Somatotrophic Axis Research Articles

IGF-I and GH Genes polymorphism and their association with milk yields, composition and reproductive performance in Holstein–Friesian dairy cattle

BackgroundThe insulin-like growth factor (IGF-I) and growth hormone (GH) genes have been identified as major regulators of milk yield and composition, and reproductive performance in cattle. Genetic variations/polymorphism in these genes have been found to influence milk production, yield and quality. This investigation aimed to explore the association between IGF-I and GH polymorphisms and milk yield and composition, and reproductive performance in a herd consisting of 1000 Holstein–Friesian (HF) dairy cattle from El-Alamia farm. The experimental animals were 76 ± 7.25 months in age, with an average live weight of 750 ± 50.49 kg, and raised under the same conditions of feeding and weather. The studied animals were divided into three categories; high producers (n = 280), medium producers (n = 318) and low producers (n = 402).ResultsThe digestion of 249 bp for IGF-I-SnaBI using the Restriction-fragment-length-polymorphism (RFLP) technique yielded two alleles; T (0.59) and C (0.41) and three genotypes; TT (0.52), TC (0.39) and CC (0.09) and this agrees with the results of DNA/gene sequencing technique. The sequencing analysis of the IGF-I gene revealed polymorphism in position 472 (C > T). Nucleotide sequencing of the amplified fragment of the IGF-I gene of different genotypes was done and submitted to the NCBI GenBank with Accession no. MH156812.1 and MH156811.1. While the digestion of 432 bp for GH-AluI using the RFLP technique yielded two alleles; A (0.81) and G (0.19) and two genotypes; AA (0.77) and AG (0.23) and this agrees with the results of DNA/gene sequencing technique. The sequencing analysis of the GH gene revealed polymorphism in the position 1758 C > G and in turn led to changes in amino acid sequence as Alanine for (A) compared to Glycine for (G). Nucleotide sequencing of the amplified fragment of the GH gene was done and submitted to the NCBI GenBank with Accession no. MH156810.1. The results of this study demonstrate the effects of variants of the GH-IGF-I somatotrophic axis on milk production and composition traits in commercial HF cattle. The greatest values of milk yield and reproductive performance were observed on IGF-I-SnaBI-TC and GH-AluI-AG genotypes. While the greatest % fat and % protein values were observed on IGF-I-SnaBI-CC and GH-AluI-AA genotyped individuals.ConclusionThe genetic variation of the studied genes can be utilized in selecting animals with superior milk yield, composition and reproductive performance in Holstein–Friesian Dairy Cattle under subtropical conditions.

Implications of somatotroph axis in the behaviour of silent corticotroph tumours

Implications of somatotroph axis in the behaviour of silent corticotroph tumours

Skin assessment in congenital untreated isolated GH deficiency.

The separation between the inside and outside through the skin was fundamental for the evolution of prevertebrates, which grow through extrapituitary circuits, to vertebrates, which grow through the somatotrophic axis, namely pituitary growth hormone (GH). and circulating IGF1.Individuals with untreated isolated growth hormone (GH) deficiency (IGHD) due to a mutation in the GH-releasing hormone receptor (GHRH) gene, residing in Itabaianinha, Brazil, are vulnerable to skin cancer and have reduced sweating. However other aspects of their skin physiology are still unknown. Our objectives were to evaluate the number of skin cancers, skin aging, and functional aspects of the skin in this IGHD cohort. Twenty-six IGHD individuals and 26 controls matched by age, sex, ethnicity, and occupation were submitted to a biochemical, dermatological and a functional skin assessment by the Multi Probe Adapter Cutometer® MPA 580. There was no difference in the number of skin cancers and in the degrees of photodamage between the groups. The melanin content in the forearm was similar between the groups but was lower in the buttocks (p = 0.005), as well as skin resistance (p < 0.0001) and elasticity (p = 0.003), lower in the IGHD. There was no difference in hydration and sebum content between the two groups. IGHD is apparently associated with a neutral profile in terms of skin cancer and photodamage, with similar melanin on the forearm and lower buttocks, lower skin resistance and elasticity, with hydration and sebum similar to controls.

