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LEAP-2/ghrelin interplay in adult growth hormone deficiency: Cause or consequence? A pilot study.
Vergani, E, Bruno, C, Gavotti, C, Aversa, LS, Martire, M, Mancini, A, Currò, D
IUBMB life. 2021;(7):978-984
Abstract
Ghrelin and its endogenous antagonist liver-expressed antimicrobial peptide-2 (LEAP-2) are involved in GH secretion and glucose/lipids metabolism. LEAP-2 expression in conditions of metabolic impairment may be upregulated, usually pairing with a concomitant reduction in ghrelin secretion. Adult growth hormone deficiency (aGHD) is characterized by insulin resistance, weight gain, and increased fat mass. Therefore, the primary endpoint of this cross-sectional observational pilot study was to compare circulating LEAP-2 and ghrelin levels in aGHD and healthy controls. Thirty patients were included in the study. Group A included adult GHD: 15 patients, 8 females, and 7 males. Median and interquartile range age of the group was 53 (41-57) years, while BMI was 27.1 (25-35) kg/m2 . Group B was formed by 15 healthy controls (10 females and 5 males). Median and interquartile range age was 47 (36-57) years, while BMI 22.9 (20.8-33.1) kg/m2 . They were evaluated for serum glucose and insulin, HOMA-index, QUICKI-index, total/LDL/HDL cholesterol, triglycerides, IGF-1, ghrelin, and LEAP-2. Ghrelin levels in the aGHD group were significantly lower than in healthy controls. In contrast, LEAP-2 showed a trend toward higher levels, although the differences were not significant. However, the LEAP-2/Ghrelin ratio was significantly higher in aGHD. No significant correlations between ghrelin and LEAP-2 with BMI and HOMA index were found in aGHD population. However, a significant inverse correlation (r2 = 0.15, p = .047) between BMI and ghrelin was evidenced when considering the whole population. Taken together, these results may suggest a body adaptation to a metabolic scenario typical of aGHD. The decrease in ghrelin production could prevent further weight gain and fat mass increase, although losing its secretagogue effect.
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MANAGEMENT OF ENDOCRINE DISEASE: Etiology and outcome of acromegaly in patients with a paradoxical GH response to glucose.
Hage, M, Janot, C, Salenave, S, Chanson, P, Kamenický, P
European journal of endocrinology. 2021;(6):R261-R268
Abstract
To gain more insight on the pathogenesis of somatotroph pituitary adenomas, recent studies have focused on a subgroup of patients with acromegaly displaying a paradoxical growth hormone (GH) response during oral glucose tolerance test (OGTT). The paradoxical rise of GH after oral glucose intake occurs in about one-third of acromegaly patients and has been pathogenetically linked, by analogy to glucose-dependent insulinotropic polypeptide (GIP)-dependent Cushing's syndrome, to the ectopic expression of GIP receptor (GIPR) in somatotroph adenoma cells. GIPR-expressing adenomas are negative for activating GNAS gene mutations and display distinct cytogenetic and DNA methylation profiles, highlighting their unique molecular pathogenesis. Acromegaly patients with a paradoxical GH response pattern seem to display higher insulin-like growth factor-1 (IGF-1) concentrations and harbour smaller adenomas that are more often of the densely granulated phenotype. They seem also to show a better response to somatostatin receptor ligands. In addition, persistent paradoxical GH response after surgery may be a biological marker of the residual disease postoperatively. Targeted therapy to antagonize GIP receptor on GIPR-expressing somatotroph adenomas could be a new treatment approach for acromegaly patients with a paradoxical pattern of GH response to OGTT.
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A challenging TSH/GH co-secreting pituitary adenoma with concomitant thyroid cancer; a case report and literature review.
