, serum leptin correlates positively with fat mass. GH is lipolytic and patients with active acromegaly have lowered serum leptin compared to age, sex and body mass index (BMI)-matched controls, but a direct influence of GH on serum leptin remains unclear. In patients with acromegaly, total leptin increases following successful pituitary surgery and during somatostatin (SMS) analogue therapy (despite no change in BMI) but whether this represents changes in soluble leptin receptor, bound or free leptin is unclear. Pegvisomant, a GH receptor antagonist capable of normalizing serum IGF-I in over 97% of patients, represents a novel treatment strategy in acromegaly and its effect on leptin has not previously been reported.. Sixteen patients (nine male (M), seven female (F), median age 52 years, range 27-78 years) with active acromegaly (serum IGF-I at least 30% above the upper limit of an age-related reference range) were studied. Serum IGF-I was normalized in all subjects with pegvisomant [mean duration 7 months (range 3-11 months), median dose 20 mg/day (range 10-40 mg/day)]. A single batch measurement of leptin, bound leptin (BL), soluble leptin receptor (SLR), insulin and glucose were performed on samples from baseline and first occurrence of serum IGF-I normalization.. As in normal subjects, females with acromegaly had higher baseline serum leptin [median M = 6.1 (range 1.6-58.7), F = 25.9 (range 3.19-54.1) ng/ml; P = 0.04], which correlated positively with BMI (R = 0.78, P = 0.0004). Forward step-wise regression analysis demonstrated that BMI and gender accounted for 90% of the variance in mean serum log10 leptin. Pegvisomant-induced serum IGF-I normalization was associated with a rise in serum leptin [8.9 (range 1.6-58.3) to 12.7 (range 2.3-90.8) ng/ml, P < 0.0001]. Although the absolute increase was not significantly different, mean percentage increase was greater in men (M = 66.6 +/- 51%, F = 11.8 +/- 16%, P = 0.017) despite similar serum IGF-I and BMI in male and female subjects at baseline. No change in BL or SLR accompanied serum IGF-I normalization [0.27 (range 0.15-1.26) to 0.27 (range 0.14-1.2) nmol/l, P = 0.27 and 3.2 (range 1.2-6.8) to 2.7 (range 1-7.4) nmol/l, P = 0.5, respectively]. After normalization of serum IGF-I, a correlation between BMI and leptin remained (R = 0.86, P < 0.0001) and together BMI and gender accounted for 87% of the variance in mean log10 serum leptin (P = 0.0002).. Pegvisomant-induced serum IGF-I normalization in patients with active acromegaly is associated with a significant increase in total, and by implication, free leptin.

Topics: Acromegaly; Adult; Aged; Blood Glucose; Female; Growth Hormone; Human Growth Hormone; Humans; Insulin; Insulin-Like Growth Factor I; Leptin; Linear Models; Male; Middle Aged; Receptors, Leptin; Receptors, Somatotropin; Statistics, Nonparametric

GH excess is characterized by alterations of body composition such as decreased body fat mass; however, scant data are present regarding its effect on serum leptin levels. To better elucidate this topic, leptin secretion was studied in 20 acromegalic patients, before and after 6 months of treatment with somatostatin analogs (SR-lanreotide 30 mg and octreotide LAR). Basal GH, IGF-I, insulin, blood glucose and lipid levels were measured and the area under the curve (AUC) for insulin and glucose and oral glucose insulin sensitivity (OGIS) during oral glucose tolerance test (OGTT) were calculated. After 6 months of somatostatin analogs therapy, a significant reduction in GH and IGF-I plasma levels was observed (p<0.0005, both) with a significant increase of leptin levels (7.4+/-1.3 vs 13.2+/-1.6 ng/ml; p<0.05). Interestingly, the typical correlation of leptin with body mass index (BMI) was not present in active acromegaly, whereas it was restored after somatostatin analogs treatment; moreover, the gender difference in leptin secretion between men and women was preserved in active and controlled acromegaly. In conclusion, the gender-based leptin differences are preserved and leptin secretion/BMI ratio is normalized in acromegalic patients after somatostatin analogs therapy.

Topics: Acromegaly; Adult; Aged; Delayed-Action Preparations; Female; Human Growth Hormone; Humans; Insulin-Like Growth Factor I; Leptin; Male; Middle Aged; Octreotide; Peptides, Cyclic; Sex Characteristics; Somatostatin; Treatment Outcome