Improved overall survival in patients developing endocrine toxicity during treatment with nivolumab for advanced non-small cell lung cancer in a prospective study

PurposeImmune checkpoint inhibitors (ICPIs) disrupting PD-1/PD-L1 axis have revolutionized the management of advanced non-small cell lung cancer (NSCLC). Some studies identified the development of endocrine toxicity as predictor of better survival in cancer patients treated with ICPIs. The aim of study was to evaluate survival and new onset of immune-related endocrine adverse events (irAEs) in patients treated with nivolumab for advanced NSCLC.MethodsIn a prospective study, 73 patients with previously treated advanced NSCLC received nivolumab in monotherapy. Blood samples were collected at each cycle to monitor thyroid autoimmunity, thyroid, adrenal and somatotroph axes, while thyroid morphology was evaluated by ultrasonography.ResultsAn impaired thyroid function was recorded in 23.4% of patients (n = 15). Eight patients developed asymptomatic transient thyrotoxicosis (ATT) evolving to hypothyroidism in 50% of cases. In addition, seven patients developed overt hypothyroidism without ATT and with negative autoantibodies. Patients who developed hypothyroidism proved to have better overall survival (OS) as compared with non-developers at both univariate (p = 0.021) and multivariate analyses (p = 0.023). The survival curve of patients with reduced IGF-I at baseline, or displaying its reduction during the follow-up, showed significantly reduced median survival compared to patients with normal/high IGF-I levels (p = 0.031).ConclusionsThyroid function abnormalities are the major irAEs in patients treated with nivolumab, and hypothyroidism onset is associated with prolonged survival. Our findings indicate that the development of hypothyroidism is a positive predictive biomarker of nivolumab antitumor efficacy in patients with NSCLC. Low IGF-I levels could represent a negative prognostic factor during nivolumab therapy.

Screening of GHSR, GHRHR, GH1 genes in isolated growth hormone deficiency disease in Egyptian patients

Abstract Background Isolated growth hormone deficiency (IGHD) is a hereditary disorder that causes significant short stature. GHD has a reported incidence of 1/4000–1/10,000 births. It is caused by mutations in the major somatotroph axis genes, involving GH1, codes for growth hormone, GHSR, and GHRHR, codes for growth hormone secretagogue receptor and growth hormone-releasing hormone receptor, respectively. Aims of the study The present study aims to examine the clinical phenotype and investigate the genetic etiology of ten Egyptian patients with type I isolated growth hormone insufficiency. Patients and methods Patients recruited for the study were clinically diagnosed by two provocation tests and were subjected to a thorough history, clinical examination, and anthropometric measurements. Sanger sequencing and mutational analysis of the three genes, GH1, GHSR, and GHRHR, was our approach, performed in all enrolled IGHD patients. The variants identified were analyzed using the biological, population, sequence variants, and clinical genetics databases. Prediction of the pathogenicity of the novel variants was done by in silico prediction tools following the American College of Medical Genetics and Genomics (ACMG) guidelines. Results Sanger sequencing revealed a previously reported pathogenic mutation (NM_000823.4: c.1069C &gt; T; p.Arg357Cys) in the GHRHR gene in one patient and a novel frameshift variant (NM_198407.2: c.1043dup; Ser349Leu fs*6) in the GHSR gene in another patient. This is the fourth report highlighting the autosomal dominant inheritance of the GHSR mutation as a cause of isolated growth hormone deficiency. A number of previously reported variants, but of rare frequency, were identified in this study. In our IGHD cases, 90% of the patients were underweight, 50% had anemia, and 80% showed hypovitaminosis D. Conclusion Our findings broaden the mutational spectrum underlying the IGHD in Egyptian patients and point out the importance of mutation screening of the GHSR and GHRHR genes. This study also acknowledges the autosomal dominant mode of inheritance of the GHSR mutation as a cause for dwarfism.

Explaining Long COVID: A Pioneer Cross-Sectional Study Supporting the Endocrine Hypothesis.

In some patients, symptoms may persist after COVID-19, defined as long COVID. Its pathogenesis is still debated and many hypotheses have been raised. Our primary objective was to evaluate the corticotroph and somatotroph functions of patients previously infected with SARS-CoV-2 and experiencing post-COVID-19 syndrome to detect any deficiencies that may explain long COVID. A cross-sectional study was conducted including patients who had previously contracted SARS-CoV-2 with a postinfection period of 3 months or less to 15 months, divided into 2 groups. The first group (G1) comprised fully recovered patients, while the second group (G2) included patients experiencing long COVID. The primary outcome was the comparison of corticotroph and somatotroph functions. A total of 64 patients were divided into 2 groups, each consisting of 32 patients. G2 exhibited more frequently anterior pituitary deficits compared to G1 (P = .045): for the corticotroph axis (G1: 6.3% vs G2: 28.1%) and for the somatotroph axis (G1: 31.3% vs G2: 59.4%). Baseline cortisol level was significantly lower in G2 (G1: 13.37 µg/dL vs G2: 11.59 µg/dL) (P = .045). The peak cortisol level was also lower in G2 (G1: 23.60 µg/dL vs G2: 19.14 µg/dL) (P = .01). For the somatotroph axis, the insulin growth factor-1 level was lower in G2 (G1: 146.03 ng/mL vs G2: 132.25 ng/mL) (P = .369). The peak growth hormone level was also lower in G2 (G1: 4.82 ng/mL vs G2: 2.89 ng/mL) (P = .041). The results showed that long COVID patients in our cohort were more likely to have anterior pituitary deficiencies. The endocrine hypothesis involving anterior pituitary insufficiency can be considered to explain long COVID.

