High Growth Hormone Levels Research Articles

P-51 A RARE CASE IN WHICH ACROMEGALY IS PROVEN CLINICALLY AND BIOCHEMICALLY DESPITE NEGATIVE GH IMMUNOHISTOCHEMICAL STAINING

Abstract Introduction The diagnosis of acromegaly is confirmed by high IGF-1 and GH levels. When a GH-secreting pitNET is resected, immunocytochemistry with GH staining typically supports the diagnosis. It is very rare for these tumors to stain negatively for GH in the presence of clinical and biochemical acromegaly. We are presenting a case of growth hormone (GH)-secreting PitNET with negative immunostaining for GH. Clinical Case 50-year-old male with history of headache and visual disturbances was found to have a pituitary macroadenoma. Years before the presentation, he noticed his shoe size had increased. Physical exam was notable for enlarged nose, thick lips, mandibular prognathism, and enlarged hands and feet. Blood pressure was 140/90 mmHg. Pre-operative laboratory results were remarkable for elevated GH 5.6 ng/ml (0.03-2.47) and IGF-1 816 ng/ml (80.6-207) levels. OGTT suppressed GH nadir 3.95 ng/ml. Pituitary MRI revealed an invasive macroadenoma measuring 37x31x40 mm (Figure 1). The patient underwent transsphenoidal surgery. Although GH and IGF-1 levels decreased after surgery, they did not return to the normal range. Visual field loss improved. Surprisingly, in the histopathological examination, no immunohistochemical staining was detected with GH and other anterior pituitary hormones, and Ki-67 was found to be 2%. Due to disease activity (IGF-1:278 ng/ml; 1.3XULN), medical treatment was started first with dopamine agonist and then continued with somatostatin receptor agonist (IGF-1:322 (1.6xULN). The remaining tumor tissue remained stable under treatment. Conclusion Silent somatotrophinomas detected by immunohistochemical staining have been reported in the literature. Conversely, endocrinologists should keep in mind that there may be rare cases in which immunohistochemical GH staining is negative but clinical and hormonal acromegaly is evidenced.Figure 1Magnetic resonance imaging (MRI) revealed a pituitary macroadenoma 37x31x40 mm in size, with Knosp grade 4 on the right and grade 1 on the left

The Use of Kidney Biomarkers, Nephrin and KIM-1, for the Detection of Early Glomerular and Tubular Damage in Patients with Acromegaly: A Case-Control Pilot Study.

Acromegaly is a rare disorder caused by excessive growth hormone (GH) secreted from a pituitary tumor. High levels of GH and insulin growth factor-1 can lead to renal hypertrophy, as well as to diabetes mellitus and hypertension, which negatively impact kidney function. It is believed that high GH may also be involved in the onset of diabetic nephropathy, the main cause of end-stage kidney disease in developed countries. This case-control study was conducted on 23 acromegalic patients and on a control group represented by 21 healthy subjects. The following parameters were determined for all the subjects: serum creatinine, serum urea, estimated glomerular filtration rate (eGFR), urinary albumin/creatinine ratio (UACR), nephrin and kidney injury molecule 1 (KIM-1). Patients with acromegaly showed higher levels of UACR and lower levels of eGFR as compared to healthy subjects. No significant correlations were found between clinical or biochemical parameters associated with acromegaly and nephrin or KIM-1. There was no glomerular or proximal tubular damage at the time of the study, as proven by the normal levels of the biomarkers nephrin and KIM-1. Studies including more patients with uncontrolled disease are needed to clarify the utility of nephrin and KIM-1 for the detection of early kidney involvement in acromegalic patients.

Blood Glucose Levels Moderate the Associations Between IGF-1 Levels and Choroidal Metrics in Patients With Diabetes With Acromegaly Without Diabetic Retinopathy.