The aim of the present study was to determine the value of serum insulin-like growth factor binding protein-3 (IGFBP-3) and serum leptin measurements in comparison with plasma insulin-like growth factor I (IGF-I) measurements as indicators of treatment success in patients with acromegaly. Thirty-five acromegaly patients, 25 female and 10 male, divided into groups of patients with postadenomectomy "active" acromegaly (n = 20) and patients with postadenomectomy "controlled" acromegaly (n = 15), and 44 healthy volunteers sex- and age-matched with the acromegaly patients were included in the present study. We comparatively analyzed plasma IGF-I, serum IGFBP-3, and serum leptin levels in the aforementioned groups. Because serum leptin has sex dimorphism, the groups were divided into sexes when leptin was evaluated. As expected, the patients with active acromegaly had significantly higher mean values of plasma IGF-I and serum IGFBP-3 and lower mean values of serum leptin (only in women) than the control group. However, individual evaluation showed that 1 of 20, 9 of 20, and many patients with postadenomectomy active acromegaly patients had values that overlapped values of control subjects for plasma standard deviation score (SDS)-IGF-I, serum SDS-IGFBP-3, and sex-adjusted serum leptin, respectively. Application of the receiver operating characteristic (ROC) curves method shows that plasma IGF-I measurement has the best discriminatory power to differentiate patients with postsurgical active acromegaly from healthy people. Its area under the curve (AUC) was 0.95, with a sensitivity and specificity of 86% and 94%, respectively. Its positive and negative likelihood ratios were 14 and 0.15. Serum IGFBP-3 has certain discriminatory power, its AUC being 0.89, with a sensitivity and specificity of 83% and 77%. Its positive and negative likelihood ratios were 3.6 and 0.22. Serum leptin, both in women and in men, has a poor performance with sensitivity and specificity of 53% and 50% for women and 55% and 56% for men and positive and negative likelihood ratios of 1.06 and 0.94 for women and 1.26 and 0.8 for men. Application of the ROC curves method and the determination of positive and negative likelihood ratios in comparative evaluation of serum IGFBP-3 and serum leptin with plasma IGF-I as indicators of treatment success in acromegalic patients showed that neither serum IGFBP-3 nor serum leptin determinations have accuracy better than or similar to that of plasma IGF-I

Topics: Acromegaly; Adolescent; Adult; Aged; Biomarkers; Female; Follow-Up Studies; Humans; Insulin-Like Growth Factor Binding Protein 3; Insulin-Like Growth Factor I; Leptin; Male; Middle Aged; Predictive Value of Tests; Recurrence; Reference Values; ROC Curve; Sensitivity and Specificity; Treatment Outcome

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 sign

Topics: Acromegaly; Adult; Aged; Area Under Curve; Biomarkers; Blood Glucose; Cluster Analysis; Female; Glucose Tolerance Test; Human Growth Hormone; Humans; Hyperpituitarism; Insulin; Insulin-Like Growth Factor I; Leptin; Male; Middle Aged; Sphenoid Bone; Treatment Outcome

Body composition (BC) and adipokines share bone active properties and display an altered profile in acromegaly. The fibroblast growth factor 23 (FGF23)/α-Klotho system, also involved in bone metabolism, is upregulated in growth hormone (GH) excess states. Hence, we aimed to investigate their impact on bone in active acromegaly, compared to controls.. BC, bone mineral density (BMD) (via dual X-ray absorptiometry), serum adipokines (leptin, adiponectin, resistin), parathyroid hormone (PTH), FGF23, α-Klotho, and osteocalcin were assessed in a cross-sectional study enrolling 35 patients with active acromegaly (Acro), compared to 35 sex, age, and body mass index (BMI) one-to-one matched healthy controls (CTL).. The Acro group had higher bone density scores (p < 0.05), lower visceral fat depots (p = 0.011), and lower serum leptin (p < 0.001) but elevated adiponectin (p < 0.001) and resistin (p = 0.001) concentrations when compared to the CTL group. α-Klotho was not related to the GH/IGF1 axis in the Acro group. Resistin was higher in both diabetic and non-diabetic Acro compared to CTL (p < 0.05). Age and BC were the main independent BMD predictors in regression analysis in both groups, while IGF1 was a positive predictor of osteocalcin levels in the Acro (β = 0.48, p = 0.006). The correlations between adipokines, the FGF23/α-Klotho system, and bone parameters, respectively, were lost after adjusting for age and BC.. Age and BC were the main independent BMD predictors in the acromegalic patients with active disease, while IGF1 was independently associated with serum osteocalcin concentrations. The role of α-Klotho in evaluating acromegaly and the associated osteopathy in the long-term appears to be limited. Our study is among the first to report significant serum resistin changes in patients with active acromegaly, opening new insights in the GH-mediated insulin resistance. The GH-resistin relationship merits further investigations.

Topics: Acromegaly; Adipokines; Adiponectin; Bone Density; Cross-Sectional Studies; Fibroblast Growth Factor-23; Humans; Insulin-Like Growth Factor I; Leptin; Osteocalcin; Resistin

