High GH Levels Research Articles

Deficiency of Peptidylglycine-alpha-amidating Monooxygenase, a Cause of Sarcopenic Diabetes Mellitus.

Peptidylglycine-α-amidating monooxygenase (PAM) is a critical enzyme in the endocrine system responsible for activation, by amidation, of bioactive peptides. To define the clinical phenotype of carriers of genetic mutations associated with impaired PAM-amidating activity (PAM-AMA). We used genetic and phenotypic data from cohort studies: the Malmö Diet and Cancer (MDC; 1991-1996; reexamination in 2002-2012), the Malmö Preventive Project (MPP; 2002-2006), and the UK Biobank (UKB; 2012). Exome-wide association analysis was used to identify loss-of-function (LoF) variants associated with reduced PAM-AMA and subsequently used for association with the outcomes. This study included n∼4500 participants from a subcohort of the MDC (MDC-Cardiovascular cohort), n∼4500 from MPP, and n∼300,000 from UKB. Endocrine-metabolic traits suggested by prior literature, muscle mass, muscle function, and sarcopenia. Two LoF variants in the PAM gene, Ser539Trp (minor allele frequency: 0.7%) and Asp563Gly (5%), independently contributed to a decrease of 2.33 [95% confidence interval (CI): 2.52/2.15; P = 2.5E-140] and 0.98 (1.04/0.92; P = 1.12E-225) SD units of PAM-AMA, respectively. The cumulative effect of the LoF was associated with diabetes, reduced insulin secretion, and higher levels of GH and IGF-1. Moreover, carriers had reduced muscle mass and function, followed by a higher risk of sarcopenia. Indeed, the Ser539Trp mutation increased the risk of sarcopenia by 30% (odds ratio 1.31; 95% CI: 1.16/1.47; P = 9.8E-06), independently of age and diabetes. PAM-AMA genetic deficiency results in a prediabetic sarcopenic phenotype. Early identification of PAM LoF carriers would allow targeted exercise interventions and calls for novel therapies that restore enzymatic activity.

Non-pituitary growth hormone enables colon cell senescence evasion.

DNA damage-induced senescence is initially sustained by p53. Senescent cells produce a senescence-associated secretory phenotype (SASP) that impacts the aging microenvironment, often promoting cell transformation. Employing normal non-tumorous human colon cells (hNCC) derived from surgical biopsies and three-dimensional human intestinal organoids, we show that local non-pituitary growth hormone (npGH) induced in senescent cells is a SASP component acting to suppress p53. npGH autocrine/paracrine suppression of p53 results in senescence evasion and cell-cycle reentry, as evidenced by increased Ki67 and BrdU incorporation. Post-senescent cells exhibit activated epithelial-to-mesenchymal transition (EMT), and increased cell motility. Nu/J mice harboring GH-secreting HCT116 xenografts with resultant high GH levels and injected intrasplenic with post-senescent hNCC developed fourfold more metastases than did mice harboring control xenografts, suggesting that paracrine npGH enables post-senescent cell transformation. By contrast, senescent cells with suppressed npGH exhibit downregulated Ki67 and decreased soft agar colony formation. Mechanisms underlying these observations include npGH induction by the SASP chemokine CXCL1, which attracts immune effectors to eliminate senescent cells; GH, in turn, suppresses CXCL1, likely by inhibiting phospho-NFκB, resulting in SASP cytokine downregulation. Consistent with these findings, GH-receptor knockout mice exhibited increased colon phospho-NFκB and CXCL1, while GH excess decreased colon CXCL1. The results elucidate mechanisms for local hormonal regulation of microenvironmental changes in DNA-damaged non-tumorous epithelial cells and portray a heretofore unappreciated GH action favoring age-associated epithelial cell transformation.

Bone health and skeletal fragility in second- and third-line medical therapies for acromegaly: preliminary results from a pilot single center experience.