To examine the effects of serum growth hormone (GH) and insulin-like growth factor-1 (IGF-1) on choroidal structures with different blood glucose levels in patients with diabetes mellitus (DM) with acromegaly without diabetic retinopathy. Eighty-eight eyes of 44 patients with acromegaly were divided into a nondiabetic group (23 patients, 46 eyes) and a diabetic group (21 patients, 42 eyes). Forty-four age- and sex-matched healthy controls and 21 patients with type 2 DM without diabetic retinopathy were also included. Linear regression models with a simple slope analysis were used to identify the correlation and interaction between endocrine parameters and choroidal thickness (ChT), total choroidal area (TCA), luminal area (LA), stromal area (SA), and choroidal vascular index (CVI). Our study revealed significant increases in the ChT, LA, SA, and TCA in patients with acromegaly compared with healthy controls, with no difference in the CVI. Comparatively, patients with DM with acromegaly had greater ChT than matched patients with type 2 DM, with no significant differences in other choroidal parameters. The enhancement of SA, LA and TCA caused by an acromegalic status disappeared in patients with diabetic status, whereas ChT and CVI were not affected by the interaction. In the diabetic acromegaly, higher IGF-1 (P = 0.006) and GH levels (P = 0.049), longer DM duration (P = 0.007), lower blood glucose (P = 0.001), and the interaction between GH and blood glucose were associated independently with thicker ChT. Higher GH levels (P = 0.016, 0.004 and 0.007), longer DM duration (P = 0.022, 0.013 and 0.013), lower blood glucose (P = 0.034, 0.011 and 0.01), and the interaction of IGF-1 and blood glucose were associated independently with larger SA, LA, and TCA. As blood glucose levels increased, the positive correlation between serum GH level and ChT diminished, and became insignificant when blood glucose was more than 7.35 mM/L. The associations between serum IGF-1 levels and LA, SA, and TCA became increasingly negative, with LA, becoming significantly and negatively associated to the GH levels only when blood glucose levels were more than 8.59 mM/L. Acromegaly-related choroidal enhancements diminish in the presence of DM. In diabetic acromegaly, blood glucose levels are linked negatively with changes in choroidal metrics and their association with GH and IGF-1. We revealed the potential beneficial impacts of IGF-1 and GH on structural measures of the choroid in patients with DM at relatively well-controlled blood glucose level, which could provide a potential treatment target for diabetic retinopathy.

Association of an impaired GH-IGF-I axis with cardiac wasting in patients with advanced cancer.

Growth hormone (GH) resistance is characterized by high GH levels but low levels of insulin-like growth factor-I (IGF-I) and growth hormone binding protein (GHBP) and, for patients with chronic disease, is associated with the development of cachexia. We investigated whether GH resistance is associated with changes in left ventricular (LV) mass (cardiac wasting) in patients with cancer. We measured plasma IGF-I, GH, and GHBP in 159 women and 148 men with cancer (83% stage III/IV). Patients were grouped by tertile of echocardiographic LVmass/height2 (women, < 50, 50-61, > 61g/m2; men, < 60, 60-74, > 74g/m2) and by presence of wasting syndrome with unintentional weight loss (BMI < 24kg/m2 and weight loss ≥ 5% in the prior 12months). Repeat echocardiograms were obtained usually within 3-6months for 85 patients. Patients in the lowest LVmass/height2 tertile had higher plasma GH (median (IQR) for 1st, 2nd, and 3rd tertile women, 1.8 (0.9-4.2), 0.8 (0.2-2.2), 0.5 (0.3-1.6) ng/mL, p = 0.029; men, 2.1 (0.8-3.2), 0.6 (0.1-1.7), 0.7 (0.2-1.9) ng/mL, p = 0.003). Among women, lower LVmass was associated with higher plasma IGF-I (68 (48-116), 72 (48-95), 49 (35-76) ng/mL, p = 0.007), whereas such association did not exist for men. Patients with lower LVmass had lower log IGF-I/GH ratio (women, 1.60 ± 0.09, 2.02 ± 0.09, 1.88 ± 0.09, p = 0.004; men, 1.64 ± 0.09, 2.14 ± 0.11, 2.04 ± 0.11, p = 0.002). GHBP was not associated with LVmass. Patients with wasting syndrome with unintentional weight loss had higher plasma GH and GHBP, lower log IGF-I/GH ratio, and similar IGF-I. Overall, GHBP correlated inversely with log IGF-I/GH ratio (women, r = - 0.591, p < 0.001; men, r = - 0.575, p < 0.001). Additionally, higher baseline IGF-I was associated with a decline in LVmass during follow-up (r = - 0.318, p = 0.003). In advanced cancer, reduced LVmass is associated with increased plasma GH and reduced IGF-I/GH ratio, suggesting increasing GH resistance, especially for patients with wasting syndrome with unintentional weight loss. Higher baseline IGF-I was associatedwith a decrease in relative LVmass during follow-up.

Characterization of a novel fast-growing zebrafish: a new approach to growth hormone transgenesis.