GH activates agouti-related protein (AgRP) neurons, leading to orexigenic responses in mice. The relationship between serum GH and plasma AgRP, which has been shown to reflect hypothalamic AgRP, has not been evaluated in humans.. To test the hypothesis that central stimulatory actions of GH on hypothalamic AgRP could be reflected in plasma AgRP in acromegaly.. We studied 23 patients with active acromegaly before and for ≤2 years after surgical (n = 13) or GH receptor antagonist therapy with pegvisomant (n = 10), and 100 healthy subjects with morning fasting blood samples for AgRP, leptin, GH, and IGF-1 and anthropometric measurements.. The plasma AgRP levels were higher in those with active acromegaly than in the matched healthy subjects [median, 100 pg/mL; interquartile range (IQR), 78 to 139 pg/mL vs median, 63 pg/mL; IQR, 58 to 67 pg/mL; P < 0.0001]. Plasma AgRP decreased from before to after surgery (median, 102 pg/mL; IQR, 82 to 124 pg/mL vs median, 63 pg/mL; IQR, 55.6 to 83 pg/mL; P = 0.0024) and from before to during pegvisomant therapy (median, 97 pg/mL; IQR, 77 to 175 pg/mL vs median, 63; IQR, 61 to 109 pg/mL; P = 0.006). The plasma AgRP level correlated with GH (r = 0.319; P = 0.011) and IGF-1 (r = 0.292; P = 0.002). In repeated measure analysis, AgRP was significantly associated with IGF-1.. Our data have provided evidence of a stimulatory effect of GH on plasma AgRP in humans. The levels were greater in active acromegaly and decreased in parallel with GH and IGF-1 decreases with acromegaly treatment. Data from mice suggest that AgRP may mediate some of the known effects of GH on energy metabolism. This warrants further study in patients with acromegaly and other populations.

Topics: Acromegaly; Adenoma; Adult; Agouti-Related Protein; Female; Hormone Antagonists; Human Growth Hormone; Humans; Insulin-Like Growth Factor I; Leptin; Male; Middle Aged; Neurosurgical Procedures; Pituitary Neoplasms; Receptors, Somatotropin; Treatment Outcome; Young Adult

The studies that have extensively evaluated the relation between adipokines and metabolic parameters in acromegaly treatment are quite discordant. We aimed to evaluate and correlate a set of selected adipokines, known to have a metabolic role, with the disease activity, metabolic status and treatment modalities.. Data of 56 consecutive acromegalic patients (31 M and 25 F; aged 54 ± 12 years), admitted to the section of Endocrinology of the University of Palermo during the years 2005-2014, including 16 newly diagnosed untreated (ND), 21 during therapy with somatostatin analogues (SA), 12 with pegvisomant (PE) and 7 after surgical treatment (SU), grouped into uncontrolled (group A: No. 33) and controlled (group B: No. 23) were evaluated. Anthropometric and metabolic parameters, insulin sensitivity indexes, visceral adiposity index (VAI), leptin, soluble leptin receptor, adiponectin, visfatin, resistin, adipsin and non-esterified fatty acids (NEFAs) were assessed. In a subgroup of 21 subjects, the insulin sensitivity index (M value) derived from euglycemic clamp was calculated.. Group A showed higher Homa-IR (p < 0.001), VAI (p < 0.001), triglycerides (p < 0.001), visfatin (p < 0.001), and NEFAs (p < 0.001) and lower ISI Matsuda (p < 0.001), M value (p < 0.001), HDL cholesterol (p < 0.001) and leptin (p < 0.001) than group B. ND patients showed higher VAI, triglycerides, Homa-IR, and visfatin and lower ISI Matsuda, M-value, and leptin compared to other groups (all p < 0.050), while no differences were found among SA, PE and SU patients. IGF-1 (p = 0.048), M-value (p = 0.0029) and VAI (p = 0.010) were independently associated with visfatin, while only ISI Matsuda (p = 0.019) was associated with leptin.. In acromegaly visfatin could be considered a useful index of disease activity and metabolic alterations, such as insulin resistance and adipose dysfunction, regardless of the type of treatment.

Topics: Acromegaly; Adipokines; Adiposity; Adult; Aged; Biomarkers; Cholesterol, HDL; Cross-Sectional Studies; Cytokines; Fatty Acids, Nonesterified; Female; Humans; Insulin Resistance; Leptin; Male; Middle Aged; Nicotinamide Phosphoribosyltransferase; Triglycerides

It has been shown that acromegaly is characterized by an autonomic imbalance and by marked sympathoinhibition. However, there is no information available as to whether adrenergic inhibition is confined to selected vascular districts or, rather, is generalized. We examined 17 newly diagnosed active acromegalic patients without hyperprolactinaemia, pituitary hormone deficiencies, obstructive sleep apnoea and cardiac hypertrophy and 14 healthy subjects matched for age, sex and body mass index. For each subject, we collected information regarding anthropometric parameters and echocardiography, and collected plasma samples to investigate anterior pituitary function, glucose and lipid metabolism and plasma leptin levels. Beat-to-beat mean arterial pressure, heart rate and efferent post-ganglionic muscle and skin sympathetic nerve traffic (MSNA and SSNA, respectively; determined by microneurography) were measured. Both MSNA and SSNA were recorded in a randomized sequence over two 30 min periods. Measurements also included evaluation of SSNA responses to emotional stimulus. In addition to significant reductions in plasma leptin levels, acromegalic patients had markedly decreased MSNA compared with the healthy controls. There were no significant differences in SSNA between the two groups, either under basal conditions or in responses to arousal stimuli. There was a significant and direct correlation between MSNA and plasma leptin levels, but not between plasma leptin and SSNA. These data provide the first evidence that the sympathetic inhibition characterizing the early phase of acromegaly is not generalized to the entire cardiovascular system.

