Decrease In IGF-I Research Articles

In Vivo Effects of a GHR Synthesis Inhibitor during Prolonged Treatment in Dogs

Background: The activation of the growth hormone receptor (GHR) is a major determinant of body growth. Defective GHR signaling, as seen in human Laron dwarfism, resulted in low plasma IGF-1 concentrations and limited growth, but also marked absence in the development of breast cancer and type 2 diabetes. In vitro, we identified a small molecule (C#1) that inhibits the translation of GHR mRNA to receptor protein. Methods: Before its application in humans as a potential anticancer drug, C#1 was tested in animals to evaluate whether it could be administered to achieve a plasma concentration in vivo that inhibits cell proliferation in vitro without causing unwanted toxicity. To evaluate the efficacy and toxicity of C#1, a group of six intact female Beagle dogs was treated daily each morning for 90 days with an oral solution of C#1 in Soiae oleum emulgatum at a dose of 0.1 mg/kg body weight. During treatment, dogs were closely monitored clinically, and blood samples were taken to measure plasma C#1 concentrations, complete blood counts (CBC), clinical chemistry, and endocrinology. At the end of the treatment, dogs were euthanized for gross and histopathological analysis. An additional group of six female Beagle dogs was included for statistical reasons and only evaluated for efficacy during treatment for 30 days. Results: Daily administration of C#1 resulted in a constant mean plasma concentration of approximately 50 nmol/L. In both groups, two out of six dogs developed decreased appetite and food refusal after 4–5 weeks, and occasionally diarrhea. No significant effects in CBC or routine clinical chemistry were seen. Plasma IGF-1 concentrations, used as biomarkers for defective GHR signaling, significantly decreased by 31% over time. As plasma growth hormone (GH) concentrations decreased by 51% as well, no proof of GHR dysfunction could be established. The measured 43% decrease in plasma acylated/non-acylated ghrelin ratios will also lower plasma GH concentrations by reducing activation of the GH secretagogue receptor (GHSR). C#1 did not directly inhibit the GHSR in vivo, as shown in vitro. There were no significant effects on glucose, lipid, or folate/homocysteine metabolism. Conclusions: It is concluded that with daily dosing of 0.1 mg C#1/kg body weight, the induction of toxic effects prevented further increases in dosage. Due to the concomitant decrease in both IGF-1 and GH, in vivo inhibition of GHR could not be confirmed. Since the concept of specific inhibition of GHR synthesis by small molecules remains a promising strategy, searching for compounds similar to C#1 with lower toxicity should be worthwhile.

Changes in hormonal profiles during competition preparation in physique athletes.

Physique athletes engage in rigorous competition preparation involving intense energy restriction and physical training to enhance muscle definition. This study investigates hormonal changes and their physiological and performance impacts during such preparation. Participants included female (10 competing (COMP) and 10 non-dieting controls (CTRL)) and male (13 COMP and 10 CTRL) physique athletes. COMP participants were tested 23weeks before (PRE), one week before (MID), and 23weeks after the competition (POST). Non-dieting CTRL participants were tested at similar intervals. Measurements included body composition (DXA), muscle cross-sectional area (ultrasound), energy availability (EA) derived by subtracting exercise energy expenditure (EEE) from energy intake (EI) and dividing by fat-free mass (FFM), muscle strength, and various serum hormone concentrations (ACTH, cortisol, estradiol, FSH, IGF-1, IGFBP-3, insulin, and free and total testosterone and SHBG). During the diet, EA (p < 0.001), IGF-1 (p < 0.001), IGFBP-3 (p < 0.01), and absolute muscle strength (p < 0.01-0.001) decreased significantly in both sexes in COMP. Decreases in IGF-1 were also associated with higher loss in FFM. In males, testosterone (p < 0.01) and free testosterone (p < 0.05) decreased, while SHBG (p < 0.001) and cortisol (p < 0.05) increased. Insulin decreased significantly only in males (p < 0.001). Mood disturbances, particularly increased fatigue in males (p < 0.05), highlighted the psychological strain of competition preparation. All these changes were restored by increased EA during the post-competition recovery period. Significant reductions in IGF-1 and IGFBP-3 during competition preparation may serve as biomarkers for monitoring physiological stress. This study offers valuable insights into hormonal changes, muscle strength, and mood state during energy-restricted intense training.