THU076 GH, IGF-1 And Inflammatory Marker Interactions With Small Bowel Microbial Diversity Are Age And Sex Dependent

Abstract Disclosure: G. Leite: None. N. Tal: None. G. Barlow: None. W. Morales: None. R. de Souza Santos: None. M. Rashid: None. A. Hosseini: None. M. Pimentel: None. R. Mathur: None. Attenuated somatotroph axis function correlates inversely with age-related comorbidities in both animal and human studies. Mechanisms by which GH and IGF-1 may promote aging include increasing inflammation, DNA damage and cell senescence. Bidirectional interactions between GH, IGF-1 and stool microbial diversity occur with malnutrition, inflammatory bowel disease, colon cancer and acromegaly. Given the importance of the small bowel in sustaining immune system homeostasis, we assessed the relationship of the duodenal microbiome, GH, IGF-1 and inflammatory markers in human subjects of different age groups. Methods: Female (F) and male (M) subjects (18-80 years) undergoing upper endoscopy without colon preparation were recruited. Subjects answered a comprehensive medical history, and whole blood was collected. Duodenal luminal samples were obtained using a double lumen sterile catheter. Microbial DNA was extracted and 16S sequenced. Analyses were performed using CLC Genomics Microbial Module. Circulating GH, IGF-1, IGFBP3 and cytokine (GM-CSF, IFNγ, IL10, IL12P70, IL13, IL1B, IL2, IL4, IL5, IL6, IL8 and TNFα) levels were measured (Luminex FLEXMAP 3D). Results: 177 subjects were grouped by age (sex and BMI, P=NS): 18-35yrs (N=21, F=11), 36-50yrs (N=29, F=15), 51-65yrs (N=69, F=38) and 66-80yrs (N=58, F=28). While IGFBP3 levels were similar (P=0.22), IGF-1 levels gradually decreased in older subjects (18-35yrs: 41.8-173.8 ng/mL; 36-50yrs: 12-160 ng/mL; 51-65yrs: 2-156.8 ng/mL; 66-80yrs: 2-142.6 ng/mL, P&amp;lt;0.0001). Overall GH did not change among groups (P=0.58). In both M and F systemic GH inversely correlated with duodenal microbial diversity [Spearman r (R)=-0.234, P=0.001], and this was most pronounced in older M (66-80yrs, R=-0.517, P=0.003). GH and IGF-1 correlated positively with systemic inflammatory markers: GMCSF (GH: R=0.159, P=0.032; IGF-1: P=NS); IFNγ (GH: R=0.178, P=0.016; IGF-1: R=0.154, P=0.041); IL1B (GH: P=NS; IGF-1: R=0.210, P=0.005); IL6 (GH: R=0.160, P=0.031; IGF-1: P=NS) and IL8 (GH: R=0.219, P=0.003; IGF-1: P=NS). IL8 was negatively linked to duodenal microbial diversity (R=-0.213, P=0.001), and higher in older M and F subjects (P=0.008). All associations seen were stronger in M. In addition, systemic TNFα (P=0.024) and IL5 (P=0.011) levels were also higher in M vs. F.In M only, GH was also associated with TNFα (R=0.226, P=0.034) and IL5 (R=0.279, P=0.008). Conclusion: IGF-1 and GH are associated with circulating inflammatory biomarkers in both a sex-and age- dependent manner. We show that systemic levels of GH and the specific inflammatory marker IL-8 are associated with diminished duodenal microbial diversity. This association is most profound in older males. Considering that IL8 is an important senescence marker, the mutual regulation of the small bowel microbiome and the somatotroph axis suggest a novel mechanism promoting inflammation and aging. Presentation: Thursday, June 15, 2023