Topics: Acromegaly; Adenoma; Adrenergic Neurons; Adult; Autonomic Nervous System; Cardiovascular System; Female; Growth Hormone-Secreting Pituitary Adenoma; Humans; Leptin; Male; Middle Aged; Muscle, Skeletal; Neural Inhibition; Peripheral Nervous System; Pituitary Gland, Anterior; Severity of Illness Index; Skin; Sympathetic Nervous System; Synaptic Transmission

To find out how resistin and leptin levels were affected in patients with acromegaly and whether there is a relation between resistin levels and cardiac parameters. We also aimed to investigate whether resistin and leptin may be a link between insulin resistance and cardiac functions as well as these affected cardiac functions in the patients with acromegaly.. We included 30 subjects (15 men and 15 women) who had a diagnosis of acromegaly and 30 healthy (10 men and 20 women) subjects. Serum glucose, insulin, growth hormone, insulinlike growth factor 1 (IGF-1), resistin, and leptin levels were obtained, and insulin resistance of subjects were calculated. Echocardiographic studies of the subjects were performed.. Resistin levels of the patients with acromegaly were found lower than controls. This difference was statistically significant (P = 0.001). Leptin levels were lower in the patients with acromegaly than in the controls, but this difference was not statistically significant. Resistin and leptin levels were not correlated with growth hormone, IGF-1, and with insulin-like growth factor binding protein 3 levels. Homeostasis model assessment of insulin resistance was positively correlated with resistin levels. (P = 0.03; r = 0.531) but not correlated with leptin levels. There was a positive correlation between body mass index and leptin levels in the patients with acromegaly (P = 0.007; r = 0.482). Interventricular septum thickness, posterior wall thickness, left ventricle mass index, peak early mitral inflow velocity-peak late mitral inflow velocity ratio, deceleration time, ejection time, isovolumetric relaxation time, velocity propagation, and left ventricular end-systolic volume values were significantly greater in the patients with acromegaly. Leptin levels in the acromegalic patients were not correlated with any of them.. We found biventricular hypertrophy and impairment of diastolic and systolic function in the patients with acromegaly. We conclude that changes in resistin and leptin levels are unlikely to account for the insulin resistance of acromegaly. They do not also seem to be contributing factors of cardiovascular changes in patients with acromegaly.

Topics: Acromegaly; Adult; Case-Control Studies; Echocardiography; Female; Humans; Leptin; Male; Middle Aged; Resistin

Sympathovagal imbalance has been shown in acromegaly by indirect measurements of adrenergic tone. Data regarding direct measurement of sympathetic activity are lacking as yet. Aim of this study was to assess the adrenergic tone through direct recording of muscle sympathetic nerve activity (MSNA) in acromegalic patients.. Fifteen patients (age 26-66 years, eight women) with newly diagnosed active acromegaly without hyperprolactinaemia, pituitary hormone deficiencies, obstructive sleep apnoea and cardiac hypertrophy, and 15 healthy subjects matched for age, sex and body mass index were recruited. After evaluating anthropometric and echocardiographic parameters, anterior pituitary function, glucose and lipid metabolism, and measuring plasma leptin, direct recording of sympathetic outflow via the microneurographic technique was performed.. For similar anthropometric and metabolic parameters in patients and controls, HOMA index was significantly increased in the former (4·2 ± 2·39 vs 1·6 ± 0·19, P < 0·001). Surprisingly, this finding of insulin resistance was accompanied by a marked sympathetic inhibition (MSNA 18·3 ± 8·10 vs 37·3 ± 6·48 bursts/min, P < 0·0001, respectively in patients and controls). A reduction in plasma leptin (1·6 ± 1·04 vs 6·5 ± 2·01 μg/l, P < 0·0001) was also recorded in the patients. MSNA was positively correlated with leptin (P < 0·0001).. Newly diagnosed acromegalic patients without cardiac hypertrophy display a decreased sympathetic outflow in spite of insulin resistance. This finding might be related to hypoleptinaemia.

Topics: Acromegaly; Adult; Aged; Blood Glucose; Case-Control Studies; Female; Humans; Insulin Resistance; Leptin; Lipid Metabolism; Male; Middle Aged; Sympathetic Nervous System