The manipulation of the somatotropic axis, governing growth, has been a focus of numerous transgenic approaches aimed at developing fast-growing fish for research, medicine and aquaculture purposes. However, the excessively high growth hormone (GH) levels in these transgenic fish often result in deformities that impact both fish health and consumer acceptance. In an effort to mitigate these issues and synchronize exogenous GH expression with reproductive processes, we employed a novel transgenic construct driven by a tilapia luteinizing hormone (LH) promoter. This approach was anticipated to induce more localized and lower exogenous GH secretion. In this study, we characterized the growth and reproduction of these transgenic LHp-GH zebrafish using hormonal and physiological parameters. Our findings reveal that LHp-GH fish exhibited accelerated growth in both length and weight, along with a lower feed conversion ratio, indicating more efficient feed utilization, all while maintaining unchanged body proportions. These fish demonstrated higher expression levels of LH and GH in the pituitary and elevated IGF-1 levels in the liver compared to wild-type fish. An examination of reproductive function in LHp-GH fish unveiled lower pituitary LH and FSH contents, smaller follicle diameter in female gonads, and reduced relative fecundity. However, in transgenic males, neither the distribution of spermatogenesis stages nor sperm concentrations differed significantly between the fish lines. These results suggest that coupling exogenous GH expression with endogenous LH expression in females directs resource investment toward somatic growth at the expense of reproductive processes. Consequently, we conclude that incorporating GH under the LH promoter represents a suitable construct for the genetic engineering of commercial fish species, providing accelerated growth while preserving body proportions.

The disrupting effect of chlormequat chloride on growth hormone is associated with pregnancy

Since chlormequat chloride is widely applied as a plant growth regulator in agriculture and horticulture, its exposure through food consumption is common. We demonstrated previously that chlormequat chloride exposure during pregnancy led to embryos with bigger sizes associated with higher levels of growth hormone (GH) on gestation day 11 (GD11). However, the dose-effect relationship of chlormequat chloride at a lower dose range was not established, and the underlying mechanisms of its promoting effects on embryonic growth and development were not fully elucidated. To address these, pregnant rats were orally exposed to chlormequat chloride at 0, 0.05, 0.5 and 5 mg/kg.bw from GD0 to 11 and the embryonic growth and growth related hormones were evaluated on GD11. We found that the growth and development of the embryos was significantly promoted in a dose dependent manner by chlormequat chloride. Chlormequat chloride also increased embryonic GH, GH releasing hormone (GHRH), and somatostatin (SRIF), and inhibited the embryonic cAMP dependent protein kinase A (PKA) signaling pathway. Chlormequat chloride increased GH synthesis modulated by GHRH/SRIF-PKA-Pituitary specific transcription factor 1 (Pit-1) in the maternal rats. Intriguingly, chlormequat chloride did not show any effects on GH and PKA signaling pathways in the non-pregnant female rats. These findings together suggest that the disrupting effect of chlormequat chloride on GH is associated with pregnancy.

Skeletal Muscle Evaluation in Patients With Acromegaly.

Patients with acromegaly are characterized by chronic exposure to high growth hormone (GH) and insulin-like growth factor-1 levels, known for their anabolic effect on skeletal muscle. Therefore, an increased skeletal muscle mass could be hypothesized in these individuals. Herein, we have performed a systematic revision of published evidence regarding skeletal muscle mass, quality, and performance in patients with acromegaly. A systematic review of the literature in the PubMed database up to September 1, 2023, was conducted with the following query: acromegaly AND ("muscle mass" OR "skeletal muscle"). We excluded studies that did not compare different disease states or used nonradiological methods for the skeletal muscle analyses, except for bioelectrical impedance analysis. Fifteen studies met the inclusion criteria. A total of 360 patients were evaluated for skeletal muscle mass, 122 for muscle fatty atrophy, and 192 for muscle performance. No clear evidence of increased skeletal muscle mass in patients with active disease compared to control or healthy individuals emerged. As for skeletal muscle quality, we observed a trend toward higher fatty infiltration among patients with acromegaly compared to healthy participants. Likewise, patients with active disease showed consistently worse physical performance compared to control or healthy individuals. Skeletal muscle in acromegaly has lower quality and performance compared to that of healthy individuals. The small number of published studies and multiple confounding factors (eg, use of different radiological techniques) contributed to mixed results, especially regarding skeletal muscle mass. Well-designed prospective studies are needed to investigate skeletal muscle mass in patients with acromegaly.