Palmitic Acid Modulation of the Insulin-Like Growth Factor System in Hypothalamic Astrocytes and Neurons

Introduction: Insulin-like growth factor (IGF)1 and IGF2 have neuroprotective effects, but less is known regarding how other members of the IGF system, including IGF binding proteins (IGFBPs) and the regulatory proteinase pappalysin-1 (PAPP-A) and its endogenous inhibitor stanniocalcin-2 (STC2) participate in this process. Here, we analyzed whether these members of the IGF system are modified in neurons and astrocytes in response to palmitic acid (PA), a fatty acid that induces cell stress when increased centrally. Methods: Primary hypothalamic astrocyte cultures from male and female PND2 rats and the pro-opiomelanocortin (POMC) neuronal cell line, mHypoA-POMC/GFP-2, were treated with PA, IGF1 or both. To analyze the role of STC2 in astrocytes, siRNA assays were employed. Results: In astrocytes of both sexes, PA rapidly increased cell stress factors followed by increased Pappa and Stc2 mRNA levels and then a decrease in Igf1, Igf2, and Igfbp2 expression and cell number. Exogenous IGF1 did not revert these effects. In mHypoA-POMC/GFP-2 neurons, PA reduced cell number and Pomc and Igf1 mRNA levels, and increased Igfbp2 and Stc2, again with no effect of exogenous IGF1. PA increased STC2 expression, but no effects of decreasing its levels by interference assays or exogenous STC2 treatment in astrocytes were found. Conclusions: The response of the IGF system to PA was cell and sex specific, but no protective effects of the IGFs were found. However, the modifications in hypothalamic PAPP-A and STC2 indicate that further studies are required to determine their role in the response to fatty acids and possibly in metabolic control.

Abstract P4-07-31: A whole food, plant-based (WFPB) dietary intervention to improve cardiometabolic and cancer-related outcomes in women with breast cancer

Abstract Background: With dramatically rising obesity rates in the US, obesity at breast cancer diagnosis is common; further compounding the problem is that breast cancer treatment often results in additional weight gain. Among women undergoing breast cancer treatment, both obesity at diagnosis and post-diagnosis weight gain are associated with increased all-cause mortality and increased breast cancer mortality. We tested a WFPB dietary intervention in metastatic breast cancer patients to improve cardiometabolic and cancer-related outcomes, as it has been shown to reduce weight and improves cardiometabolic health in overweight and obese individuals. Methods: Women with stage 4 breast cancer receiving treatment were randomized 2:1 into 2 arms: 1) a WFPB diet (N=21) or 2) usual diet (N=11) for 8 weeks with assessments at baseline, 4, and 8 weeks. Our WFPB diet consisted of an ad libitum whole food, plant-based diet; 3 meals/day were provided to WFPB subjects, which included fruits, vegetables, whole grains, nuts and seeds, and excluded meat, dairy, eggs, and added oils/solid fats. WFPB subjects received weekly education regarding diet. Subjects in the usual care group were asked to continue their usual diet for the next 8 weeks. Outcomes include cardiometabolic risk factors, related sex hormones, and cancer progression markers. Effects of the WFPB diet on the outcomes were assessed by comparing marginal means by arm estimated at 8 weeks from the analysis of covariance model controlling for the baseline value. Results: Of the 32 subjects randomized, 30 subjects (20 WFPB and 10 usual care) completed all 3 assessments. Reductions in weight, BMI, total cholesterol, and LDL cholesterol were statistically significant as well as clinically meaningful, both within the WFPB group and between the groups. In the WFPB group, subjects lost a mean of 6.2% of their body weight versus 0.7% body weight loss in the control group (p&amp;lt; 0.01). LDL cholesterol was reduced by a mean of 20.0% in the WFPB subjects versus a 10.6% increase in control subjects (p&amp;lt; 0.01). Reductions in insulin and HOMA-IR, a measure of insulin sensitivity, were statistically significant within the WFPB group and trended towards significance between the groups. Sex hormone binding globulin (SHBG) levels increased significantly both within the WFPB group and between groups. There was a significant decrease in both IGF-1 and free testosterone within the WFPB group from baseline to week 8. Conclusions: Our WFPB intervention resulted in improvements in several cardiometabolic and hormonal markers. The intentional weight loss, which was clinically large given the duration of the trial, was accompanied by reduced cholesterol, insulin resistance, free testosterone, and IGF-1. Given the moderate to large effect sizes noted, further study is warranted to evaluate the sustainability of benefits over time and to assess their potential impact on cancer-related outcomes. Table 1: Cardiometabolic and Cancer-Related Outcomes Citation Format: Erin Campbell, Thomas Campbell, Eva Culakova, Nellie Wixom, Joseph Guido, Lisa Blanchard, James Fetten, Michelle Janelsins, Karen Mustian, Luke Peppone. A whole food, plant-based (WFPB) dietary intervention to improve cardiometabolic and cancer-related outcomes in women with breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-07-31.