Yoon, JH, Choi, W, Park, JY, Hong, AR, Kim, SS, Kim, HK, Kang, HC
BMC endocrine disorders. 2021;(1):177
Abstract
BACKGROUND Thyroid stimulating hormone (TSH) secreting pituitary adenoma (TSHoma) with coexisting thyroid cancer is extremely rare, and proper treatment of both diseases may pose a unique clinical challenge. When TSHoma has plurihormonality, particularly involving the co-secretion of growth hormone (GH), management can be more complicated. Herein, we present a difficult-to-manage case of papillary thyroid cancer with an incurable TSH/GH-secreting pituitary adenoma. CASE PRESENTATION A 59-year-old man was referred to our hospital due to memory impairment and inappropriate TSH level. Sella magnetic resonance imaging revealed a huge pituitary mass extending to the suprasellar area. Clinical diagnosis of TSH/GH co-secreting pituitary adenoma was made based on elevated free T4, total T3, serum α-subunit, insulin-like growth factor-1 levels and non-suppressible GH levels after oral glucose loading. Rectal cancer and multifocal papillary thyroid microcarcinoma (PTMC) were diagnosed during initial screening for internal malignancy; lower anterior resection was performed and close observation was planned for PTMC. Long-acting octreotide therapy was commenced, which resulted in a dramatic reduction in TSHoma size and facilitated control of hormonal excess. Total thyroidectomy and radioactive iodine (RAI) therapy were needed during follow up due to the growth of PTMC. After the surgery, the pituitary adenoma represented resistance to somatostatin analogue therapy and the tumor size gradually increased despite the addition of dopamine agonist therapy. Furthermore, TSH suppressive therapy with levothyroxine was impossible and an adequate TSH level for RAI therapy was unmountable. Late debulking pituitary surgery was ineffective, and the patient gradually deteriorated and lost to follow up. CONCLUSION We report the first aggravated case of TSH/GH co-secreting pituitary tumor after total thyroidectomy for concomitant multifocal PTMC. Deferring of thyroid surgery until the TSHoma is well controlled may be the optimal therapeutic strategy in patients with TSHoma and coexistent thyroid cancer; ablative thyroid surgery may result in catastrophic pituitary tumor growth.
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IGF-I deficiency and enhanced insulin sensitivity due to a mutated growth hormone receptor gene in humans.
Guevara-Aguirre, J, Torres, C, Peña, G, Palacios, M, Bautista, C, Guevara, A, Gavilanes, AW
Molecular and cellular endocrinology. 2021;:111044
Abstract
Human size is achieved by the coordinated expression of many genes. From conception to adulthood, a given genomic endowment is modified by highly variable environmental circumstances. During each stage of a person's life, distinct nutritional and hormonal influences continuously shape growing physical features until mature characteristics are attained. Underlying processes depend on precise provision of substrates and energy extracted by insulin action from nutrients, which allows cell proliferation, differentiation, and survival, under the concerted actions of growth hormone and insulin-like growth factor-I (IGF-I). It should be noted that growth and metabolic signaling pathways are interdependent and superimposed at multiple levels. Attainment of a fully developed human phenotype should be considered as a harmonious increment in body size rather than a simple increase in height. From this perspective we herein analyze adult features of individuals with an inactive growth hormone receptor, who consequently have severely diminished concentrations of serum insulin and endocrine IGF-I.
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[Acromegaly and it's cardiovascular implications].
Cadena-Obando, DA, Remba-Shapiro, I, Abreu-Rosario, CG, Mercado, M
Revista medica del Instituto Mexicano del Seguro Social. 2021;(1):73-80
Abstract
Acromegaly is a chronic and slowly progressive disease that results from the hypersecretion of growth hormone (GH) and consequently insulin-like growth factor type 1 (IGF-1), due to a GH-secreting pituitary adenoma in 95-98% of cases. There are several complications or co-morbidities associated with acromegaly, the most frequent being cardiovascular, metabolic and neoplastic. The cardiovascular complications of acromegaly go from arterial hypertension to a peculiar form of cardiomyopathy and are the result of the long-standing exposure to high GH and IGF-1 levels. The pathophysiology of these complications is complex and includes an increased tubular reabsorption of sodium and the direct effects of GH and IGF-1 on the endothelium and the cardiac tissue itself. Frequently, the cardiovascular comorbidities of acromegaly occur concomitantly with metabolic complications such as diabetes and respiratory abnormalities such as the sleep apnea syndrome. In this brief review we analyze the pathophysiology, the clinical manifestations and the management of the cardiovascular complications of acromegaly.
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Growth Hormone Treatment for Adults With Prader-Willi Syndrome: A Meta-Analysis.
Rosenberg, AGW, Passone, CGB, Pellikaan, K, Damiani, D, van der Lely, AJ, Polak, M, Bernardo, WM, de Graaff, LCG
The Journal of clinical endocrinology and metabolism. 2021;(10):3068-3091
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Abstract
CONTEXT Features of Prader-Willi syndrome (PWS) overlap with features of growth hormone (GH) deficiency, like small hands and feet, short stature, increased body fat, and low muscle mass and strength. In children with PWS, GH treatment (GHt) improves physical health and cognition. GHt has become the standard of care in PWS children, but in adults this is not yet the case. OBJECTIVE This work aims to provide an overview of the current knowledge on GHt in PWS adults. METHODS Medline, Embase, and the Cochrane Central Register of Controlled Trials databases were searched. Study selection included randomized clinical trials (RCTs) and nonrandomized (un)controlled trials (NRCTs) that reported data for adults with PWS, who received GHt for at least 6 months. Data on body composition, body mass index (BMI), cardiovascular end points, bone, cognitive function, quality of life, and safety were extracted. RESULTS Nine RCTs and 20 NRCTs were included. Body composition improved during 12 months of GHt with an increase in mean (95% CI) lean body mass of 1.95 kg (0.04 to 3.87 kg) and a reduction of mean (95% CI) fat mass of -2.23% (-4.10% to -0.36%). BMI, low-density lipoprotein cholesterol levels, fasting glucose levels, and bone mineral density did not change during GHt. There were no major safety issues. CONCLUSION GHt appears to be safe and improves body composition in adults with PWS. Because poor body composition is closely linked to the observed high incidence of cardiovascular morbidity in adults with PWS, improving body composition might reduce cardiovascular complications in this vulnerable patient group.