SAT033 Disruption Of GHR In “Middle Aged” Mice Enhances Insulin Sensitivity And Extends Male Lifespan

Abstract Disclosure: S. Duran-Ortiz: None. E.O. List: None. J.A. Young: None. S.C. Mathes: None. R. Basu: None. Y.B. Slama: None. D.E. Berryman: None. Reduced growth hormone (GH) action has been shown to extend healthspan and lifespan in several organisms. In fact, mice and humans with a congenital disruption in the GH receptor (R) gene (GHRKO mice and patients with Laron Syndrome, respectively) have improved insulin sensitivity and are resistant to diabetes, cancer and age-associated cognitive decline. Importantly, the GHRKO mice hold the record for the longest-lived laboratory mice, with a lifespan one week shy of five years of age. GHRKO mice also show reduced markers of aging such as adipose tissue senescence and mTORC1 signaling in liver, kidney, heart and muscle. However, as GH action is required for normal growth and development, we and others have hypothesized that targeted inhibition of GH action at an adult age could be a potent method to extend healthy lifespan. To test this hypothesis and to elucidate how far in development would disruption of GHR extend healthy lifespan, our laboratory recently reported on two mouse lines with post-natal ablation of the GHR at a pubertal age (1.5 months - 1.5mGHRKO mice) and at mature-adult age (6 months - 6mGHRKO mice). We found that ablation of the GHR gene at both 1.5- and 6-months of age extends maximal and mean lifespan preferentially in females. Furthermore, 6mGHRKO mice showed improved oxidative stress resistance while males had improved insulin sensitivity and reduced cancer incidence. With these promising results, we believe that interventions to extend aging should be effective when administered later in life. In the current study, we disrupted the GHR in middle aged mice (12 months - 12mGHRKO mice) using the Cre-Lox system. We found that 12mGHRKO mice exhibit GH insensitivity (high serum GH and low IGF-1 levels), increased adipose tissue mass, reduced lean mass, minimal impact on body weight and length, improved insulin sensitivity and reduced glucose levels in males as well as decreased adipose tissue fibrosis in females compared to males. Moreover, despite the increased fat mass, motor coordination and strength as measured by rotarod and grip strength tests show no deficit in 12mGHRKO mice compared to the controls. Importantly, the male 12mGHRKO mice showed a preferential and significant lifespan extension compared to control mice. Collectively, our results indicate that not only does post-natal GHR disruption does not affect growth and development, but it also confers several crucial healthspan and lifespan advantages. Acknowledgements: This work is supported by the State of Ohio's Eminent Scholar Program, by NIH grant AG059779, by the American Federation for Aging Research (AFAR) and by the Diabetes Institute and by the AMVETS. Presentation: Saturday, June 17, 2023

A pharmacophore screening approach of homeopathic phenols for a renovated design of fragment-optimized Bauhiniastatin-1 as a drug against acromegaly.

Acromegaly is a fatal and chronic disease that is caused by the abnormal secretion of growth hormone (GH) by the pituitary adenoma or pituitary tumor, resulting in an increased circulated concentration of insulin-like growth factors 1 (IGF-1), where in most of the cases it is secreted by a pituitary tumor. Higher levels of GH cause an increase in IGF-1 in the liver leading to multiple conditions such as cardiovascular diseases, glucose imbalance, cancer, and sleep apnea. Medical treatments such as surgery and radiotherapy can be used as the first choice of patients; however, specified human growth hormone control should be an essential treatment strategy due to an incidence rate of 0.2-1.1 yearly. Therefore, the main focus of this study is to develop a novel drug for treating acromegaly by exploiting medicinal plants that have been screened using phenol as a pharmacophore model to identify target therapeutic medicinal plant phenols. The screening identified thirty-four pharmacophore matches of medicinal plant phenols. These were selected as suitable ligands and were docked against the growth hormone receptor to calculate their binding affinity. The candidate with the highest screened score was fragment-optimized and subjected to absorption, distribution, metabolism, and excretion (ADME) analysis, in-depth toxicity predictions, interpretation of Lipinski's rule, and molecular dynamic simulations to check the behavior of the growth hormone with the fragment-optimized candidate. The highest docking energy was calculated as -6.5 K/mol for Bauhiniastatin-1. Enhancing the performance of Bauhiniastatin-1 against the growth hormone receptor with fragment optimization portrayed that human growth hormone inhibition can be executed in a more efficient and better way. Fragment-optimized Bauhiniastatin-1 (FOB) was predicted with high gastrointestinal absorption, a water solubility of -2.61 as soluble, and synthetic accessibility of 4.50, achieving Lipinski's rule of 5, with low organ toxicity prediction and interpreting a positive behavior against the targeted protein. The discovery of a de novo drug candidate was confirmed by the docking of fragment-optimized Bauhiniastatin-1 (FOB), which had an energy of -4,070 Kcal/mol. Although successful and completely harmless, present healthcare treatment does not always eradicate the disease in some individuals. Therefore, novel formulas or combinations of currently marketed medications and emergent phytochemicals will provide new possibilities for these instances.

Long-term opioid treatment and endocrine measures in chronic non-cancer pain patients.