The Influence of Shiitake Mushroom (Lentinus Edodes) Extract on Dietary and Metabolic Control Hormone

This study attempted to verify the effects of &lt;i&gt;Lentinus edodes&lt;/i&gt;mycelium by applying a high-fat diet (HFD) to animals. For this, the &lt;i&gt;Lentinus edodes&lt;/i&gt;mycelium ‘MC-LE’ was administered to the HFD animals, investigating its influence on dietary efficiency, hormones, blood and lipocytes. An experiment was performed a normal group with regular diet, HFD/Control group and HFD/MC-LE (360 mg/kg) group over 10 weeks. Compared to the HFD/Control group, the HFD/MC-LE group revealed a decrease in dietary efficiency. A significant drop was also found in the appetite-suppressing hormone ‘leptin’. Furthermore, increase in the adipose (fat) accumulationrelated adiponectin and decrease in IGF-1, glucose and free fatty acid accelerated lipid metabolism, confirming inhibition of fat accumulation through the size and number of fat cells. Other words, in the HFD/MC-LE group, dietary control hormone suppressed diet and accelerated lipid metabolism, reducing fat accumulation. The above results confirm that the &lt;i&gt;Lentinus edodes&lt;/i&gt;mycelium ‘MC-LE’ would be useful as a material for obesity treatment.

In missed abortion the decrease of IGF-1 down-regulates PI3K/AKT signaling pathway reducing the secretion of progesterone and β-hCG

ObjectiveTo explore whether the reduction of IGF-1 in missed abortion down-regulates PI3K/AKT signaling pathway, thereby causing trophoblast cell apoptosis and reducing the secretion of β-hCG and progesterone. Design12 pairs of serum and villous tissues were selected from missed abortion patients and normal early pregnant women who had terminated pregnancy by artificial abortion. The subjects in two groups had same age and gestational week. Wes Simple Western system and qRT-PCR were used to detect the expression of IGF-1, IGF-1R, PI3K/AKT signaling pathway and apoptosis-related factors in villous tissues. Radioimmunoassay and Enzyme-linked immunosorbent assay were used to detect β-hCG, progesterone and IGF-1 in serum. ResultsThe serum levels of β-hCG, progesterone and IGF-1 were decreased in missed abortion group than those in normal early pregnant women. In addition, compared with normal early pregnant women, the genes and proteins levels of IGF-1 and PI3K/AKT signaling pathway and anti-apoptosis related factors were significantly decreased. ConclusionsOur results suggested that the reduction of IGF-1 in missed abortion patients could down-regulate the expression of PI3K/AKT signaling pathway, thereby increasing the apoptosis of trophoblast cells, leading to decreased secretion of β-hCG and progesterone, which may be one of the important mechanisms of missed abortion.

Liver is a primary source of insulin-like growth factor-1 in skin wound healing.

Insulin-like growth factor (IGF)-1 plays important role in tissue repair through its ability to stimulate wound cell activity. While IGF-1 is expressed locally by wound cells, liver-derived IGF-1 is also present at high levels in the circulation, and the contributions of local vs circulating IGF-1 to wound levels remain undefined. The hypothesis of this study was that liver is a primary source of IGF-1 during skin wound healing. To test this hypothesis, we utilized a model that allows inducible ablation of IGF-1 specifically in liver of adult mice. We demonstrate that ablation of liver IGF-1 leads to >85% loss of circulating IGF-1 and ~60% decrease in wound IGF-1 during the proliferative phase of healing in both male and female mice. This reduction of liver-derived IGF-1 did not alter local mRNA expression of Igf1 in wounds. Knockdown of liver IGF-1 significantly delayed wound re-epithelialization and reduced granulation tissue formation and collagen deposition. Knockdown of liver IGF-1 also significantly reduced angiogenesis and resulted in persistent macrophage accumulation. In summary, liver is a primary source of IGF-1 in skin wounds and contributes to many aspects of both epithelial and dermal healing.

Relationship between IGF-1 and body weight in inflammatory bowel diseases: Cellular and molecular mechanisms involved

Inflammatory bowel diseases (IBD), represented by ulcerative colitis (UC) and Crohn's disease (CD), are characterized by chronic inflammation of the gastrointestinal tract, what leads to diarrhea, malnutrition, and weight loss. Depression of the growth hormone-insulin-like growth factor-1 axis (GH-IGF-1 axis) could be responsible of these symptoms. We demonstrate that long-term treatment (54 weeks) of adult CD patients with adalimumab (ADA) results in a decrease in serum IGF-1 without changes in serum IGF-1 binding protein (IGF1BP4). These results prompted us to conduct a preclinical study to test the efficiency of IGF-1 in the medication for experimental colitis. IGF-1 treatment of rats with DSS-induced colitis has a beneficial effect on the following circulating biochemical parameters: glucose, albumin, and total protein levels. In this experimental group we also observed healthy maintenance of colon size, body weight, and lean mass in comparison with the DSS-only group. Histological analysis revealed restoration of the mucosal barrier with the IGF-1 treatment, which was characterized by healthy quantities of mucin production, structural maintenance of adherers junctions (AJs), recuperation of E-cadherin and β-catenin levels and decrease in infiltrating immune cells and in metalloproteinase-2 levels. The experimentally induced colitis caused activation of apoptosis markers, including cleaved caspase 3, caspase 8, and PARP and decreases cell-cycle checkpoint activators including phosphorylated Rb, cyclin E, and E2F1. The IGF-1 treatment inhibited cyclin E depletion and partially protects PARP levels. The beneficial effects of IGF-1 in experimental colitis could be explained by a re-sensitization of the IGF-1/IRS-1/AKT cascade to exogenous IGF-1. Given these results, we postulate that IGF-1 treatment of IBD patients could prove to be successful in reducing disease pathology.