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Adherence to treatment in children with growth hormone deficiency, small for gestational age and Turner syndrome in Mexico: results of the Easypod™ connect observational study (ECOS).
Blanco-López, A, Antillón-Ferreira, C, Saavedra-Castillo, E, Barrientos-Pérez, M, Rivero-Escalante, H, Flores-Caloca, O, Calzada-León, R, Rosas-Guerra, CC, Koledova, E, Chiquete, E, et al
Journal of endocrinological investigation. 2020;(10):1447-1452
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Abstract
BACKGROUND Assessing adherence to growth hormone (GH) is challenging. The Easypod™ connect device delivers pre-set doses of recombinant human GH (r-hGH) and stores a digital record of adherence that can be shared with healthcare provider. We assessed adherence to r-hGH delivered with Easypod™ according to the approved pediatric indications for r-hGH: growth hormone deficiency (GHD), born small for gestational age (SGA) who failed to show catch-up growth and Turner syndrome (TS). METHODS ECOS (NCT01555528) was a multicenter (24 countries), 5-year, longitudinal, observational study, which aimed to evaluate country-specific adherence to r-hGH therapy prescribed via the Easypod™ electronic injection device. The primary endpoint was yearly adherence. Secondary endpoints were height velocity, height velocity standard deviation scores (SDS), height, height SDS and IGF-1 concentrations. Clinical and auxological data were obtained from medical records and adherence from Easypod™ logs. RESULTS This study included 147 Easypod™-naïve Mexican children assessed during 3 years (mean age: 9.96 ± 3.41 years, 56.8% boys, mean height SDS at baseline: - 2.17 ± 0.97): 118 with GHD, 24 SGA and 5 with TS. A total of 105 (71.4%) patients were GH naïve. Overall median adherence was > 90% over the first year of treatment and > 80% at 3 years. Adherence was not different by r-hGH indication or between GH-naïve or experienced patients. At 1-year follow-up, mean change in height SDS was 0.57 ± 0.34, whereas mean height velocity SDS was 2.85 ± 2.51. In all, 84.7% patients had normal IGF-1 concentrations at 1-year follow-up. Adherence was associated with change in height SDS (r = 0.239, p = 0.005) and height velocity SDS (r = 0.194, p = 0.027). CONCLUSION Adherence rates with the Easypod™ device are high and maintained over time in GHD, SGA and TS Easypod™-naïve Mexican patients. High adherence is associated with better outcomes. Easypod™ assists physicians in monitoring adherence to r-hGH.
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Ten years with biosimilar rhGH in clinical practice in Sweden - experience from the prospective PATRO children and adult studies.
Lundberg, E, Kriström, B, Zouater, H, Deleskog, A, Höybye, C
BMC endocrine disorders. 2020;(1):55
Abstract
BACKGROUND In 2007, Omnitrope® was the first biosimilar recombinant human growth hormone (rhGH) to be approved in Sweden for treatment in adults and children. Over 10 years' safety and effectiveness data for biosimilar rhGH can now be presented. METHODS PATRO Children and PATRO Adults are multicenter, longitudinal, observational, post-marketing surveillance studies. Eligible patients include children 0-18 years and adults receiving biosimilar rhGH treatment. Adverse events (AEs) are monitored for safety evaluation. Growth variables in children and metabolic data in adults are recorded for effectiveness evaluation. RESULTS As of January 2019, data from 136 children (48% male) were reported from Swedish centers. Mean age in rhGH treatment-naïve patients at study entry (n = 114) was 7.5 years, with mean 3.6 years treatment duration. No severe AEs of diabetes, impaired glucose tolerance, or malignancy were reported. The most frequently reported AE was nasopharyngitis (n = 16 patients). No clinically relevant anti-hGH or neutralizing antibodies were observed. The mean change from baseline in height standard deviation score (SDS) in naïve prepubertal GH deficiency patients was + 0.79 at 1 year, + 1.27 at 2 years, and + 1.55 at 3 years. Data from 293 adults (44% rhGH-naïve, 51% male) were included. Fatigue was the most frequently reported AE (n = 26 patients). The incidence of new neoplasms or existing neoplasm progression was 23.8 patients per 1000 patient-years. Type 2 diabetes mellitus was reported in four patients. At baseline in rhGH-naïve adults, mean (SD) body mass index (BMI) was 29.1 (5.6) kg/m2 and mean (SD) insulin-like growth factor (IGF)-I SDS was - 3.0 (1.4). Mean daily dose increased from 0.1 mg at baseline to 0.3 mg after 4 years. IGF-I SDS normalized during the first year of treatment. Mean BMI and glucose were unchanged over 4 years, while low-/high-density lipoprotein cholesterol ratio decreased. CONCLUSIONS For the first time, Swedish data from the PATRO Children and Adults studies are presented. The 10-year data suggest that biosimilar rhGH is well tolerated across pediatric and adult indications. Safety and effectiveness were similar to previous reports for other rhGH preparations. These results need to be confirmed in larger cohorts, highlighting the importance of long-term post-marketing studies.