THU075 Sex And Age Specificity Of Correlations Among IGF-1, GH, And Duodenal Microbial Diversity Predicting TMA Biosynthesis

Abstract Disclosure: N. Tal: None. G. Leite: None. G. Barlow: None. W. Morales: None. R. de Souza Santos: None. M. Pimentel: None. R. Mathur: None. Varied gut microbial profiles and functional potentials may increase or decrease cardiovascular (CVD) disease risk. Trimethylamine (TMA), a known bacterial metabolite associated with red meat ingestion, is linked to increased CVD risk and morbidity through its liver-transformed form trimethylamine N-oxide (TMAO). As the somatotroph axis is also linked both to the microbiome and CVD morbidity, we explored the relationships between the duodenal microbiome, microbial pathways, IGF-1 and GH levels. Methods: Female (F) and male (M) subjects undergoing upper endoscopy without colon prep were enrolled and completed a medical history including CV conditions and risk factors such as exercise and diet. Whole blood was collected and duodenal aspirates obtained using a double lumen sterile catheter. Microbial DNA was extracted and 16S sequenced. Analyses were performed with CLC Microbial Module. Predicted pathways were identified using MetaCyc Database. Fasting circulating GH, IGF-1 (Luminex FLEXMAP) and cholesterol fractions (Cobas 400) were measured. Results: 177 subjects were grouped by age (sex and BMI, P=NS): 18-35yrs (N=21, F=11), 36-50yrs (N=29, F=15), 51-65yrs (N=69, F=38) and 66-80yrs (N=58, F=28). IGF-1 levels gradually decreased in older subjects (P&amp;lt;0.0001). In older M (66-80yrs), GH correlated positively with IGF-1 (R=0.371, P=0.044) and negatively with duodenal microbial diversity (R=-0.517, P=0.003). M and F had similar CVD risks (hypertension, smoking, exercise habits, obesity, LDL levels and weekly red meat consumption [P=NS for all]). In M only: 1) GH levels correlated with overall number of CV conditions (R=0.339, P=0.001), 2) Red meat consumption correlated with GH (R=0.353, P=0.002) and predicted microbial TMA biosynthesis from L-carnitine (R=0.272, P=0.009), and 3) Higher IGF-1 correlated with predicted microbial TMA production from L-carnitine (R=0.208, P=0.05) and predicted microbial conversion of TMA to TMAO (R=0.257, P=0.018). Duodenal relative abundance (RA) of Prevotellaceae (which positively impacts duodenal microbial diversity) inversely correlated with both GH (R=-0.174, P=0.019) and predicted TMA production (R=-0.174, P=0.019). Positive associations among Prevotellaceae and duodenal diversity (R=0.570, P&amp;lt;0.0001) and inverse associations with TMA production (R=-0.354, P=0.029) were stronger in older M (66-80yrs). In M, Prevotellaceae RA decreased gradually with age (P=0.023). Conclusion: IGF-1 and GH levels exhibit differential relationships with the duodenal microbiome and cardiovascular risk. In males, IGF-1 levels strongly associate with duodenal microbial pathways linked to TMA production and conversion to TMAO. Red meat consumption is linked to GH levels and to predicted TMA biosynthesis pathways. The microbial family Prevotellaceae appears to mitigate predicted TMA production and its relative abundance is lower in older men. Presentation: Thursday, June 15, 2023

Musculoskeletal complications of Cushing syndrome.

Prolonged exposure to an excess of glucocorticosteroids (GCs), both endogenous and exogenous, leads to a wide range of comorbidities, including cardiovascular, metabolic, psychiatric, and musculoskeletal disorders. The latter comprise osteopenia and osteoporosis leading to skeletal fractures and myopathy. Although endogenous hypercortisolemia is a rare disorder, GCs are among the most frequently prescribed drugs, often administered chronically and despite multiple side effects, impossible to taper off due to therapeutic reasons. The pathophysiology of the effect of GC excess on bone often leads to fractures despite normal or low-normal bone mineral density and it includes direct (mainly disturbance in bone formation processes, through inactivation of the Wnt/β-catenin signalling pathway) and indirect mechanisms (through suppressing the gonadal and somatotrophic axis, and also through antagonizing vitamin D actions). Glucocorticosteroid-induced fast-twitch, glycolytic muscles atrophy occurs due to increased protein catabolism and impaired synthesis. Protein degradation is a result of activation of the ubiquitin proteasome and the lysosomes stimulated through overexpression of several atrogenes (such as FOXO-1 and atrogin-1). This review will discuss pathophysiology, clinical presentation, prevention, and management of GC-induced osteoporosis (including calcium and vitamin D supplementation, and bisphosphonates) and myopathy associated with GC excess.