The prevalence of chronic non-cancer pain (CNCP) has increased dramatically the past decades, which combined with indiscriminate use of prescribed opioids has become a public health problem. Endocrine dysfunction may be a complication of long-term opioid treatment (L-TOT), but the evidence is limited. This study aimed at investigating the associations between L-TOT and endocrine measures in CNCP patients. Cortisol (spot and after stimulation), thyrotropin (TSH), thyroxin (T4), insulin-like growth factor 1 (IGF-1), prolactin (PRL), 17-hydroxyprogesterone, androstenedione, dehydroepiandrosterone (DHEAS), sex hormone-binding globulin (SHBG), total testosterone (TT) and free testosterone (fT) were measured. Group comparisons were done between CNCP patients in L-TOT and controls as well as between patients on high- or low-dose morphine equivalents. Eighty-two CNCP patients (38 in L-TOT and 44 controls not receiving opioids) were included. Low TT (p = 0.004) and fT concentrations (p < 0.001), high SHBG (p = 0.042), low DEAS (p = 0.017) and low IGF-1 (p = 0.003) in men were found when comparing those in L-TOT to controls and high PRL (p = 0.018), low IGF-1 standard deviation score (SDS) (p = 0.006) along with a lesser, but normal cortisol response to stimulation (p = 0.016; p = 0.012) were found when comparing L-TOT to controls. Finally, a correlation between low IGF-1 levels and high opioid dose was observed (p < 0.001). Our study not only supports previous findings but even more interestingly disclosed new associations. We recommend future studies to investigate endocrine effects of opioids in larger, longitudinal studies. In the meanwhile, we recommend monitoring endocrine function in CNCP patients when prescribing L-TOT. This clinical study found associations between L-TOT, androgens, growth hormone and prolactin in patients with CNCP compared to controls. The results support previous studies as well as add new knowledge to the field, including an association between high opioid dose and low growth hormone levels. Compared to existing research this study has strict inclusion/exclusion criteria, a fixed time period for blood sample collection, and adjustments for potential confounders, which has not been done before.

High growth hormone serum partially protects mice against Trypanosoma cruzi infection.

Chagas disease (CD) is one of the most devasting parasitic diseases in the Americas, affecting 7-8 million people worldwide. In vitro and in vivo experiments have demonstrated that growth hormone (GH) serum levels decrease as CD progresses. Interestingly, inactivating mutations in the GH receptor in humans result in Laron syndrome (LS), a clinical entity characterized by increased serum levels of GH and decreased insulin growth factor-1 (IGF-1). The largest cohort of LS subjects lives in the southern provinces of Ecuador. Remarkably, no clinical CD cases have been reported in these individuals despite living in highly endemic areas. In the current ex vivo study, we employed serum from GHR-/- mice, also known as LS mice (a model of GH resistance with high GH and low IGF-1 levels), and serum from bovine GH (bGH) transgenic mice (high GH and IGF-1), to test the effect on Trypanosoma cruzi infection. We infected mouse fibroblast L-cells with T. cruzi (etiological CD infectious agent) and treated them with serum from each mouse type. Treatment with GHR-/- serum (LS mice) significantly decreased L-cell infection by 28% compared with 48% from control wild-type mouse serum (WT). Treatment with bGH mouse serum significantly decreased infection of cells by 41% compared with 54% from WT controls. Our results suggest that high GH and low IGF-1 in blood circulation, as typically seen in LS individuals, confer partial protection against T. cruzi infection. This study is the first to report decreased T. cruzi infection using serum collected from two modified mouse lines with altered GH action (GHR-/- and bGH).

Central growth hormone action regulates neuroglial and proinflammatory markers in the hypothalamus of male mice

Growth hormone (GH) action in specific neuronal populations regulates neuroendocrine responses, metabolism, and behavior. However, the potential role of central GH action on glial function is less understood. The present study aims to determine how the hypothalamic expression of several neuroglial markers is affected by central GH action in male mice. The dwarf GH- and insulin-like growth factor-1 (IGF-1)-deficient Ghrhrlit/lit mice showed decreased mRNA expression of Nes (Nestin), Gfap, Iba1, Adgre1 (F4/80), and Tnf (TNFα) in the hypothalamus, compared to wild-type animals. In contrast, transgenic overexpression of GH led to high serum GH and IGF-1 levels, and increased hypothalamic expression of Nes, Gfap, Adgre1, Iba1, and Rax. Hepatocyte-specific GH receptor (GHR) knockout mice, which are characterized by high serum GH levels, but reduced IGF-1 secretion, showed increased mRNA expression of Gfap, Iba1, Tnf, and Sox10, demonstrating that the increase in GH levels alters the hypothalamic expression of glial markers associated with neuroinflammation, independently of IGF-1. Conversely, brain-specific GHR knockout mice showed reduced expression of Gfap, Adgre1, and Vim (vimentin), indicating that brain GHR signaling is necessary to mediate GH-induced changes in the expression of several neuroglial markers. In conclusion, the hypothalamic mRNA levels of several neuroglial markers associated with inflammation are directly modulated by GHR signaling in male mice.