Alcohol-induced damage to skeletal muscles in women with chronic alcohol intoxication

In Russia, there is a high level of alcohol consumption among women in doses that represent a high risk of developing alcoholic diseases, manifested, in particular, by damage to skeletal muscles.The purpose of the study. Analysis of clinical, biochemical, neurophysiological, as well as morphometric and immunohistochemical features of alcoholic skeletal muscle damage in women with chronic alcohol intoxication.Material and methods. A clinical and laboratory examination of 30 women aged 20 to 60 years with chronic alcohol intoxication was performed, which included the determination of creatine phosphokinase (CPK) and insulin-like growth factor I (IGF-I) in blood plasma, stimulation and needle electromyography (EMG), as well as morphological and immunohistochemical examination of biopsies of the quadriceps femoris.Results. Myopathic syndrome in the form of proximal para-or tetraparesis was observed in 73.3% of the examined women in combination with a decrease in IGF-1 at normal values of CPK in blood plasma. The EMG results indicated the absence of changes in the parameters of the potentials of motor units, characteristic of primary muscular lesions, and of conduction disturbances along the femoral nerve. Morphometric and immunohistochemical studies of skeletal muscle biopsies showed a decrease in the cross-sectional area of muscle fibers of types I and II without signs of muscle tissue necrosis.Conclusion. Chronic alcoholic myopathy is a common manifestation of alcoholic disease in women with long-term alcohol intoxication. The severity of the atrophic process in the skeletal muscle is comparable to the degree of proximal paresis. Violations of systemic protein synthesis and acceleration of apoptosis are considered as pathogenetic mechanisms of the atrophic process in the muscles in chronic alcoholic myopathy in women.

Effects of Antidepressant Treatment on Neurotrophic Factors (BDNF and IGF-1) in Patients with Major Depressive Disorder (MDD).

Major depressive disorder (MDD) remains the subject of ongoing research as a multifactorial disease and a serious public health problem. There is a growing body of literature focusing on the role of neurotrophic factors in pathophysiology of MDD. A neurotrophic hypothesis of depression proposes that abnormalities of neurotrophins serum levels lead to neuronal atrophy and decreased neurogenesis, resulting in mood disorders. Consequently, in accordance with recent findings, antidepressant treatment modifies the serum levels of neurotrophins and thus leads to a clinical improvement of MDD. The purpose of this review is to summarize the available data on the effects of various antidepressants on serum levels of neurotrophins such as brain-derived neurotrophic factor (BDNF) and insulin-like growth factor (IGF-1). In addition, the authors discuss their role as prognostic factors for treatment response in MDD. A literature search was performed using the PubMed database. Following the inclusion and exclusion criteria, nine original articles and three meta-analyses were selected. The vast majority of studies have confirmed the effect of antidepressants on BDNF levels. Research on IGF-1 is limited and insufficient to describe the correlation between different antidepressant drugs and factor serum levels; however, four studies indicated a decrease in IGF-1 after treatment. Preliminary data suggest BDNF as a promising predictor of treatment response in MDD patients. The role of IGF-1 needs further investigation.

Pegvisomant as Monotherapy or Combination Therapy in Somatostatin Refractory Acromegaly