Skeletal fragility is a clinically relevant and not-reversible complication of acromegaly, involving around 30-40% of patients since the disease diagnosis. Few studies have investigated the effects on skeletal health of medical therapies for acromegaly. In this retrospective longitudinal monocentre study, we investigated the outcome of skeletal fragility in patients treated with Pasireotide Lar in combination with Pegvisomant (Pasi-Lar + Peg-V), also comparing those observed in patients treated with conventional therapies. We included 6 patients treated with Pasi-Lar + Peg-V, 5 patients treated with Peg-V in monotherapy (m-Peg-V), 16 patients treated with Peg-V plus first-generation somatostatin receptor ligands (fg-SRLs + Peg-V), 9 patients treated with Pasi-Lar. None of the patients treated with Pasi-Lar + Peg-V experienced worsening of spine and femoral bone mineral density (BMD) and incident vertebral fractures (i-VFs). Eight patients experienced i-VFs. The frequency of i-VFs was significantly lower in patients treated with the Pasi-Lar + Peg-V (0/8; 0%), as compared to those observed in m-Peg-V treated patients (4/8; 50%, p = 0.02). The frequency of i-VFs was slightly but not significantly higher in Pasi-Lar treated patients (1/8; 12.5% p = 0.6) and in fg-SRLs + Peg-V treated patients (3/8; 37.5% p = 0.364), concerning those treated with Pasi-Lar + Peg-V (0/8; 0%). I-VFs occurred more frequently in patients with higher GH levels at acromegaly diagnosis (p < 0.001), and in patients who experienced a BMD worsening (p = 0.005). Our preliminary data suggested that in conventional and multi-drug resistant acromegaly, the combination therapy Pasi-Lar + Peg-V may prevent the worsening of BMD and the occurrence of i-VFs. Prospective and translational studies should further validate these results and ascertain underlying physiopathology mechanisms.

The allostery and modification of hGHRH molecules and specific dimer produced significant fertility effect by proliferating and activating in-situ ovarian mesenchymal stem cells

The negative coordination of growth hormone secretagogue receptor (GHS-R) and growth hormone-releasing hormone receptor (GHRH-R) involves in the repair processes of cellular injury. The allosteric U- or H-like modified GHRH dimer Grinodin and 2Y were comparatively evaluated in normal Kunming mice and hamster infertility models induced by CPA treatment. 1–3–9 µg of Grinodin or 2Y per hamster stem-cell-exhaustion model was subcutaneously administered once a week, respectively inducing 75–69–46 or 45–13–50 % of birth rates. In comparison, the similar mole of human menopausal gonadotropin (hMG) or human growth hormone (hGH) was administered once a day but caused just 25 or 20 % of birth rates. Grinodin induced more big ovarian follicles and corpora lutea than 2Y, hMG, hGH. The hMG-treated group was observed many distorted interstitial cells and more connective tissues and the hGH-treated group had few ovarian follicles. 2Y had a plasma lifetime of 21 days and higher GH release in mice, inducing lower birth rate and stronger individual specificity in reproduction as well as only promoting the proliferation of mesenchymal-stem-cells (MSCs) in the models. In comparison, Grinodin had a plasma lifetime of 30 days and much lower GH release in mice. It significantly promoted the proliferation and activation of ovarian MSCs together with the development of follicles in the models by increasing Ki67 and GHS-R expressions, and decreasing GHRH-R expression in a dose-dependent manner. However, the high GH and excessive estrogen levels in the models showed a dose-dependent reduction in fertility. Therefore, unlike 2Y, the low dose of Grinodin specifically shows low GHS-R and high GHRH-R expressions thus evades GH and estrogen release and improves functions of organs, resulting in an increase of fertility.

THU068 Evaluation Of Nonalcoholic Fatty Liver Disease, Liver Fibrosis And Serum Angiopoietin-like Protein Levels In Patients With Acromegaly