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Human growth hormone level decreased in women aged <60 years but increased in men aged >50 years.
Wang, X, Wang, S, Wu, H, Jiang, M, Xue, H, Zhu, Y, Wang, C, Zha, X, Wen, Y
Medicine. 2020;(2):e18440
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To investigate the relationship amongst human growth hormone (HGH), sex, and age groups.A cross-sectional study was conducted on a health check-up population from Wannan area of China from 2014 to 2016. The study involved 6843 individuals aged 23 to 85 years. Logistic regression analysis and smooth curve were applied to determine the relationship amongst age, sex, and HGH.The average level of HGH in the population was 0.37 ± 0.59 ng/mL. There were significant differences in sex, age, body mass index (BMI), triglycerides (TG), total cholesterol (TC), systolic blood pressure (SBP), diastolic blood pressure (DBP), and glucose (GLU) amongst different quartiles of HGH (P < .001). A U-shape relationship was established between HGH and age. After sex stratification, the results showed that the thresholds of age were 60 years in women, and 50 years in men, after adjusting for body mass index, triglycerides, total cholesterol, blood pressure, and blood glucose. Logistic regression showed that HGH level decreased in women aged <60 years (OR = 1.472, P < .001) and increased in men aged >50 years (OR = 0.711, P < .001). So the distributive characteristics of HGH concentration vary with sex and age group.
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Growth hormone ameliorates high glucose-induced steatosis on in vitro cultured human HepG2 hepatocytes by inhibiting de novo lipogenesis via ChREBP and FAS suppression.
Villanueva-Ortega, E, Méndez-García, LA, Garibay-Nieto, GN, Laresgoiti-Servitje, E, Medina-Bravo, P, Olivos-García, A, Muñoz-Ortega, MH, Ventura-Juárez, J, Escobedo, G
Growth hormone & IGF research : official journal of the Growth Hormone Research Society and the International IGF Research Society. 2020;:101332
Abstract
OBJECTIVE Growth hormone (GH) deficiency has been associated with increased steatosis but the molecular mechanism has not been fully elucidated. We investigated the effect of GH on lipid accumulation of HepG2 cells cultured on an in vitro steatosis model and examined the potential involvement of insulin-like growth factor 1 (IGF-1) as well as lipogenic and lipolytic molecules. METHODS Control and steatosis conditions were induced by culturing HepG2 cells with 5.5 or 25 mmol/l glucose for 24 h, respectively. Afterward, cells were exposed to 0, 5, 10 or 20 ng/ml GH for another 24 h. Lipid content was quantified as well as mRNA and protein levels of IGF-1, carbohydrate responsive element-binding protein (ChREBP), sterol regulatory element-binding protein 1c (SREBP1c), fatty acid synthase (FAS), carnitine palmitoyltransferase 1A (CPT1A), and peroxisome proliferator-activated receptor alpha (PPAR-alpha) by qPCR and western blot, respectively. Data were analyzed by one-way ANOVA and the Games-Howell post-hoc test. RESULTS In the steatosis model, HepG2 hepatocytes showed a significant 2-fold increase in lipid amount as compared to control cells. IGF-1 mRNA and protein levels were significantly increased in control cells exposed to 10 ng/ml GH, whereas high glucose abolished this effect. High glucose also significantly increased both mRNA and protein of ChREBP and FAS without having effect on SREBP1c, CPT1A and PPAR-alpha. However, GH inhibited ChREBP and FAS production, even in HepG2 hepatocytes cultured under steatosis conditions. CONCLUSIONS Growth hormone ameliorates high glucose-induced steatosis in HepG2 cells by suppressing de novo lipogenesis via ChREBP and FAS down-regulation.