Abstract Background: Pegvisomant, a growth hormone antagonist, has been widely used as monotherapy or combination therapy with somatostatin (SST) analogs and/or dopamine agonists in acromegaly poorly controlled by SST analogs. Limited information is available to compare pegvisomant monotherapy, combination with SST analogs or dopamine agonists, and combination of all three agents. Method: In this retrospective cohort study, we identified 23 patients with SST analog refractory acromegaly who received pegvisomant as monotherapy or in combination with SST analogs and/or dopamine agonists through the Research Patient Data Registry. We divided the patients into four groups: Group 1. pegvisomant alone (n=8); Group 2. pegvisomant plus a SST analog (pasireotide, octreotide or lanreotide) (n=8); Group 3. pegvisomant plus cabergoline (n=5) Group 4. Pegvisomant plus SST analog and dopamine agonist (n=2). We analyzed the changes in IGF-1, HbA1C, ALT and AST, blood pressure, and radiographic tumor size before and 6 months after treatment. Results: In 6 months, the mean IGF-1 level (ng/ml) changed from baseline 482 to 290 and decreased by 40% (P = 0.050) in group 1, changed from baseline 623 to 291 and decreased by 53% (P= 0.003) in group 2, changed from baseline 579 to 367 and decreased by 36% (p = 0.100) in group 3, and decreased 47% from 609 to 326 (P= 0.100) in group 4. The mean systolic blood pressure (mmHg) before and 6 months after treatment changed from 139 to 128 (p = 0.001) in group 1, changed from 130 to 126 (p = 0.553) in group 2, changed from 134 to 126 (p = 0.373) in group 3, and changed from 125 to 127 (p= 0.700) in group 4. Diastolic blood pressure (mmHg) changed from 82 to 76 (P = 0.110) in group 1, changed from 79 to 76 (p = 0.325) in group 2, changed from 80 to 74 (p=0.002) in group 3, and changed from 80 to 75 (p=0.126) in group 4. There were no significant changes in ALT and AST and A1C before and 6 months after treatment in all groups. In terms of radiographic tumor size change before and 6 months after the treatment, there was no change in tumor size in 5 of 5 patients in group 1. In group 2, the tumor size in 4 of 7 remained unchanged but 3 of 7 patients had increased tumor sizes. In group 3, there was no change in tumor size in 3 of 3 patients. In group 4, there was no change in tumor size in 2 of 2 patients. Conclusion: Our results suggest that in somatostain analog refractory acromegaly, combination pegvisomant and a SST analog significantly decreased IGF-1 level although decrease in IGF-1 in pegvisomant monotherapy almost reach statistical significance (P = 0.050). Although there was a trend in decrease of blood pressure in all groups, the decrease reached significant significance in systolic blood pressure in group 1 and diastolic blood pressure in group 3. Finally, except group 2, the tumor size remained unchanged.

Vertebral Fractures Occur Regardless of Acromegaly Activity and Are Best Predicted by Proximal Femur Cortical Volumetric Bone Mineral Density

Introduction: Vertebral fractures (VFs) in patients with acromegaly are not associated with bone mineral density (BMD) decrease. Previous studies showed impaired trabecular bone parameters among acromegaly patients. However, recent studies suggest that cortical bone could also play a role in VF development. Objective: Evaluate the utility of dual energy x-ray absorptiometry (DXA) BMD and bone structural parameters to determine VF risk among acromegaly patients. Patients and Methods: A single-center two years prospective follow up of acromegaly patients regardless of age, gender, disease activity or associated treatments was conducted. Pituitary hormones, glucose metabolism and bone turnover markers in all subjects were assessed. Each subject had L1-4 spine, femoral neck (FN) and total hip (TH) BMD measured using DXA, and TBS measurement performed ± 7 days from blood sampling. 3D Shaper was used to assess proximal femur trabecular and cortical volumetric (v) BMD, cortical surface (s) BMD and cortical thickness (Cth). VF assessment was performed using the lateral spine imaging IVA™ mode with a Hologic Horizon® densitometer using semi-quantitative approach. Study outcomes were assessed at two time points - baseline and month 24. Results: Seventy subjects (34 M/36F), mean age 55.1 years, including 26 with active disease were studied. After two years a significant decrease in IGF-1 (-30%), osteocalcin (-18%) and TH cortical vBMD (-3%; all p≤0.05) was observed. During follow-up, 13 patients nine of them with controlled disease, developed VF; these patients had greater increase in CTx and decrease in TBS, sBMD, cortical and trabecular vBMD at TH and neck. Multivariate analysis of fracture prediction showed cortical vBMD at TH and neck as best parameters for fracture prediction with AUC 0.766 and 0.774; respectively. TBS was negatively associated with fasting plasma glucose (FPG), HBA1c at each time period. Conclusions: Decrease in cortical vBMD was the most sensitive and specific predictor of incident VF suggesting that cortical bone is involved in fracture development among acromegaly patients. In addition, TBS was strongly negatively associated with glucose metabolism, suggesting glucose intolerance could lead to trabecular bone impairment.

Insulin-like growth factor-I predicts sinusoidal obstruction syndrome following pediatric hematopoietic stem cell transplantation.

Sinusoidal obstruction syndrome (SOS) is a potentially fatal complication of hematopoietic stem cell transplantation (HSCT) initiated through damage of sinusoidal endothelium and inflammation. Insulin-like growth factor-l (IGF-l) maintains and repairs endothelium and intestinal mucosa. We hypothesized that low IGF-l levels may increase the risk of inflammatory complications, such as SOS, in HSCT-patients. We prospectively measured IGF-l concentrations in 121 pediatric patients before, during, and after allogeneic HSCT. Overall, IGF-l levels were significantly reduced compared with healthy sex- and age-matched children. IGF-I levels pre-HSCT and at day 0 were inversely associated with C-reactive protein levels, hyperbilirubinemia, and number of platelet transfusions within the first 21 days post-transplant. Low levels of IGF-I before conditioning and at day of transplant were associated with increased risk of SOS diagnosed by the modified Seattle criteria (pre-HSCT: OR = 1.7 (95% CI: 1.2-2.6, p = 0.01), and the pediatric EBMT criteria (pre-HSCT: 1.7 (1.2-2.5, p = 0.009) and day 0: 1.7 (1.3-2.5, p = 0.001)/SDS decrease in IGF-1). These data suggest that IGF-I is protective against cytotoxic damage and SOS, most likely through trophic effects on endothelial cells and anti-inflammatory properties, and may prove useful as a predictive biomarker of SOS.