Abstract Disclosure: I. Eroglu: None. B. Gonul Iremli: None. I. Idilman: None. D. Yuce: None. I. Lay: None. D. Akata: None. T. Erbas: None. Background: Due to their impaired glucose and lipid metabolism, acromegaly patients are potentially at risk for NAFLD. However, limited data exist about acromegaly and NAFLD relation. In this study (cross-sectional, case-controlled), we evaluated the risk of NAFLD and hepatic fibrosis in acromegalic patients and its association with noninvasive hepatosteatosis scores (NS) and angiopoietin-like protein-8 (ANGPTL-8) level for the first time in the literature. Methods: Thirty-two (15F/17M - median age=50.15 yrs) acromegalic patients (n=15 active acromegaly - AA and n=17 controlled acromegaly - CA) compared to 19 healthy controls (C) in terms of liver fat ratio (LFR), liver stiffness measurement (LSM), and ANGPTL-8 levels. Subjects had MRI-PDFF to determine LFR and MR elastography to quantify LSM. NAFLD was confirmed in those with LFR of ≥5%, and increased LSM in those with LSM of ≥2.5 kPa. VAI (visceral adipocity index), FLI (fatty liver index), HSI (hepatic steatosis index), and TyG (Triglyceride-glucose index) were calculated as NS. Results: Age, gender and BMI were similiar across groups. The GH and IGF-1 levels in AA group was greater than in CA, and C (p&amp;lt; 0.001). The CA had greater frequency of NAFLD than AA (p&amp;lt;0.001). Increased LSM was detected in three (21.4%) of AA, four (23.5%) of CA, and two (10.5%) of C.The median LFR was 1.75% in the AA group, 6.5% in the CA group, and 3.5% in the control group. LFR was lower in the AA group than in the CA (p=0.026). According to MRI-PDFF results, none of the patients in the AA group were diagnosed with NAFLD, while 58.8% (n=10) in the CA group and 26.3% (n=5) in the control group were diagnosed with NAFLD. The prevalence of NAFLD was found to be higher in the CA group than in the AA group (p&amp;lt;0.001). In acromegaly patients, LFR was positively correlated with TyG (r=0.675, p&amp;lt;0.001), VAI (r=0.508, p=0.004), and FLI (r=0.482, p=0.006). However, no correlation was seen between LFR and traditional risk factors for NAFLD (including BMI, waist circumference, Hba1c, HOMA-IR, and CRP) in acromegalics.ANGPTL-8 was lower in CA group (0.61 ng/mL) than in AA group (0.89 ng/mL) (p=0.006). When all acromegaly patients were evaluated independently, those with NAFLD had lower ANGPTL-8 levels than those without NAFLD (p=0.036). Conclusion: In conclusion, high GH levels seem to be protective against fatty liver in patients with active acromegaly, even if the metabolic profileis impaired. There was no relation observed between LFR and conventional risk factors in acromegaly patients. The strongest connection was found between LFR and TyG index among the noninvasive hepatosteatosis scores. ANGPTL-8 levels were lower in acromegaly patients with NAFLD, suggesting that high levels represent a reaction to insulin resistance rather than a cause of NAFLD. Treatment planning at a level that does not cause GH deficiency while maintaining disease control may be helpful to prevent NAFLD in acromegaly. Presentation: Thursday, June 15, 2023

FRI307 Gigantism Due To Transcriptional Activation Of GHRH: The First Case Of Hormone-encoding Gene Overexpression Underlying A Congenital Disorder

Abstract Disclosure: A. Hattori: None. Y. Katoh-Fukui: None. R. Zhang: None. M. Terao: None. S. Takada: None. K. Nakabayashi: None. K. Hata: None. Y. Yamada: None. N. Matsuura: None. M. Fukami: None. Background: Pituitary gigantism is characterized by tall stature due to GH overproduction. To date, known genetic causes of pituitary gigantism are invariably associated with predispositions to tumors producing GH or GHRH. Clinical and genetic findings of the patient: The patient was a Japanese woman who was born mildly large for gestational age. Her overgrowth started in her first year of life. Despite radiation and pharmacotherapy starting at age three years, she reached an adult height of 197 cm (+7.4 SD). She developed panhypopituitarism associated with empty sella in adulthood and was deceased during sleep at age 53 years. Exome sequencing identified no pathogenic variant causing acromegaly or gigantism. Chromosomal microarray analysis detected a 752-kb deletion upstream of GHRH. This deletion was predicted to create a chimeric gene consisting of the 5´-UTR of TTI1, a ubiquitously expressed gene, and the coding region of GHRH. Reverse transcription PCR (RT-PCR) using mRNA of immortalized lymphoblastoid cells detected the chimeric transcript. Analysis of model mice: We established a mouse model harboring a 676-kb deletion upstream of Ghrh using the CRISPR/Cas9 system. RT-PCR detected a chimeric transcript consisting of the 5´-UTR of Tti1 and the coding region of Ghrh, which mimicked the patient’s chimeric transcript. Mutant mice started to overgrow at two weeks of age and showed high serum GH levels and long tibia at 12-13 weeks of age. Quantitative RT-PCR showed that the median level of Ghrh expression in the hypothalamus of the mutant mice was three-fold higher than that of the wildtype mice. Furthermore, the mutant mice had ectopic Ghrh expression in all analyzed tissues (the pituitary, thymus, heart, liver, and gonad). Discussion: Our findings propose a novel etiology of gigantism. In the present case, the GHRH gene obtained a constitutively active promoter through germline genomic microdeletion. The newly acquired promoter likely led to the constant expression of GHRH in various tissues including the hypothalamus. Possible explanations for GH overproduction in the present case include (1) GHRH overproduction in the hypothalamus, (2) paracrine and autocrine effects of GHRH secreted from the pituitary, and (3) endocrine effects of GHRH produced outside the hypothalamic-pituitary unit. The patient’s clinical course suggests that prenatal GHRH overproduction only mildly affects human growth. More importantly, this is the first case in which transcriptional activation of a hormone-encoding gene caused a human congenital disorder. Presentation: Friday, June 16, 2023

Gigantism: microsurgical treatment by transsphenoidal approach and prognostic factors