Intrathymic somatotropic circuitry: consequences upon thymus involution.

Growth hormone (GH) is a classic pituitary-derived hormone crucial to body growth and metabolism. In the pituitary gland, GH production is stimulated by GH-releasing hormone and inhibited by somatostatin. GH secretion can also be induced by other peptides, such as ghrelin, which interacts with receptors present in somatotropic cells. It is well established that GH acts directly on target cells or indirectly by stimulating the production of insulin-like growth factors (IGFs), particularly IGF-1. Notably, such somatotropic circuitry is also involved in the development and function of immune cells and organs, including the thymus. Interestingly, GH, IGF-1, ghrelin, and somatostatin are expressed in the thymus in the lymphoid and microenvironmental compartments, where they stimulate the secretion of soluble factors and extracellular matrix molecules involved in the general process of intrathymic T-cell development. Clinical trials in which GH was used to treat immunocompromised patients successfully recovered thymic function. Additionally, there is evidence that the reduction in the function of the somatotropic axis is associated with age-related thymus atrophy. Treatment with GH, IGF-1 or ghrelin can restore thymopoiesis of old animals, thus in keeping with a clinical study showing that treatment with GH, associated with metformin and dehydroepiandrosterone, could induce thymus regeneration in healthy aged individuals. In conclusion, the molecules of the somatotrophic axis can be envisioned as potential therapeutic targets for thymus regeneration in age-related or pathological thymus involution.

The hepatic integrated stress response suppresses the somatotroph axis to control liver damage in nonalcoholic fatty liver disease

Nonalcoholic fatty liver disease (NAFLD) can be ameliorated by calorie restriction, which leads to the suppressed somatotroph axis. Paradoxically, the suppressed somatotroph axis is associated with patients with NAFLD and is correlated with the severity of fibrosis. How the somatotroph axis becomes dysregulated and whether the repressed somatotroph axis impacts liver damage during the progression of NAFLD are unclear. Here, we identify a regulatory branch of the hepatic integrated stress response (ISR), which represses the somatotroph axis in hepatocytes through ATF3, resulting in enhanced cell survival and reduced cell proliferation. In mouse models of NAFLD, the ISR represses the somatotroph axis, leading to reduced apoptosis and inflammation but decreased hepatocyte proliferation and exacerbated fibrosis in the liver. NAD+ repletion reduces the ISR, rescues the dysregulated somatotroph axis, and alleviates NAFLD. These results establish that the hepatic ISR suppresses the somatotroph axis to control cell fate decisions and liver damage in NAFLD.

Enhancing gosling growth and secretion of somatotrophic and thyrotrophic axis hormones through egg turning during incubation

ABSTRACT 1. Growth performance of Yangzhou geese hatched from eggs with turning angles of 50° or 70° was evaluated in association with serum hormones and somatotrophic gene mRNA expression. 2. Egg turning at 70° significantly (P< 0.05) increased hatchability, gosling quality and hatching weight. Gosling post-hatch body weight, leg and breast muscle weight in the 70° turning group was significantly heavier until 50 d of age. 3. Serum concentrations of GH were significantly higher until 30 d of age in the 70° turning group goslings, and those of IGF-I and T3 were higher from hatching to 50 d of age. 4. The mRNA expression of GHRH, pituitary GH, liver and leg muscle IGF-I were all significantly higher at 1 and 30 d of age after hatch, but not at 70 d after hatch, in the 70° turning group. 5. Egg turning at 70° during incubation improves embryo and gosling quality and growth performance through up-regulation of gene expression and secretion of somatotrophic axis hormones, GHRH, GH and IGF-I, as well as T3.