Long-term facial changes and clinical correlations in patients with treated acromegaly: a cohort study.

Facial abnormality is the most significant feature in acromegaly patients. However, it is unclear whether and how patient facial appearance improves after treatment. This study aimed to identify 3D facial changes in acromegaly patients after surgical treatment. This study included 30 acromegaly patients who underwent resection of a pituitary GH adenoma. The location and extent of facial changes were identified by comparing baseline and 2-year follow-up 3D images of the face. Relationships between facial changes and GH and IGF-1 were evaluated with simple or multivariable linear regression models. Significant soft tissue improvements were observed in acromegaly patients with complete remission, especially in the nose and lip region. Significant reductions in nasal width (3.46 mm, P < 0.001), tip protrusion (1.18 mm, P = 0.003), face curve length (3.89 mm, P = 0.004) and vermilion area (1.42 cm3, P = 0.001) were observed at the 2-year follow-up. Further, changes in nasal width were associated with decreases in GH (β = 4.440, P = 0.017), the GH nadir (β = 4.393, P = 0.011) and IGF-1 (β = 5.263, P = 0.002). The associations were maintained after adjusting for confounders. Acromegaly patients achieved considerable facial improvements after surgical treatment. The change in nose width was associated with GH and IGF-1 decrease. Better control of patient hormone levels after surgery improves patient facial recovery.

Efficacy and predictors of short-term first-generation somatostatin analog presurgical treatment in acromegaly: A hospital-based study of 237 cases

ObjectiveTo investigate the effectiveness and predictors of short-term somatostatin analog (SSA) presurgical therapy in a large cohort and to assess the correlation between clinical and pathological variables. Design237 newly diagnosed patients with acromegaly received presurgical SSA treatment for three months were recruited. Clinical characteristics were collected, and response to SSA in hormone and tumor size was evaluated. The correlation between clinical information and pathological variables were analyzed. ResultsAfter 3 months presurgical SSA therapy, 51 (21.5%) patients were biochemically responsive with ≥50% decrease in IGF-1 while 126 (53.2%) patients showed at least 20% tumor size decrease. Biochemical responders were associated with a smaller maximum tumor diameter (MTD) and an older age (OR, 0.448; P = 0.003; OR, 1.050; P = 0.001). Tumor size responders were associated with a smaller MTD (OR, 0.435; P < 0.001). A combination of MTD < 2 cm and age ≥49 years predicted biochemical responders (PPV, 54.5%; NPV, 86.0%; P < 0.001), while MTD ≤2.2 cm (PPV, 67.1%; NPV, 67.0%; P < 0.001) predicted tumor size responders. Compared to patients with MTD < 2 cm, patients with MTD ≥ 2 cm showed higher percentage of sparsely granulated (SG) adenoma (62.1% vs. 31.3%, P = 0.005). In addition, the percentage of SG adenoma tended to be higher in patients < 49 years than ≥49 years (48.1% and 31.0% P = 0.089). ConclusionsThe baseline MTD and age correlate with granulation patterns and may be used as easily acquired predictors of presurgical SSA treatment in acromegaly. Patients over their 50s with a tumor less than 2 cm in diameter are more likely to have a response to the short-term presurgical SSA therapy.

Somatostatin receptor expression and patients' response to targeted medical treatment in pituitary tumors: evidences and controversies.

Somatostatin receptors (SSTs) are widely co-expressed in pituitary tumors. SST2 and SST5 are the most represented SST subtypes. First-generation somatostatin receptor ligands (SRLs) mainly target SST2, while pasireotide, a multi-receptor ligand, shows high binding affinity for both SST5 and SST2. Therefore, SRLs are routinely used as medical treatment for GH-, TSH-, and ACTH-secreting pituitary tumors. Critical revision of literature data correlating SST expression with patients' response to SRLs. SST2 expression in somatroph tumors directly correlates with GH and IGF-1 decrease after first-generation SRL treatment. SST2 immunohistochemistry represents a valuable tool to predict biochemical response to first-generation SRLs in acromegalic patients. Pasireotide seems to exert its biological effects via SST2 in unselected patients. However, in those subjects resistant to first-generation SRLs, harbouring tumors with negligible SST2 expression, pasireotide can act throughout SST5. More than somatotroph tumors, TSH-omas represent the paradigm of tumors showing a satisfactory response to SRLs. This is probably due to the high SST2 expression observed in nearly 100% of cases, as well as to the balanced amount of SST5. In corticotroph tumors, pasireotide mainly act via SST5, although there is a need for translational studies correlating its efficacy with SST expression in this peculiar tumor histotype. The assumption "more target receptor, more drug efficacy" is not straightforward for SRLs. The complex pathophysiology of SSTs, and the technical challenges faced to translate research findings into clinical practice, still need our full commitment to make receptor evaluation a worthwhile procedure for individualizing treatment decisions.