PurposeWe present the results of transsphenoidal microsurgical treatment in 14 patients with gigantism. The influence on the prognosis of factors such as the tumor size and preoperative levels of GH and IGF-1 is also quantified.Materials and methodsThe patients, operated between 1982 and 2004, were reviewed retrospectively in June 2022. All patients had complete endocrinological studies in the preoperative period and a postoperative control between 6 days and 3 weeks. Follow-up has been supported with annual check-ups between 3 and 31 years. We have compared the preoperative levels of GH and IGF-1 of these patients with the levels of a series of acromegalic patients operated on in the same Center.ResultsIn this series there were 4 women and 10 men. The age ranged between 14 and 21 years. In 6 patients, postoperative hormone levels achieved the disease control criteria (42.8%). The CT/MRI studies revealed the existence of invasive tumors in 10 of the patients (71.4%). Postoperative CT/MRI showed no tumor tissue in 3 patients but in 7 patients there were tumor remains. The remaining 4 patients had abnormal images although not considered as tumor. A statistical comparison of preoperative serum GH and IGF-1 levels in patients with gigantism and patients with acromegaly showed a significant elevation in the former.ConclusionPituitary adenomas that cause gigantism are generally large and invasive, which makes them difficult to cure. High preoperative levels of GH and IGF-1 are also factors that decrease remission.

Surgery for acromegaly: Indications and goals.

Acromegaly is a disease that occurs secondary to high levels of GH, most often from a hormone-secreting pituitary adenoma, with multisystem adverse effects. Diagnosis includes serum GH and IGF-1 levels, and obtaining an MRI pituitary protocol to assess for a functional pituitary adenoma. Attempted gross total resection of the GH-secreting adenoma is the gold standard in treatment for patients with acromegaly for a goal of biochemical remission. Medical and radiation therapies are available when patients do not achieve biochemical cure after surgical therapy.

The Effect of the GH/IGF-1 Axis During Trypanosoma Cruzi Infection

Trypanosoma cruzi is the parasite responsible for Chagas disease (CD), that affects 6-8 million people worldwide. CD treatment is limited to two drugs (benznidazole and nifurtimox). Treatment is mostly effective during the acute phase of the disease (initial two months post-infection), while their efficacy during the chronic phase is controversial. In the absence of treatment, 30% of infected individuals suffer irreversible chronic cardiac and digestive damages, which lead to inability and, in some instances, death. Patients with Laron Syndrome (LS, a form of congenital GH insensitivity) are short in stature with low levels of IGF-1, elevated levels of GH and, surprisingly, are resistant to cancer and diabetes. A cohort of LS patients living in southern Ecuador, where CD is endemic, has been studied by Dr. Jaime Guevara for over 25 years (1). Few, if any, cases of CD have been reported among these patients (Dr. Guevara, personal communications). T. cruzi infection has been shown to directly modulate pituitary hormones such as GH, PRL and glucocorticoids (stress related hormones), leading to immunosuppression and thymic atrophy by depletion of CD4+ CD8+ cells. Previously, rats infected with T. cruzi and treated with GH showed reduced parasitism and less tissue damage compared to controls (2). The purpose of this research is to investigate the in vitro effect of GH during T. cruzi infection, simulating conditions of GH insensitivity. First, we separately treated T. cruzi and the host cells [human cervical cancer cell line (HeLa) and male mouse fibroblast (L-cells)] with relatively low or high levels of GH, IGF-1, PRL, and EGF. Next, we treated the parasite and host cells simultaneously with these hormones. When the parasites were treated alone, T. cruzi responded to exogenous GH (5ng/ml-50ng/ml) by significantly increasing the percentage of amastigotes (less infective form of the parasite). Also, when GH (50ng/ml) were administered to the host cells, T. cruzi infectivity was significantly reduced by 12% (percentage of infection) compared to 20% from untreated conditions. Similarly, both parasite and host cells treated with GH significantly reduced T. cruzi infectivity (10%) compared to untreated conditions (18%). We further treated both cell lines with a combination of GH/IGF-1. Conditions used were as follows: control (no-treatment), moderate levels (5ng/ml GH+150 ng/ml IGF-1), relatively high levels (50ng/ml GH+600ng/ml IGF-1), or levels that would simulate those found in patients with LS(50ng/ml GH+20 ng/ml IGF-1). Of these, the LS concentrations significantly reduced infection in both cell lines (11%) compared to control (16%). Together these results indicate that GH can influence T. cruzi infectivity and that GH, not IGF-1, is mediating the decreased infectivity. Finally, the results suggest that high concentrations of GH, as seen in LS patients, could be protective during T. cruzi infection.1)Guevara-Aguirre et al., 2011 2) Frare et al., 2010

Laron syndrome - A historical perspective.