Pegvisomant (peg) is a GH receptor antagonist. In de novo acromegalic patients with high GH levels, ghrelin and leptin levels are reduced, suggesting a direct GH-mediated effect. The aim of our study was to evaluate whether peg treatment in acromegalic patients may abolish the GH impact on ghrelin and leptin levels.. Ghrelin, leptin and endogenous GH were measured in ten peg-treated acromegalic patients (three females/seven males, 47 years (28-57)), ten patients with active (act) and ten patients with inactive disease (inact) as well as in ten gender-, age- and body mass index (BMI)-matched healthy volunteers (controls). Endogenous GH was measured using a special in-house assay without interference by peg; total ghrelin and leptin were determined using a commercial RIA and an immunofluorometric in-house assay respectively.. Age and BMI did not differ significantly between groups. Endogenous GH was significantly higher in peg (6.3 μg/l (1.5-41)) and act (9.3 μg/l (1.7-70)) compared with controls (0.1 μg/l (0.1-3.1)) and inact (0.35 μg/l (0.1-2.0), P<0.001). Ghrelin was significantly higher in peg (232  ng/l (96-351)) compared with act (102 ng/l (33-232), P<0.01), whereas ghrelin was not significantly different between the other groups. Leptin was highest in controls (19 μg/l (4-57)) and lowest in act (6 μg/l (2-21)), but this difference did not reach significance.. Treatment with peg seems to disrupt the feedback loop of ghrelin and GH, leading to elevated ghrelin levels. Furthermore, peg therapy appears not to have a strong impact on leptin levels, as acromegalic patients with and without peg treatment showed similar leptin levels.

Topics: Acromegaly; Adult; Aged, 80 and over; Biomarkers; Cross-Sectional Studies; Female; Ghrelin; Human Growth Hormone; Humans; Leptin; Male; Middle Aged; Receptors, Somatotropin

Starvation exerts critical influence on somatotroph and leptin secretion. Fasting enhances GH levels in normal subjects, but not in GH hyposecretory states, while it always inhibits leptin secretion. We aimed to clarify the GH/IGF-I and metabolic response to short-term fasting in a GH hypersecretory state such as acromegaly. To this goal, in 8 active acromegalic (ACRO) and in 7 normal women (NS) we evaluated mean GH (mGHc), leptin (mLEPc), insulin (mINSc), glucose (mGLUc) concentrations as well as IGF-I, IGF binding protein (IGFBP)-3, IGFBP-1, and free fatty acid (FFA) levels before and after 36-h fasting. Before fasting, mGHc, IGF-I, mINSc, mGLUc, and FFA levels in ACRO were higher (p<0.01) than in NS. IGFBP-3, IGFBP-1, and mLEPc were similar in ACRO and in NS. Fasting clearly (p<0.02) increased mGHc in NS only. After 36-h fasting, significant IGF-I reduction was recorded in NS only (p<0.03). IGFBP-3 did not change both in ACRO and NS. IGFBP-1 significantly increased (p<0.05) after fasting in both groups but in ACRO were lower (p<0.03) than in NS. Fasting decreased (p<0.03) mLEPc, mGLUc, and mINSc in ACRO as well as in NS; mINSc and mGLUc after fasting in ACRO persisted higher (p<0.005) than in NS. FFA levels were increased by fasting in NS (p<0.02), but not in ACRO. This study shows that GH/IGF-I axis, glucose metabolism, and lypolisis but not leptin display some degree of refractoriness to short-term fasting in acromegaly. The lack of any GH response to fasting in acromegaly would likely reflect neuroendocrine alterations secondary to the GH hypersecretory state. On the other hand, the lack of somatotropic response and the peculiarly blunted metabolic reaction to short-term fasting would partially reflect the delayed adaptation of insulin resistance to starvation.

Topics: Acromegaly; Adult; Aged; Blood Glucose; Case-Control Studies; Fasting; Female; Human Growth Hormone; Humans; Insulin-Like Growth Factor I; Leptin; Lipolysis; Male; Metabolic Diseases; Middle Aged; Signal Transduction; Young Adult

Ghrelin is a novel gastric peptide known to stimulate GH secretion, but the relationship between ghrelin and the GH-insulin-like growth factor (IGF)-1 axis in GH excess or deficiency is poorly understood. This study investigated dysregulation of ghrelin secretion in acromegaly and its short-term postoperative recovery.. A prospective study was conducted on eight patients who underwent complete transsphenoidal resection of GH-producing pituitary adenomas (acromegaly group) and 22 for endocrinologically nonfunctioning pituitary tumours (control group). Active and total plasma ghrelin levels were measured serially before and after surgery.. Preoperative active and total plasma ghrelin concentrations (mean +/- SD; fmol/ml) were significantly reduced in acromegalic patients when compared with those in the controls (9.6 +/- 4.3 and 157.4 +/- 65.6 vs. 21.8 +/- 13.0 and 267.1 +/- 111.4; P = 0.023 and P = 0.021, respectively). Both levels were still significantly suppressed on postoperative Day 7 in the acromegaly group when compared with those in the control group (11.7 +/- 4.3 and 197.8 +/- 68.9 vs. 22.5 +/- 12.6 and 302.7 +/- 100.0; P = 0.038 and P = 0.018, respectively). The ratios of active to total ghrelin were not significantly different between the two groups before and after operation. In acromegalic patients, active and total ghrelin levels remained significantly suppressed even after normalization of serum GH levels.. The putative negative feedback mechanism of GH on ghrelin secretion may in part account for the low ghrelin levels observed in acromegalic patients, and the mechanism may persist even after normalization of serum GH.