OR14-4 Acute sleep disruption does not diminish pulsatile growth hormone secretion in pubertal children

Abstract Context: Growth hormone (GH) plays a critical role in glucose homeostasis and linear growth during childhood. GH secretion is controlled by multiple neurotransmitters and hormones. Sleep is also a powerful stimulus for GH secretion. In children, GH pulses occur after sleep onset in association with slow-wave sleep (SWS), but it is unclear if undisrupted sleep is required for normal GH secretion. Given the rising incidence of pediatric sleep disorders such as obstructive sleep apnea (OSA) that cause sleep fragmentation, it is critical to determine whether sleep fragmentation during childhood may dysregulate the somatotropic axis. Objective To quantify how undisrupted vs fragmented sleep affects GH secretion in children. Methods Pubertal subjects (10 M, 9 F; 9.1-14.4 yrs) were randomized to two overnight polysomnographic studies with frequent blood sampling (q10min) to measure GH: fourteen were healthy subjects studied with or without SWS disruption via auditory stimuli (3 sec, 1500 Hz tones, 40-100 dB followed by 18 sec of a 75 dB noise simulating a knock on the door) and five were subjects with OSA studied with or without prescribed continuous positive airway pressure (CPAP); the latter condition was expected to have sleep fragmentation due to untreated OSA. GH pulses were identified using sparse deconvolution. Studies without auditory stimuli or when using CPAP were combined and analyzed as 'undisrupted sleep'. The relationship between GH pulse rate per hour and sleep stage was evaluated using Poisson generalized estimating equations. Results In SWS disruption studies, an average of 77.51 ± 13.61 (range 23-190) auditory stimuli were delivered, causing a 40.02 ± 7.78% decrease in SWS in favor of lighter sleep stages. In subjects with OSA, CPAP withdrawal caused a slight increase in the apnea hypopnea index (1.08 ± 0.10 vs. 2.20 ± 1.70 events/hour of sleep, p=0.07) with no change in sleep stage durations. During undisrupted sleep, subjects had an average of 0.91 ± 0.067 GH pulses/hour with a mean pulse amplitude of 10.03 ± 1.00 ng/mL and mean basal secretion rate of 0.26 ± 0.10 ng/ml per min. GH pulses occurred more frequently during SWS (2.3 pulses/hour SWS, amplitude 9.92 ± 2.59 ng/mL) than during any other sleep stage (P &amp;lt; 0.001). Neither form of sleep disruption affected the distribution of GH pulses across sleep stages, GH pulse amplitude and frequency, nor basal GH secretion. Conclusion In children, nocturnal GH pulses are temporally associated with SWS. However, neither acute fragmentation of SWS nor nocturnal arousals from OSA altered basal or pulsatile GH secretion, indicating that somatotrophic axis activity is preserved in the face of acute sleep disruption in children. Presentation: Sunday, June 12, 2022 11:45 a.m. - 12:00 p.m.

Quantitative measures of the vascular and neural components of the retina in adult individuals with congenital and untreated growth hormone deficiency

BackgroundThe somatotrophic axis, including hypothalamic growth hormone (GH)-releasing hormone (GHRH), pituitary GH and circulating IGF-I, is critical for body size. However, the local production of GH/IGF-I (and IGF-II) and other peptides is relevant for other body functions, such as vascular, brain, and retinal function. The consequences of GH deficiency (GHD) on the retinal structure are still unclear, possibly reflecting the heterogeneity of patients and the different types of assessment in previous publications. Our purpose was to assess quantitative measures of the vascular and neural components of the retina in subjects with severe congenital isolated GHD (IGHD).MethodsA cross-sectional study was carried out in 25 adult IGHD subjects and 25 age- and gender-matched controls. Interview, physical examination, laboratory data, optical coherence tomography (OCT) and OCT angiography (OCTA) were performed.ResultsOCT revealed no difference in the areas of the nerve fiber layer average, nor in the areas of superior, inferior, or nasal quadrants, between the two groups. However, areas of the temporal quadrant (p = 0.041), the optical disc (p = 0.042), the cup (p < 0.0001), as well as the cup/disc ratio (p < 0.0001), were higher in IGHD subjects than controls. The rim area was smaller (p = 0.002), although still normal. In OCTA, there was no difference in the minimum foveal thickness, central fovea, foveal avascular zone, and retinal density in any assessed area.ConclusionsIn conclusion, congenital IGHD does not affect quantitative measures of the vascular and neural retina, and it is associated with increased optical disc in this genetically homogeneous cohort.