Laron Syndrome (LS) [OMIm#262500], or primary GH insensitivity, was first described in 1966 in consanguineous Jewish families from Yemen. LS is characterized by a typical phenotype that includes dwarfism, obesity and hypogenitalism. The disease is caused by deletions or mutations of the GH-receptor gene, causing high serum GH and low IGF-I serum levels. We studied 75 patients from childhood to adult age. After early hypoglycemia due to the progressive obesity, patients tend to develop glucose intolerance and diabetes. The treatment is by recombinant IGF-I, which improves the height and restores some of the metabolic parameters. An unexpected finding was that patients homozygous for GH-R defects are protected from malignancy lifelong, not so heterozygotes or double heterozygote subjects. We estimate that there are at least 500 patients worldwide, unfortunately only few treated.

Prognostic factors of biochemical remission after transsphenoidal surgery for acromegaly: a structured review.

Biochemical control is the main determinant of survival, clinical manifestations and comorbidities in acromegaly. Transsphenoidal selective adenomectomy (TSA) is the initial treatment of choice with reported biochemical remission rates varying between 32 and 85%. Understanding the limiting factors is essential for identification of patients who require medical treatment. We reviewed the English literature published in Medline/Pubmed until Dec 31, 2019 to identify eligible studies that described outcomes of TSA as primary therapy and performed analyses to determine the main predictors of remission. Most publications reported single-institution, retrospective studies. The following preoperative parameters were consistently associated with lower remission rates: cavernous sinus invasion by imaging, larger tumor size and higher GH levels. Young age and preoperative IGF-1 levels were predictive in some studies. When controlled for covariates, the best single preoperative predictor was cavernous sinus invasion, followed by preoperative GH levels. Conversely, low GH level in the first few days postoperatively was a robust predictor of durable remission. The influence of tumor histology (sparsely granular pattern, co-expression of prolactin and proliferation markers) on surgical remission remains to be established. Few studies developed predictive models that yielded much higher predictive values than individual parameters. Surgical outcome prognostication systems could be further generated by machine learning algorithms in order to support development and implementation of personalized care in patients with acromegaly.

Impact of the GH‐IGF Axis on Adipose Tissue and Obesity: Are there Benefits of Endocrine Defects

Disruption of the mouse growth hormone receptor gene (GHR−/−) results in dwarf, obese, GH resistant mice that possess low levels of IGF‐1 and high levels of GH with intense insulin sensitivity. These mice are similar to humans with Laron Syndrome (LS) in which the individuals are small in stature with low IGF‐1 and high GH levels. Cancer and diabetes rates in both the GHR−/− mice and LS individuals are low or non‐existent. In this regard, GHR−/− mice have extended longevity, in fact, they are the longest‐lived laboratory mouse. Thus, a defect in the action of GH may be beneficial for increased health‐span and longevity. In attempts to dissect which, if any, of the insulin sensitive tissue contribute to the extended health and lifespan of these mice, we have individually disrupted the GHR gene in liver, muscle, and adipose tissue. Surprisingly, only muscle specific GHR gene disruption resulted in a modest increase in life span while none of the others have the impressive extended longevity seen in GHR−/− mice. Since a decrease in the GH/IGF‐1 axis is important for extended health and lifespan, the ability to down regulate its action in adult life may be beneficial. To that end we have, and are, attempting to disrupt the mouse GHR in adult life. To date, disruption at 6 weeks of age results in female mice with extended longevity. Experiments to ‘knock‐out’ the GHR gene at 6 months and one year are ongoing. Also, since adipose tissue (AT) is metabolically important, data regarding the location and function of AT in these mice will be presented.Support or Funding InformationThis work was and supported by the State of Ohio’s Eminent Scholar Program that includes a gift by Milton and Lawrence Goll, the AMVETS, and NIH R01AG059779.