Topics: Acromegaly; Adult; Analysis of Variance; Biomarkers; Case-Control Studies; Chi-Square Distribution; Depression, Chemical; Feedback, Physiological; Female; Ghrelin; Growth Hormone; Humans; Insulin-Like Growth Factor I; Leptin; Male; Middle Aged; Pituitary Neoplasms; Postoperative Period

Correction of GH and IGF-I levels are associated with improvements in insulin secretion, cardiac performance and body composition in patients with acromegaly, but whether these parallel post-treatment levels of GH-IGF-I axis activity is undefined. We investigate whether various biochemical outcomes after transsphenoidal pituitary surgery (TSS) in these patients are associated with clinically relevant differences in cardiac performance, insulin resistance and body composition.. Cross-sectional study of consecutive patients with acromegaly admitted to the hospital between 2001 and 2002.. Forty-one patients after TSS for somatotroph pituitary adenoma and 23 patients with naive acromegaly serving as positive controls were enrolled in the study. Mean daily GH levels (mGH), IGF-I, leptin and lipid levels, glucose, insulin and GH concentrations during oral glucose tolerance test (oGTT) were measured in all study participants. Insulin resistance was measured by homeostatic model index (R(HOMA)). Body composition was assessed by dual-energy X-ray absorptiometry. Left ventricular mass index (LVM(i)) and cardiac index (C(i)) were determined by echocardiography.. We found no difference in cardiac indices, insulin resistance, body composition and leptin levels between patients with complete biochemical remission and those with inadequately controlled disease (P > 0.05 for all) after TSS. Cured patients had lower values (mean +/- SD) of cardiac index (2.2 +/- 0.7 vs. 3.0 +/- 1.0 l/min/m(2); P = 0.04) compared with naive patients. A similar decrease in LVM(i) was observed in controlled (108.4 +/- 30.0 g/m(2); P = 0.015) and inadequately controlled disease (108.8 +/- 30.7 g/m(2); P = 0.03) in comparison with naive disease (160.3 +/- 80.6 g/m(2)). Insulin resistance and leptin changed in opposite ways. In controlled and inadequately controlled disease, R(HOMA) index was lower (2.2 +/- 1.4; P = 0.001 and 3.1 +/- 2.0; P = 0.05 vs. 5.1 +/- 3.1) while leptin concentration was higher (14.9 +/- 8.7 microg/l, P = 0.004 and 12.8 +/- 7.8 microg/l, P = 0.05 vs. 7.4 +/- 3.8 microg/l) than in naive disease. In all patients, leptin correlated negatively with cardiac index (r = -0.46; P = 0.001) and IGF-I levels (r = -0.45; P < 0.001). Independent predictors of biochemical remission, based on normal IGF-I levels only, were cardiac [P = 0.04, odds ratio (OR) 0.4; 95% confidence interval (CI) 0.2-0.9] and R(HOMA) index (P = 0.009, OR 0.6; 95% CI 0.4-0.8). Similar results were obtained if the definition of cure included both normal IGF-I levels and the ability to achieve GH nadir < 1 microg/l during oGTT. Insulin resistance (P = 0.02, OR 0.6; 95% CI 0.4-0.9) and leptin level (P = 0.002, OR 1.3; 95% CI 1.1-1.6) were independent predictors of normalized mGH values.. This study shows that cardiac indices, insulin resistance and body composition were not different between patients with complete biochemical remission and those with discordant GH and IGF-I levels. It appears that even incomplete disease control after TSS can result in improvement of these clinical markers.

Topics: Absorptiometry, Photon; Acromegaly; Adenoma; Adult; Aged; Area Under Curve; Biomarkers; Blood Glucose; Body Composition; Echocardiography; Female; Growth Hormone; Humans; Insulin; Insulin-Like Growth Factor I; Leptin; Lipids; Logistic Models; Male; Middle Aged; Pituitary Neoplasms; Remission Induction; Treatment Failure

Insulin resistance, impaired glucose tolerance and type 2 diabetes are common in acromegalic subjects. The mechanism underlying this insulin resistance is unclear.. We investigated the levels of the adipocytokines, resistin, adiponectin and leptin in a group of 18 acromegalic subjects and 18 control subjects matched for age, gender and body mass index.. Here we demonstrate for the first time significant elevation in adiponectin levels in acromegalic subjects compared to control subjects 12.5 +/- 1.2 vs. 8.97 +/- 1.1 mg/l, P = 0.029. The resistin levels were similar in acromegalic subjects and controls; 20.65 +/- 2.99 vs. 19.03 +/- 4.72 micro g/l. No evidence of a correlation between adiponectin and insulin resistance as calculated from HOMA-R was found. No correlation was observed either between adiponectin or resistin levels and GH levels, total IGF-I or free IGF-I levels. Leptin levels were significantly reduced in acromegalic subjects, 8.22 +/- 2.26 vs. 18.3 +/- 4.1 micro g/l, P = 0.004. In control subjects, significant correlations between leptin levels and HOMA-R and between resistin levels and HOMA-R were observed. These relationships were not apparent in acromegalic subjects.. From these data we conclude that changes in resistin and adiponectin levels are unlikely to account for the insulin resistance of acromegaly.