SAT-054 Gigantism and Hypothalamic Obesity: Rare Endocrine Manifestations of Neurofibromatosis Type 1

Background: Neurofibromatosis type 1 (NF-1) is a heritable, autosomal dominant, multisystem disorder caused by mutations or deletions in NF1, with approximately 30-50% of cases arising from de novo mutations. In the pediatric population, growth hormone deficiency is among one of the most commonly described endocrine sequelae, although aberrations of pubertal development are also commonly seen. Clinical Case: A 3-year-old female, who was clinically diagnosed with NF-1 at the age of 4 months based on the presence of multiple café-au-lait macules, underwent screening MRI, which noted a left optic glioma and a hypothalamic mass favored to represent a hypothalamic glioma. Review of her growth chart showed a height much greater than the 99th percentile, with an increase in height velocity beginning 1 year prior. Weight was also noted to be much greater than the 99th percentile, with an increase in weight gain coinciding with the timing of alterations in linear growth. Mid-parental height is at the 95th percentile, and the patient’s height had tracked between the 86th and the 99th percentiles until age 2 years. Weight had tracked between the 68th and the 95th percentiles during that period. Initial laboratory evaluation showed an IGF-1 of 644 ng/mL (26-164 ng/mL). Gonadotropins were prepubertal; prolactin and thyroid studies were normal. ACTH stimulation demonstrated a rise in serum cortisol from 6.8 mcg/dL to 30.2 mcg/dL at 60 minutes. Growth hormone failed to suppress following an oral glucose load with a baseline GH of 4.4 ng/mL and values of 3.7, 6.5, 6.8, and 9.0 ng/mL at time +30, +60, +90, and +120 minutes respectively. Leuprolide stimulation did not show significant rises in gonadotropins. Bone age was advanced by more than 1 year. The patient was started on subcutaneous octreotide with a decrease in IGF-1 to 258 ng/mL after 1 month of therapy. On treatment, linear growth velocity slowed with no interval height gain over the initial 1-month period; however, the patient’s weight continued to increase with a gain of 1.8 kg. Parents additionally reported hyperphagia, which prompted concern for hypothalamic obesity in the setting of her known hypothalamic mass. Thyroid function remained normal on somatostatin therapy. To date, there has been no concern for diabetes insipidus. Conclusion: Growth hormone excess may rarely complicate a diagnosis of NF-1 in the setting of intracranial gliomas. Increased height velocity and/or tall stature for family should raise clinical suspicion and prompt evaluation. Hyperphagia and significant increases in weight in the setting of hypothalamic gliomas in patients with NF-1 should raise suspicion for hypothalamic obesity and prompt lifestyle modifications to curb ongoing weight gain.

High temperature impairs rabbit viability, feed consumption, growth and fecundity: examination of endocrine mechanisms

The aim of the present study was to examine the effect of high ambient temperature on rabbit feed consumption, growth, viability, and fecundity, as well as the morphology and endocrine function of gonadal and adrenal cells. Adult does and their offspring were kept at either a comfortable (20°C; control) or high (36°C) temperature throughout pregnancy and up until weaning of pups. Doe mortality and fecundity, and plasma concentrations of hormones were evaluated. In addition, granulosa cells were cultured with and without FSH to assess progesterone production. In the offspring, we assessed mortality, total feed consumption, feed efficiency, growth, plasma hormone concentrations, as well as the microstructure in ovarian granulosa cells, testicular Leydig cells, and adrenocortical cells. We observed greater mortality of both adult animals and offspring at the higher ambient temperature compared with the control. The higher ambient temperature suppressed feed consumption, feed efficiency, and growth of pups. Adult and young females exposed to a high temperature had lower circulating concentrations of progesterone, but not of estradiol, compared with controls. Young males exposed to a high ambient temperature had greater circulating concentrations of testosterone, but not progesterone, compared with controls. High ambient temperature reduced circulating IGF-I concentrations in all the animals. Corticosterone level was increased in plasma of young but not of adult animals. Granulosa cells isolated from the ovaries of does subjected to high temperatures released less progesterone, and they had poorer response to the stimulatory action of FSH than the cells from control does. High temperatures induced fragmentation of nucleoli in ovarian granulosa cells, but they did not alter the state of other organelles in ovarian, testicular, or adrenocortical cells. A negative influence of high temperature on rabbit feed consumption, growth, viability, and fecundity was observed. Taken together, these changes could be due to a decrease in IGF-I and/or progesterone secretion, destruction of ovarian cell nucleoli, and/or impaired ovarian cell response to FSH.