Enhancing early life nutrition alters the hepatic transcriptome of Angus × Holstein-Friesian heifer calves

Early life nutrition has a major influence on subsequent lifetime performance in cattle. The aim of this experiment was to investigate the effect of plane of nutrition from 3 to 21 weeks of age on the liver transcriptome. Holstein-Friesian × Angus heifer calves with a mean (±SD) age and BW of 19 (±5) days and 51.2 (±7.8) kg, respectively, were assigned to either a high-energy diet to support a mean average daily gain (ADG) of 1.2 kg/day (HI; n = 15) or a moderate diet (MOD; n = 15) to support a mean ADG of 0.5 kg/day. At 145 ± 3 days of age, all calves were euthanised, liver tissue samples collected and flash-frozen in liquid nitrogen. Following RNA sequence analysis, the total number of differentially expressed genes (DEGs) (at false discovery rate (FDR) > 0.05) was 537; 308 upregulated and 229 downregulated in HI compared to MOD. The number of DEGs mapped to IPA (at FDR > 0.05) was 460; 264 upregulated and 196 downregulated. There was greater expression of genes associated with cellular development and metabolism in heifers on the HI compared to the MOD diet. The genes (fold change) of the somatotrophic axis; IGF1 (3.7), IGFALS (2.6) and GHR (1.5) were upregulated in the HI compared to MOD diet. The cytokine receptor genes, IL17RB (1.7) and IL20RA (3.3), were upregulated in the HI heifers, which were detected in a network interacting with metabolically regulated genes. The potential enhanced cell-to-cell communication evident from DEGs would increase the calves’ ability to combat health challenges. The findings of this study indicate that enhancing the early life plane of nutrition in heifer calves results in the upregulation of genes that are associated with increased metabolic activity and thus metabolic capacity. Moreover, the interaction between metabolic and immune communication genes indicates that enhanced nutrition has the potential to improve the immune response in the liver which will play a central role in ensuring optimal lifetime performance.

Abstract #1178145: A Rare case of Pituitary Apoplexy associated with COVID infection presenting with Central Diabetes Insipidus

Pituitary apoplexy (PA) is rare and occurs in up to 20% of patients with a non-functioning pituitary adenoma. It can occur de novo or can be precipitated by surgery, head trauma, anticoagulant therapy, and pregnancy among others. Incidence of persistent Diabetes Insipidus (DI) is only about 2% in such patients. Limited literature exists on the association of PA and COVID infection. We present a case of PA and subsequent central DI in a patient with a pituitary adenoma and severe COVID-19 pneumonia. A 64-year-old male with a history of a non-functioning pituitary macroadenoma (2 cm) of 5 months duration, primary hypothyroidism, and acute myeloid leukemia on chemotherapy presented to the emergency department with one day of headache, fever, and cough. He was diagnosed with COVID-19 pneumonia and started on dexamethasone, broad spectrum antibiotics and supplemental oxygen. Sudden loss of peripheral vision in his left eye with a persistent headache and altered mental status led to plain computed tomography that revealed a hyperattenuating suprasellar mass compressing the optic chiasm. MRI brain showed a T2 hypointense acutely hemorrhagic suprasellar mass compressing the infundibulum and the optic chiasm indicative of PA. Labs showed thrombocytopenia with platelet count 55,000/mcL (130-400), low AM cortisol 3 mcg/dL, normal prolactin 10 ng/mL, normal thyroid function and preserved somatotrophic axis. In addition, the patient developed polyuria with a urine output of up to 8 liters in a 24-hour period, acute hypernatremia (sodium 172 mmol/L), urine specific gravity < 1.005 and serum osmolality 360 mOsm/kg (275-295 mOsm/kg). Conservative management with stress dose hydrocortisone and desmopressin was the first line of therapy. Levothyroxine was continued at home dose. After resolution of COVID-19 pneumonia and improvement in electrolyte disarray, the patient underwent pituitary decompression surgery in 3 weeks with subsequent resolution of DI post-operatively. He was discharged home on hydrocortisone (20 mg total daily dose) and levothyroxine with close endocrinology follow up. Association of COVID infection and PA has been reported in 10 patients in the literature so far. Although the exact mechanism is unknown, SARS-CoV-2 neural invasion via cerebral ACE-2 expression can lead to oxidative stress and thrombogenesis, ultimately predisposing to neural hemorrhage. Thrombocytopenia secondary to chemotherapy can be a contributing factor in our patient. DI is rare and usually resolves after decompression surgery. Further research focusing on the association and pathophysiology of COVID-19 with PA in those without precipitating factors are needed.