Topics: Acromegaly; Adiponectin; Adult; Blood Glucose; Case-Control Studies; Female; Growth Hormone; Hormones, Ectopic; Humans; Insulin; Insulin Resistance; Insulin-Like Growth Factor Binding Protein 1; Insulin-Like Growth Factor Binding Protein 3; Insulin-Like Growth Factor I; Intercellular Signaling Peptides and Proteins; Leptin; Linear Models; Male; Middle Aged; Proteins; Resistin

Ghrelin exerts a wide range of metabolic functions. In contrast to the body of information accumulated on the role of ghrelin on energy balance, the possible relevance of the peptide on GH secretion in physiological and pathological conditions has so far been poorly investigated.. The aim of the present study was to evaluate circulating ghrelin levels in acromegalic patients in basal conditions and in response to oral glucose tolerance test (OGTT).. Serum ghrelin, insulin and leptin levels were measured in 31 healthy normal weight subjects as controls, 25 patients with simple obesity and 17 non-diabetic acromegalic patients. Ghrelin and insulin response to OGTT was evaluated in six controls, four obese and six acromegalic patients.. The acromegalic patients showed ghrelin levels lower than those observed in normal weight subjects (201+/-20 vs 329+/-32 pmol/l, P<0.05) and similar to those found in obese subjects (165+/-14 pmol/l, P=not significant). Both obese and acromegalic patients had insulin levels significantly higher than controls, while high levels of leptin were detected only in obese subjects. Serum ghrelin levels showed a significant negative correlation with insulin, leptin and body mass index (P<0.05) in normal and obese subjects. No correlation was observed in acromegalic patients, although those with severe insulin resistance showed the lowest ghrelin values (161+/-20 pmol/l). In controls and obese subjects, ghrelin levels showed a significant decrease (25-40%) during OGTT, while no effect was detectable in acromegalic patients.. This study reports that patients with active acromegaly show low levels of circulating ghrelin that are not further reduced by OGTT, this pattern of secretion probably depending on both GH-induced insulin resistance and the putative GH/IGF-I negative feedback control on ghrelin secretion.

Topics: Acromegaly; Adult; Aged; Body Mass Index; Female; Ghrelin; Glucose Tolerance Test; Human Growth Hormone; Humans; Insulin; Insulin Resistance; Leptin; Male; Middle Aged; Obesity; Peptide Hormones; Peptides

Leptin plays an important role in controlling satiety and maintaining energy balance. Acromegaly is characterized by decreased fat, which increases after the disease is cured. Our objective was to investigate serum leptin in acromegaly in terms of disease activity, body fat content, insulin and glucose levels, and selected anthropometric variables.. We examined 40 patients with acromegaly and 20 sex- and age-matched controls for the levels of serum GH, IGF-I, leptin, glucose, and insulin, and for body composition by DEXA, BMI and WHR. In 10 cases the acute effect on serum leptin of a somatostatin analogue, lanreotide, was studied.. We observed lower leptin in patients with active acromegaly than in cured patients and controls. Body fat was higher in cured than active patients. In the patients, we found significant correlations (p<0.05) between leptin and percent body fat (r=0.77), leptin and body fat mass (r=0.74), leptin and fasting insulin (r=0.62), leptin and fasting insulin/glucose ratio (r=0.97), leptin and BMI (r=0.44), leptin and height (r=-0.47). In the controls there was a significant correlation (p<0.05) only between leptin and WHR (r=-0.45). A paradoxical decrease of the leptin level after lanreotide was observed in 7 out of 10 patients with active acromegaly.. Changes in leptin release in acromegaly are related to differences in body fat content and mass, and in insulin resistance. Leptin in acromegaly is not influenced directly by GH or IGF-I secretion. The acute effect of medical treatment of acromegaly by a somatostatin analogue on leptin levels differs from the effect of a radical cure following pituitary adenoma surgery.

Topics: Acromegaly; Adipose Tissue; Adult; Blood Glucose; Fasting; Female; Growth Hormone; Humans; Insulin; Insulin-Like Growth Factor I; Leptin; Male; Middle Aged; Statistics as Topic