Somatotrope Responses to Acute and Prolonged Loss of Leptin Signaling

In mice and humans, fasting results in a rise of serum growth hormone (GH). In mice, this coincides with increased Gh and growth hormone releasing hormone receptor (Ghrhr) mRNA. Fasting also results in increased serum ghrelin and decreased serum leptin. We have shown that pituitary somatotropes are dependent on circulating leptin to maintain sufficient stores of GH and GHRHR proteins. We hypothesized that the GH rise seen in fasted mice with reduced serum leptin was due to ghrelin‐stimulated pathways. However, a review of the literature revealed a study by Steyn et al. (2011) which demonstrated an acute decline in GH pulses in male mice after 12–18 h of fasting. This study suggests that somatotropes may have time‐dependent responses, with shorter fasting responses driven by the absence of leptin signals.Our fasting study was composed of three groups of male mice: 1) mice fasted for 6, 12, 24, or 48 hours, 2) mice fasted for 24 and 48 hours with 10% glucose in the drinking water, and 3) mice fed ad libitum. Body weight and serum glucose were significantly reduced with all fasting times. After 6 h of fasting, serum leptin levels were reduced from 9625.63 pg/ml (fed controls) to 1798.15 pg/mL with a further reduction to 774.17 pg/ml after 12 h, which was maintained following 24 and 48 h fasting. Ghrelin levels were unchanged with 6, 12 and 24 h fasting but significantly increased by 55.4% with 48 h fasting. Serum GH was unchanged with 6 and 12 h fasting, but was significantly reduced from 7765 pg/ml (fed) to 2253 pg/ml after the 24 h fast (p=0.03 ANOVA). In the 48 h fasted mice, serum GH was significantly increased over fed mice, from 1828 pg/ml (fed) to 10569 pg/ml (p=0.01 ANOVA). There were significant increases in pituitary Ghrhr mRNA after 24 and 48 h fasting and Gh mRNA was increased after 6 and 48 h of fasting. However, GH and GHRHR content were unchanged.This study has uncovered time‐dependent differential responses to fasting by somatotropes in male mice. The reduced serum GH after 24 h correlated well with the reduction in serum leptin. Similarly, the prolonged fasting (48 h) and elevated serum GH correlated well with the rise in ghrelin. The high Gh and Ghrhr mRNA levels corresponds with rising ghrelin levels. Reduced serum GH at 24 h indicates that somatotropes remain dependent on leptin signals for GH secretion. However, with normal GH or GHRHR content, this points to a defect in a signaling pathway needed for secretion that has yet to be determined.Support or Funding InformationNIH grants 5 R01 HD087057‐03 (GVC and AM), 5 R01 HD 093461‐01 (AM and GVC), and 5 R01 DK113776‐02 (GVC and AM). NIGMS grants P20 GM103425 and P30GM11070 (PI Dr. Edgar Garcia‐Rill). NSF funded Southern Regional Education Board Dissertation Award (TKM).

MON-LB047 GH Values in Serum and Blood Spots on Filter Paper Samples in Infants until 60 Days of Life by Electrochemiluminescence (ECLIA)

Congenital Growth Hormone Deficiency (GHD) in newborn is an infrequent condition, which can cause threat to life due mainly to hypoglycemia that begins in the first week of life. Severe neonatal GHD needs a fast diagnosis and the substitution with recombinant human GH because of the risk the morbi-mortality. A GH basal level (whether random or associated with spontaneous hypoglycemia) that distinguishes infants with GHD from those with GH sufficiency in the neonatal period is not conclusive. Few data have been reported about the GH measurements in serum and dried blood spots on filter paper samples in healthy neonates born appropriate for gestational age (AGA). Aims: To compare and correlate the GH values in serum and blood spots on filter paper samples in infants until 60 days of life. To establish GH reference values in healthy newborn until 15 days of life. To analyzed the correlation between GH concentrations in serum and blood spot and with hormones of the hypothalamic-pituitary-gonadal and adrenal axis. Subjects and methods: We analyzed 301 serum and whole blood spots samples obtained from AGA neonates between 2-60 days of life (2-15 days n=216, 16-30 days n=65 and 31-60 days n=20 (F: 154, M: 147). GH concentrations were measured by ECLIA Roche C600, which is calibrated against the 2nd International Standard Code 98/574 in serum as well as eluted from filter paper samples. The mean and SD GH value, P 5.0 and P 95.0 were calculated. The statistical analysis was performed by Spearman correlation coefficient. Results: 2-5 days: serum GH (ng/mL) mean value (SD): 20.81(15.8); P5: 6.30, P95: 42.30; 6-15 days: mean GH value 8.78 (4.34); P5: 3.29, P95: 15.19; 16-30 days: mean GH value: F: 10.55 (4.58), M: 7.72 (3.75) and 31-60 days: mean GH value: F: 4.67 (2.75), M 6.82 (4.57). Blood spots GH (ng/mL) mean value (SD): 2-5 days: 17.58 (9.95); P5: 5.68, P95: 33.60; 6-15 days: mean GH value: 10.31 (5.88), P5: 3.0, P95: 21.02; 16-30 days: mean GH value: F: 10.41 (6.01), M: 10.99 (7.78) and 31-60 days: mean GH value: 7.02 (5.25), M 9.12 (8.08). The Spearman correlation obtained between both techniques in parallel measurements was r2=0.85 (p< 0.0001). Conclusions: In agreement with different reports, our results showed high average GH levels in the first few days of life. Human GH secretion is pulsatile from the very beginning, however, newborn screening card spotted with blood during the first week of life, when neonatal hypersomatotropism is present, provides such high levels that, even at the nadir of GH pulsatility a basal value could contribute to detect GHD accurately. The good correlation obtained between both type of samples would indicate that the measurement of GH in dried blood spot samples is an appropriate and reliable method which can be incorporated in the diagnosis of neonatal GHD. The newborn screening samples may be a valuable resource for retrospectively assessing GH sufficiency if this neonatal window has passed. Unless otherwise noted, all abstracts presented at ENDO are embargoed until the date and time of presentation. For oral presentations, the abstracts are embargoed until the session begins. s presented at a news conference are embargoed until the date and time of the news conference. The Endocrine Society reserves the right to lift the embargo on specific abstracts that are selected for promotion prior to or during ENDO.