Intraoperative characteristics of somatotropinomas

Background. Acromegaly is a rare disease associated with insulin‑like growth factor 1 hyperproduction due to the presence of pituitary adenoma in the patient. The first‑line treatment of such patients is surgical removal of the formation in order to normalize hormonal status. The main predictors of the ineffectiveness of surgical treatment and relapse of the disease are large tumor size, tumor invasion into the cavernous sinus, and high preoperative levels of growth hormone, as well as Ki‑6 % expression. The search for additional risk factors for disease recurrence, which according to various sources is approximately 30 % after primary surgical treatment, is an urgent task for researchers. In our work, we studied the intraoperative characteristics of the tumor, size of pituitary adenomas according to preoperative magnetic resonance imaging of the brain, degree of invasion of the tumor into the cavernous sinus according to the Knosp classification and compared them with disease outcomes after a year of follow‑up after surgical treatment.Aim. To identify new markers of aggressive progression of pituitary tumors.Materials and methods. A retrospective analysis of medical documentation, protocols of operations of 90 patients aged between 19 and 73 years with the diagnosis of growth hormone‑secreting pituitary adenoma was performed. The dia gnosis was confirmed based on clinical picture, laboratory and instrumental examination methods. All patients underwent endoscopic transsphenoidal removal of pituitary adenoma by one surgeon in one medical institution between 2017 and 2019.Results. Intraoperative characteristics of the tumor, such as the color of the solid component, density, degree of vascularization were compared with the results of laboratory and instrumental data, as well as the results of surgical treatment after a year of follow‑up.Conclusion. Such intraoperative characteristics of growth hormone‑secreting pituitary adenomas as the purplish‑gray color of the solid component, high vascularization, as well as dense‑elastic consistency of the tumor, can be considered high risk factors for continued tumor growth in the first 6 months after surgical treatment or relapse of the disease during a year of follow‑up.

Effects of GHR Deficiency and Juvenile Hypoglycemia on Immune Cells of a Porcine Model for Laron Syndrome

Laron syndrome (LS) is a rare genetic disorder characterized by low levels of insulin-like growth factor 1 (IGF1) and high levels of growth hormone (GH) due to mutations in the growth hormone receptor gene (GHR). A GHR-knockout (GHR-KO) pig was developed as a model for LS, which displays many of the same features as humans with LS-like transient juvenile hypoglycemia. This study aimed to investigate the effects of impaired GHR signaling on immune functions and immunometabolism in GHR-KO pigs. GHR are located on various cell types of the immune system. Therefore, we investigated lymphocyte subsets, proliferative and respiratory capacity of peripheral blood mononuclear cells (PBMCs), proteome profiles of CD4- and CD4+ lymphocytes and IFN-α serum levels between wild-type (WT) controls and GHR-KO pigs, which revealed significant differences in the relative proportion of the CD4+CD8α- subpopulation and in IFN-α levels. We detected no significant difference in the respiratory capacity and the capacity for polyclonal stimulation in PBMCs between the two groups. But proteome analysis of CD4+ and CD4- lymphocyte populations revealed multiple significant protein abundance differences between GHR-KO and WT pigs, involving pathways related to amino acid metabolism, beta-oxidation of fatty acids, insulin secretion signaling, and oxidative phosphorylation. This study highlights the potential use of GHR-KO pigs as a model for studying the effects of impaired GHR signaling on immune functions.

Spectrum of Growth Hormone Disorders in Children: A Case Series of 5 Cases

Growth Hormone Deficiency (GHD) is one of the most important treatable endocrine causes of short stature. A problem anywhere in the Growth Hormone (GH) - Insulin-Like Growth Factor-1 (IGF-1) axis can lead to short stature. Childhood GH deficiency can be congenital, acquired, or idiopathic. Hereby, the authors present a case series consisting of five cases of short stature, aimed to provide an overview of the spectrum of GH-related disorders. All five patients presented to the Paediatric Endocrinology Outpatient Department of a tertiary care Institute with complaints of not gaining height. The patients in present case series had significant short stature (Z score for height &lt;-3 SD (Standard Deviation) in each case). These patients were suspected of having GH deficiency based on clinical presentation and investigations. After a proper diagnostic work-up and GH stimulation tests, cases 1 to 4 were found to have GH deficiency. The 5th case was suspected of having Laron Syndrome based on high GH levels and low IGF-1. There were subtle differences in the spectrum of GH deficiency. The 1st case had Multiple Pituitary Hormone Deficiency (MPHD). Cases 2 to 4 had Isolated Growth Hormone Deficiency (IGHD). Case 2 had findings of pituitary stalk interruption on brain imaging. We found a genetic association in the 3rd case, while the 4th case had almost normal brain imaging. Cases 1 to 4 received GH therapy, and all showed appreciable height gain. These subtle differences can sometimes make the diagnosis difficult, and often a different approach to treatment is required.