Serum leptin levels are decreased in patients with acromegaly and rise after GH is normalized by surgical treatment. We have evaluated the effect of Sandostatin LAR on leptin levels in acromegalic patients since there are recent data to suggest that somatostatin, in addition to its GH lowering effect, also reduces serum leptin levels in humans. Nineteen patients with active acromegaly were studied. Eleven patients received monthly injection of Sandostatin LAR and eight patients underwent transsphenoidal surgery. Serum concentrations of leptin, GH, IGF-1 and insulin were measured before and after treatment. Serum leptin concentrations were lower in patients with active acromegaly than controls matched for age, sex and body mass index (BMI) [2.79 microg/l (2.60) vs. 4.41 microg/l (5.07); median (inter-quartile range); P < 0.01]. A positive correlation between serum leptin concentrations and BMI was observed in the controls (r = 0.46, P < 0.05) but not in the acromegalic patients before treatment (r = 0.32, ns). In the group of patients treated with Sandostatin LAR, a marked reduction in GH and IGF-1 was achieved by week 8 and GH and IGF-1 remained suppressed throughout the 6 months of treatment. There was no change in BMI. A significant increase in leptin levels only became evident after 6 months of treatment [2.99 microg/l (2.60) vs. 4.21 microg/l (3.84), P < 0.05]. Leptin levels also significantly increased after transsphenoidal surgery [3.05 microg/l (5.73) vs. 5.19 microg/l (4.93), P < 0.05]. The positive correlation between serum leptin concentrations and BMI was restored in acromegalic patients both after treatment with Sandostatin LAR (r = 0.62, P < 0.05) and after surgery (r = 0.81, P < 0.05). Leptin concentrations were decreased in patients with active acromegaly and lowering GH by either Sandostatin LAR or transsphenoidal surgery led to an increase in leptin concentrations.

Topics: Acromegaly; Adult; Analysis of Variance; Body Mass Index; Case-Control Studies; Delayed-Action Preparations; Female; Growth Hormone; Humans; Insulin-Like Growth Factor I; Leptin; Male; Middle Aged; Octreotide; Somatostatin; Time Factors

In order to identify the mutual interaction between GH and leptin, we studied the effect of GH on fatty Zucker rats. GH administration at a high dose (5.0 IU/kg) reduced % body fat after 7 days. The leptin mRNA level in subcutaneous fat tissue was not changed but that in epididymal fat tissue was decreased by an even lower dose of GH (1.5 IU/kg). IGF-I treatment (200 microg/kg/day) did not change the % body fat or leptin mRNA level. These observations suggest that GH directly interacts with visceral fat and reduces fat mass and leptin expression. We also measured serum leptin levels in patients. The levels in patients with acromegaly were significantly lower than those in normal subjects with the same amount of body fat, but serum IGF-I and urinary C peptide excretion rates were higher in the acromegalic. These observations also suggests that GH directly interacts with adipose tissue and reduces leptin expression. Next we investigated the direct action of leptin on GH release from the pituitary. Leptin pretreatment of pituitary cells in culture or rats in a fasted or fed condition did not change GRH induced GH secretion. As indicated also by other recent studies, leptin may increase GRH or decrease somatostatin secretion by the hypothalamus. Thus GH interacts with fat tissues and leptin may be a good marker of the interaction.

Topics: Acromegaly; Adipose Tissue; Animals; Body Composition; C-Peptide; Female; Gene Expression Regulation; Growth Hormone; Humans; Insulin-Like Growth Factor I; Leptin; Male; Obesity; Rats; Rats, Wistar; Rats, Zucker; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger

As leptin, an ob gene product, plays a pivotal role in the regulation of adiposity and energy homeostasis, the level of its expression is likely to fluctuate under various physiological, nutritional, and disease conditions. Reports regarding the effect of GH on serum leptin levels are inconsistent. We have measured serum leptin levels and correlated them with several variables in patients with acromegaly, patients with adult GH deficiency (GHD), and normal controls. In 116 normal subjects, the mean serum concentration of leptin was 5.0+/-2.8 (mean +/- SD) ng/mL in men (n = 42) and 10.7+/-7.3 ng/mL in women (n = 73), respectively. As reported previously, the leptin levels in women were significantly (P < 0.001) higher than in men, and there was a strong positive correlation between log-transformed serum leptin levels and percent body fat in simple regression analysis (in men: r = 0.606; P < 0.0001; in women: r = 0.707; P < 0.0001). In 36 acromegalic patients, the percent body fat mass was significantly lower than that in normal subjects, and the mean serum leptin level was 2.2+/-1.8 ng/mL in men (n = 18) and 3.6+/-2.5 ng/mL in women (n = 18). Analysis of covariance revealed that serum leptin levels in acromegalics were significantly lower than those in normal subjects after correcting percent body fat (P = 0.016 for men and P < 0001 for women). In male patients with GHD (n = 20), the mean percent body fat was significantly (P < 0.05) higher than that in age-matched controls, whereas the value in female GHD patients (n = 15) did not differ from that in age-matched controls. Serum leptin levels in GHD patients were 5.1+/-2.5 ng/mL in men and 11.5+/-8.1 ng/mL in women, which were not different from those in normal subjects adjusted for percent body fat mass. In multiple regression analysis models with log-transformed leptin as the dependent variable, gender, percent body fat (or body fat mass), and serum insulin-like growth factor I levels entered the equations at a statistically significant level. These data suggest that excess GH/insulin-like growth factor I reduces serum leptin levels by reducing body fat mass and/or by unknown mechanisms.

Topics: Acromegaly; Adipose Tissue; Adult; Body Composition; Body Mass Index; Female; Human Growth Hormone; Humans; Insulin-Like Growth Factor I; Leptin; Male; Middle Aged; Osmolar Concentration; Proteins; Reference Values; Sex Characteristics