Why Do Normal Children Have Acromegalic Levels of IGF-I During Puberty?

The rapid pubertal height growth is unique to humans, but why do we have it? Although the spurt contributes 13% to 15% to the final adult height, we hypothesized that the biological significance of the high acromegalic levels of GH and IGF-I, which are behind the pubertal growth spurt, might primarily occur to stimulate the reproductive organs. Animal data have demonstrated that adult Igf1 and Igf2 gene knockout mice that survive show a dramatic reduction in the size of the reproductive organs and are infertile. In humans, case reports of mutations in the genes affecting the GH-IGF axis and growth (GH, GHRH, GH-R, STAT5b, IGF-I, IGF-II, IGF-1R, PAPPA2) are also characterized by delayed pubertal onset and micropenis. Furthermore, GH treatment will tend to normalize the penile size in patients with GH deficiency. Thus, the endocrine effects of high IGF-I levels might be needed for the transition of the sexual organs, including the secondary sex characteristics, from the "dormant" stages of childhood into fully functioning reproductive systems. The peak IGF-I levels, on average, occur 2 years after the peak height growth velocity, suggesting reasons other than longitudinal growth for the high IGF-I levels, and remain high in the years after the height spurt, when the reproductive systems become fully functional. We suggest that the serum levels of IGF-I should be monitored in children with poor development of sexual organs, although it remains to be investigated whether GH should be added to sex steroids in the management of hypogonadism for some pubertal children (e.g., boys with micropenis).

Plasma GH as a diagnostic and prognostic biomarker in HCC without cirrhosis.

227 Background: The association between the GH/IGF-1 axis and HCC was reported in patients (pt) with underlying cirrhosis. However, there is limited information among HCC pt without (w/o) cirrhosis. We herein investigated the role of GH as a circulating biomarker for HCC diagnosis and prognosis in pt w/o cirrhosis. Methods: Under IRB approval, we prospectively enrolled 1267 newly-diagnosed HCC pt in a case control study at the MD Anderson Cancer Center (2000-2015). Controls were healthy individuals (n = 1104). Plasma GH and AFP were measured 274 HCC pt w/o cirrhosis 200 healthy controls. IGF-1 was measured in 133 and 82 pt, respectively. We classified HCC pt into higher and lower GH values (cutoff for women, 3.7 µg/L; men, &gt; 0.9 µg/L). Results: Most pt (74%) were male, with advanced BCLC staging (C-D, 74%) and 61% were older than 60y. Baseline GH was higher in HCC w/o cirrhosis (mean 3.3 µg/L) than controls (mean 0.4 µg/) (p &lt; .001). ROC curve was plotted to assess diagnostic role. The AUC for AFP was 82.9 (p &lt; .001); for GH 78.2 (p &lt; .001). When only non-cirrhotic HCC pt with early stage (CLIP 0-2) and AFP &lt; 20 ng/m were compared to controls, the GH/IGF-1 ratio had high prediction of early stage HCC - AUC 83 (95% CI 78-89%) (p &lt; .0001). At a specificity of 90%, sensitivity of GH/IGF ratio was 67%. In addition, among HCC w/o cirrhosis, higher GH levels correlated with presence of vascular invasion (p &lt; .001) and thrombosis (p = .004), tumor involvement of &gt; 50% liver (p = .003), and more advanced BCLC (p &lt; .001) and TNM staging (p &lt; .001). Median overall survival (months) of HCC pt w/o cirrhosis with high GH levels was 13.1 (10.8-15.4) compared to 37.4 (19.8-55.1) of pt with lower plasma GH (p &lt; .001). Multivariate cox-regression analysis identified high GH as an independent risk factor for mortality (HR = 1.8; 95% CI, 1.3-2.4; p &lt; .001). Conclusions: Our study demonstrates the diagnostic and prognostic role of plasma GH in non-cirrhotic HCC and identifies the GH/IGF-1 ratio as a promising diagnostic marker for early stage HCC w/o cirrhosis and low AFP; this analysis excludes the confounding effect hepatocyte impaired function by presence of cirrhosis. Further studies are warranted to assess the causes of the observed differences.