PSUN239 Severe Insulin Resistance and Hyperglycemia with Mild COVID-19 Infection

Abstract Introduction Covid-19 infection (CI) is known to cause hyperglycemia and insulin resistance in patients with and without diabetes. Prior reports have correlated the degree of hyperglycemia to the severity of the CI. However, not much data is available regarding severe insulin resistance in patients with mild CI who are otherwise asymptomatic and not on steroids. Case We report a 48-year old male with type-1 diabetes, asymptomatic CI and renal failure, on dialysis who was admitted with diabetic ketoacidosis (DKA). Patient had refused insulin and hemodialysis treatments for one week and was noted to be confused by staff in his long-term facility. Upon presentation, he was initiated on intravenous (IVIT) insulin infusion therapy and transitioned to subcutaneous (SQ) insulin the following morning. That evening, hyperglycemia worsened (&amp;gt;500 mg/dl), necessitating reinstatement of the IVIT. Hyperglycemia persisted (no excess carbohydrate intake reported by nursing) and IVIT was continued as attempts to change to SQ therapy were unsuccessful. He was dialyzed for two consecutive days after admission and then changed to alternate day schedule. On day 4, hyperglycemia worsened to &amp;gt;500 mg/dl persistently, IVIT rate was increased to 24 units/hr but blood sugars persisted in the &amp;gt;500 range. Work up for evaluating Covid-related inflammation and insulin resistance was sent. After 6 hours of IVIT at 24 U/hr, he was given a relatively higher dose of SQ-insulin (insulin glargine 20 units and insulin lispro 30 units SQ). IVIT rate was gradually tapered based on blood sugars and stopped 6 hours after SQ-insulin was given. Approximately eight hours after receiving SQ-insulin, he was noted to be hypoglycemic, and he received two amps of D-50. His blood sugar stabilized, and he continued to do well subsequently and was maintained on basal-bolus therapy. The on-call nurse confirmed good IV access for the IVIT access line. The IV insulin infusion fluid from bag was sent for analysis which showed that insulin was present in the infusion bag. Inflammatory markers showed high levels of cortisol, ferritin, growth hormone, C-reactive protein and sedimentation rate. Insulin antibodies were also present. D-dimer was normal, and fibrinogen was only mildly elevated. Conclusion This is a rare case of severe insulin resistance in a patient with mild Covid-19 infection and underlying type 1 diabetes, who developed severe insulin resistance with poor response to high doses IV insulin. He ultimately responded a combination of high dose subcutaneous insulin and high doses IV insulin infusion therapy with resolution of ketoacidosis and hyperglycemia. Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.

Survivin: A Potential Marker of Resistance to Somatostatin Receptor Ligands.

Invasive and somatostatin receptor ligand (SRL)-resistant pituitary tumors represent a challenge in the clinical practice of endocrinologists. Efforts have been made to elucidate reliable makers for both. Survivin and eukaryotic translation initiation factor-binding protein 1 (4EBP1) are upregulated in several cancers and involved in apoptosis and cell proliferation. We explored the role of these markers in somatotropinomas. Immunostains for survivin and 4EBP1, and also for somatostatin receptor type 2 (SSTR2), Ki-67, and cytokeratin 18, were analyzed in tissue microarrays containing 52 somatotropinoma samples. Tumor invasiveness was evaluated in all samples while drug resistance was evaluated in 34 patients who received SRL treatment. All these parameters were correlated with first-generation SRL (fg-SRL) responsiveness and tumor invasiveness. Low survivin expression (P = 0.04), hyperintense signal on T2 weighted image (T2WI) (P = 0.01), younger age (P = 0.01), sparsely granular adenomas (SGA) (P = 0.04), high postoperative growth hormone (GH) and insulin-like growth factor-1 (IGF-1) levels (P = 0.049 and P < 0.001, respectively), and large postoperative tumor size (P = 0.02) were associated with resistance to fg-SRL. Low survivin and SSTR2 expression and high 4EBP1 expression were associated with SGA (P = 0.04, P = 0.01, and P = 0.001, respectively). Younger age (P = 0.03), large tumor pre- and postoperative (P = 0.04 and P = 0.006, respectively), low SSTR2 expression (P = 0.03), and high baseline GH and IGF-1 (P = 0.01 and P = 0.02, respectively) were associated with tumor invasiveness. However, survivin, 4EBP1, Ki-67, and granulation patterns were not associated with tumor invasion. This study suggests that low survivin expression is predictive of resistance to fg-SRL in somatotropinomas, but not of tumor invasiveness.