Abstract PD3-06: Biomarker modulation by bazedoxifene and conjugated estrogen (Duavee®) in women at high risk for development of breast cancer

Abstract Agents which both reduce risk for development of breast cancer and relieve vasomotor symptoms are likely to have good uptake and adherence. We conducted a pilot study with 6 months of the tissue selective estrogen complex bazedoxifene (20 mg) and conjugated estrogen (0.45 mg) (Duavee®) to assess feasibility and effects on biomarkers. Risk biomarkers for postmenopausal breast cancer included fully automated mammographic volumetric density (Volpara®), benign breast tissue Ki-67, and serum levels of progesterone, IGF-1 and IGFBP3, bioavailable estradiol and testosterone. Exploratory biomarkers included selected estrogen and progesterone responsive gene expression in benign breast tissue. 28 peri- and post-menopausal women at increased risk for breast cancer were enrolled; 13 in Cohort A with baseline Ki-67 &amp;lt; 1% and 15 in Cohort B with baseline Ki-67 of 1-4%. All completed the study with &amp;gt; 85% drug adherence. An improvement in median hot flash score from 15 at baseline to 0 at 6 months, and menopause specific quality of life total, vasomotor and sexual domain scores were also observed (p&amp;lt; 0.001). Significant changes in risk biomarkers, uncorrected for multiple comparisons, were a decrease in mammographic fibroglandular volume (p=0.043); decreases in serum progesterone, bioavailable testosterone, and IGF-1 (p&amp;lt;0.01); and for women from Cohort B, a reduction in Ki-67 (p=0.017) despite an increase in serum bioavailable estradiol. Unsupervised cluster analysis of RT-qPCR results indicated two clusters with differences in change in early estrogen response genes including ERS1, TFF1, GREB1a, PGR and AREG. The 10 women in one cluster tended to have increased expression of two or more of early estrogen response genes, but not increased expression of CCND1 (cyclin D1) or genes downstream of activated progesterone receptor such as STAT5a, PdK4, and STK. A trend towards decrease in several genes with predominant stromal expression implicated in breast cancer development including FASN, LEP, CXCL12, SDF1a and B, and CYP19A1 was observed. The 17 women in cluster 2 by contrast exhibited predominately decreased expression of early estrogen response genes. Given the favorable effects on vasomotor symptoms and risk biomarkers, a placebo-controlled Phase IIB trial is warranted. This study was supported in part by grants from the Breast Cancer Research Foundation (BCRF-16-049, BCRF-17-049, BCRF-18-049); and an NIH Clinical and Translational Science Award grant (UL1 TR000001, formerly UL1RR033179) awarded to the University of Kansas Medical Center, and an internal clinical pilot grant program of the KUMC Research Institute. Citation Format: Carol J Fabian, Lauren Nye, Teresa A Phillips, Onalisa Winblad, Carola M Zalles, Christy R Hagan, Merit L Goodman, Byron J Gajewski, Devin C Koestler, Prabhakar Chalise, Bruce F Kimler. Biomarker modulation by bazedoxifene and conjugated estrogen (Duavee®) in women at high risk for development of breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr PD3-06.

Serum IGF-1 düzeyleri akut miyokard infarktüsü sonrası gerçekten azalır mı ve sol ventrikül disfonksiyonu ile ilişkili midir?

Background: Insulin-like growth factor (IGF) is the primary mediator of growth hormone. IGF-1 may have an important role in protecting the myocardial functions following an acute myocardial infarction (AMI). Literature reveals only a limited number of studies investigating the relationship between the serum IGF-1/IGF binding protein-3 (IGFBP-3) levels and the left ventricular functions post AMI. We aimed to determine IGF-1 and IGFBP-3 levels and evaluate their effect on cardiac functions post AMI.Material and Method: Sixty five patients who were included in the study and the control group had 26 patients. Blood samples of the patients were obtained on the second day of their admission. The patients underwent echocardiographic examination on the 7th day of their hospitalization.Results: The serum IGF-1 and IGFBP-3 levels of the patient group were higher than those of the control group; however only IGF-1 levels were statistically significant (243,2±87,9 ng/mL versus 177,2±81,8 ng/mL p=0,001). The increase in the wall thickness and LV chamber size did not correlate with the decrease in LVEF and IGF-1/IGFBP-3 levels. The patients who had minor cardiac events had lower IGF-1 levels but this was not statistically significant (210.5±88.5 versus 253.1±86.1 p&amp;gt;0.05). Conclusion: IGF-1 and IGFBP-3 levels elevated following an the early AMI, but these markers were not correlated with the echocardiographical measurements in early post MI period.