Survival estimation in patients with stomach and esophageal carcinoma using miRNA expression profiles

Identifying a miRNA signature associated with survival will open a new window for developing miRNA-targeted treatment strategies in stomach and esophageal cancers (STEC). Here, using data from The Cancer Genome Atlas on 516 patients with STEC, we developed a Genetic Algorithm-based Survival Estimation method, GASE, to identify a miRNA signature that could estimate survival in patients with STEC. GASE identified 27 miRNAs as a survival miRNA signature and estimated the survival time with a mean squared correlation coefficient of 0.80 ± 0.01 and a mean absolute error of 0.44 ± 0.25 years between actual and estimated survival times, and showed a good estimation capability on an independent test cohort. The miRNAs of the signature were prioritized and analyzed to explore their roles in STEC. The diagnostic ability of the identified miRNA signature was analyzed, and identified some critical miRNAs in STEC. Further, miRNA-gene target enrichment analysis revealed the involvement of these miRNAs in various pathways, including the somatotrophic axis in mammals that involves the growth hormone and transforming growth factor beta signaling pathways, and gene ontology annotations. The identified miRNA signature provides evidence for survival-related miRNAs and their involvement in STEC, which would aid in developing miRNA-target based therapeutics.

Etiology and Treatment of Growth Delay in Noonan Syndrome.

Noonan syndrome is characterized by multiple phenotypic features, including growth retardation, which represents the main cause of consultation to the clinician. Longitudinal growth during childhood and adolescence depends on several factors, among them an intact somatotrophic axis, which is characterized by an adequate growth hormone (GH) secretion by the pituitary, subsequent binding to its receptor, proper function of the post-receptor signaling pathway for this hormone (JAK-STAT5b and RAS/MAPK), and ultimately by the production of its main effector, insulin like growth factor 1 (IGF-1). Several studies regarding the function of the somatotrophic axis in patients with Noonan syndrome and data from murine models, suggest that partial GH insensitivity at a post-receptor level, as well as possible derangements in the RAS/MAPK pathway, are the most likely causes for the growth failure in these patients. Treatment with recombinant human growth hormone (rhGH) has been used extensively to promote linear growth in these patients. Numerous treatment protocols have been employed so far, but the published studies are quite heterogeneous regarding patient selection, length of treatment, and dose of rhGH utilized, so the true benefit of GH therapy is somewhat difficult to establish. This review will discuss the possible etiologies for the growth delay, as well as the outcomes following rhGH treatment in patients with Noonan syndrome.

A Screening Tool to Detect Chronic Critically Ill Cardiac Surgery Patients at Risk for Low Levels of Testosterone and Somatomedin C: A Prospective Observational Pilot Study.

ObjectiveThe neuroendocrine response to critical illness is dichotomous as it is adaptive during the acute phase then transitions to maladaptive as critical illness becomes prolonged in 25-30% of patients. Presently, monitoring all critically ill patients for endocrinopathies is not the standard of care. However, given the negative impact on patient prognosis, a need to identify those at risk for endocrinopathies, may exist. Thus, a screening tool to identify endocrinopathies along the somatotroph and gonadal axes in a cardiothoracic surgery population was developed.MethodsA prospective observational pilot study was conducted in two cardiothoracic surgery intensive care units (ICU) within a multi-site healthcare system. Total testosterone and somatomedin C levels were obtained from 20 adult patients who remained in the ICU for greater than seven days after cardiothoracic surgery and were tolerating nutrition, had a risk of malnutrition and a mobility score of moderate to dependent assistance.ResultsTwenty patients were included for descriptive analysis (seven females). Thirteen patients tested low for total testosterone, with males more likely to have a testosterone-related endocrinopathy as compared to females (100% vs. 0 to 43%, p = 0.0072). A higher proportion of low somatomedin C levels was found in females than males (57% vs. 31%); however, the difference was not statistically significant (p = 0.251).ConclusionsThe screening tool used in this pilot study accurately predicted low total testosterone in all men and reasonably predicted low somatomedin C in a majority of women. However, the ability of the tool to predict low total testosterone in women and low somatomedin C in men is less certain. A gender-specific screening tool might be necessary to predict hormonal deficiencies.

Pituitary gland and growth hormone

The pituitary gland (PG) is said to be a “master” endocrine gland and through its tropic hormones influences other endocrine glands to secrete hormones that have a variety of effects on body systems. Growth hormone (GH) is a pituitary gland hormone that has direct and indirect effects produced by somatotrophs in early fetal life. It is essential for normal postnatal growth and has diverse effects across multiple physiological systems. The somatotrophic axis is made predominantly of GH, insulin-like growth factor 1 (IGF-1) and other factors regulating growth. This review summarises the relevant anatomical relationships of the PG, the basic aspect of GH physiology which includes mechanism of action (MOA), regulation and secretion and a direct and indirect action of GH through IGF-1, an important mediator of most of the peripheral action of GH.