Blood Levels Of Hormones, Cytokines And Leukocyte Content Versus Hypertrophic Scar Laser Treatment Outcome

The goal was to identify the changes in blood levels of hormones, cytokines, and the number of leukocytes associated with the success of laser treatment of hypertrophic scars. Material and Methods — The lipid, hormonal, cytokine and leukocyte composition of blood was studied in 15 women with normotrophic scars (Group 1) and 30 women with hypertrophic scars (Group 2). Blood was taken before treatment on days 5-7 of the menstrual cycle, followed by laser treatment. The clinical parameters of scars were assessed before treatment and 3 months after it, and two subgroups were identified: with a successful treatment outcome (2a) and with an unsuccessful outcome (2b). A retrospective analysis of blood composition was performed in each subgroup. The data were processed using the methods of nonparametric statistics. The differences were considered statistically significant at p&lt;0.05. Results — At a successful treatment outcome, the clinical parameters of scars were associated with low estradiol level, high progesterone content and high number of segmented neutrophils. These changes create conditions for scar hypertrophy, but retain the body’s capability of responding to the treatment by inflammatory process with normotrophic scarring. At an unsuccessful treatment outcome, the scar hypertrophy was restored under conditions of low blood content of luteinizing hormone, and high levels of growth hormone and transforming growth factor β. Conclusion — Features of changes in the blood levels of hormones, cytokines, and leukocyte content are associated with the success of laser treatment of hypertrophic scars.

Predictive factors for recovery from adult growth hormone deficiency after transsphenoidal surgery for nonfunctioning pituitary adenoma.

Recovery from adult growth hormone deficiency (AGHD) after transsphenoidal surgery (TSS) has not been well discussed because of the lack of examinations including pituitary provocation tests (PPTs) before and after the procedure. This study aimed to evaluate the growth hormone (GH) axis function of patients with nonfunctioning pituitary adenoma (NFPA) via pre- and postoperative PPTs. Moreover, the predictive factors for recovery from AGHD after TSS were validated to facilitate surgery for AGHD in patients with NFPA. In total, 276 patients (median age 60.0 years) who underwent TSS for NFPA were included in this study. PPTs were performed before and 3 months after TSS. Then, the relationships between recovery from AGHD after TSS and clinical, surgical, and hormonal factors, including peak GH level based on PPTs, were evaluated statistically. In this study, 114 patients were diagnosed with preoperative AGHD. Approximately 25.4% recovered from AGHD after TSS. In contrast, among the 162 patients without preoperative AGHD, 13 (8.0%) had newly developed postoperative AGHD. The predictive factors for recovery from AGHD were younger age, female sex, initial TSS, and high peak GH level based on preoperative PPT. According to the receiver operating characteristic curve analysis, patients who were aged ≤ 62.2 years and had a peak GH level of ≥ 0.74 μg/L based on preoperative PPT were likely to recover from AGHD (sensitivity: 82.8%, specificity: 72.9%, and area under the curve: 0.8229). AGHD caused by NFPA can improve after initial TSS among young patients with certain peak GH levels assessed by preoperative PPT. Whether TSS for NFPA can promote recovery from AGHD is worth considering in some patients.

Morphological predictors of aggressive course of STH secreting pituitar y adenomas in patients with acromegaly

Acromegaly is a rare disease that occurs against the background of existing pituitary adenoma, leading to disability and high mortality as a result of secondary complications caused by chronic hyperproduction of IGF-1. The main predictors of disease recurrence and ineffectiveness of surgical treatment currently remain the size of the tumor, the presence of tumor invasion into the cavernous sinus, high preoperative levels of growth hormone and IGF-1. According to the literature, surgical remission is achieved on average in 57% -89% of patients. The search for factors of a negative outcome of surgical treatment remains an urgent problem. Based on our experience of surgical treatment of 144 patients with acromegaly, we analyzed the sex and age differences of patients and compared them with the outcomes of treatment after a year of follow-up. The male sex in our study was a risk factor for suprasellar tumor spread, the detection of a residual tumor a year after surgical treatment. However, there were in the relapse of the disease after a year of follow-up. The younger age of patients is associated with high tumor invasion into the cavity of the cavernous sinus and a low frequency of remission of the disease during the year of follow-up.