Regulatory Role for Growth Hormone in Statural Growth: IGF-Dependent and IGF-Independent Effects on Growth Plate Chondrogenesis and Longitudinal Bone Growth.

It was initially thought that the growth-promoting effects of GH were exclusively mediated by liver-derived Insulin-like Growth Factor-I (IGF-I). Subsequent studies demonstrated that GH promotes IGF-I synthesis and activity in other organs and in the growth plate. GH has also IGF-I-independent growth-promoting effects. In Igf1 null mice, high circulating GH levels may be responsible for normal chondrocyte proliferation. Furthermore, tibial growth is reduced more in Ghr null mice than in Igf1 null mice, while the body of mice lacking both Ghr and Igf1 is smaller than that of mice lacking Igf1 or Ghr. The increased IGF-II expression in the growth plate in Igf1 null mice suggests that the IGF-I-independent effects of GH may be mediated by IGF-II. The effects of Igf1 receptor (Igf1r) gene deletion in chondrocytes indicate that GH may promote growth directly at the growth plate even when the local effects of IGF-I and IGF-II are abrogated.

The role of pericardial adipose tissue in the heart of obese minipigs.

Pericardial adipose tissue (PAT) volume is highly associated with the presence and severity of cardiometabolic diseases, but the underlying mechanism is unknown. We previously demonstrated that a high-fat diet (HFD) induced metabolic dysregulation, cardiac fibrosis and accumulation of more PAT in minipigs. This study used our obese minipig model to investigate the characteristics of PAT and omental visceral fat (VAT) induced by a HFD, and the potential link between PAT and HFD-related myocardial fibrosis. Five-month-old Lee-Sung minipigs were made obese by feeding a HFD for 6months. The HFD induced dyslipidemia, cardiac fibrosis and more fat accumulation in the visceral and pericardial depots. The HFD changes the fatty acid composition in the adipose tissue by decreasing the portion of linoleic acid in the VAT and PAT. No arachidonic acid was detected in the VAT and PAT of control pigs, whereas it existed in the same tissues of obese pigs fed the HFD. Compared with the control pigs, elevated levels of malondialdehyde and TNFα were exhibited in the plasma and PAT of obese pigs. HFD induced greater size of adipocytes in VAT and PAT. Higher levels of GH, leptin, OPG, PDGF, resistin, SAA and TGFβ were observed in obese pig PAT compared to VAT. This study demonstrated the similarities and dissimilarities between PAT and VAT under HFD stimulus. In addition, this study suggested that alteration in PAT contributed to the myocardial damage.

Acromegaly with metastatic renal cell carcinoma: Lung, gluteal and scapular metastasis

The association between acromegaly and increased incidence of malignancy has been reported due to high GH and IGF levels. Although the incidence of all malignancies increases in patients with acromegaly, renal cell carcinoma (RCC) has been rarely reported. Herein, we report an acromegaly case with lung, gluteal and scapular metastatic RCC. The risk of cancer and cancer metastasis is high in uncontrolled acromegaly. At this point, treating acromegaly and controlling the disease progress are both important to enhance the life expectancy of a patient.

Laron Syndrome: Siblings with Extreme Short Stature and Very High Growth Hormone

Primary growth hormone resistance or growth hormone insensitivity syndrome (GHIS), also known as Laron syndrome, is a hereditary disease caused by deletions or different types of mutations in the growth hormone receptor gene or by post-receptor defects. This disorder is characterized by a clinical appearance attributable to severe growth hormone deficiency with high levels of circulating growth hormone in contrast to low serum insulin-like growth factor-1 (IGF-1) and low serum insulin-like growth factor binding protein (IGFBP-3)values. It is an autosomal recessive disorder and to date, more than 70 unique growth hormone receptor (GHR) mutations have been identified in more than 250 GHIS patients. We report the case of an 8-year-old boy and his 12-year-old sister born to first cousin parent that presented with severe short stature who had the classic feature of GH deficiency. Investigations revealed high plasma GH levels in both the cases. Subsequently, IGF-1 and IGFBP-3 assay were done and the levels were found to be very low. These reports along with elevated GH level in the context of typical picture of GH deficiency confirmed the diagnosis of GHIS. Genetic testing could not be done because of unavailability in our context. Regrettably specific therapy in the form of recombinant IGF-1 could not be offered as it is not commercially available in our country.