Serum Growth Hormone Levels Research Articles

Intranasal Delivery of a Ghrelin Mimetic Engages the Brain Ghrelin Signaling System in Mice.

Ghrelin, the endogenous ligand of the growth hormone secretagogue receptor (GHSR), promotes food intake and other feeding behaviors, and stimulates growth hormone (GH) release from the pituitary. Growth hormone secretagogues (GHS), such as GHRP-6 and MK-0677, are synthetic GHSR ligands that activate orexigenic neuropeptide Y neurons that coexpress agouti-related peptide (AgRP) in the arcuate nucleus of the hypothalamus when administered systemically. Systemic GHRP-6 also stimulates GH release in humans and rats. Thus, GHS and ghrelin have therapeutic relevance in patients who could benefit from its orexigenic and/or GH-releasing effects. This study examined whether intranasal delivery of ghrelin, GHRP-6, or MK-0677 engages the brain ghrelin signaling system. Effective compounds and doses were selected based on increased food intake after intranasal application in mice. Only GHRP-6 (5 mg/kg) increased food intake without adverse effects, prompting detailed analysis of meal patterns, neuronal activation in the arcuate nucleus (via Fos mapping) and neurochemical identification of c-fos messenger RNA (mRNA)-expressing neurons using RNAscope. We also assessed the effect of intranasal GHRP-6 on serum GH levels. Intranasal GHRP-6 increased food intake by increasing meal frequency and size. Fos expression in the arcuate nucleus was higher in GHRP-6-treated mice than in saline controls. When examining the neurochemical identity of c-fos-mRNA-expressing neurons, we found coexpression with 63.5 ± 1.9% Ghsr mRNA, 79 ± 6.8% Agrp mRNA, and 11.4 ± 2.5% Ghrh mRNA, demonstrating GHRP-6's ability to engage arcuate nucleus neurons involved in food intake and GH release. Additionally, intranasal GHRP-6 elevated GH serum levels. These findings suggest that intranasal GHRP-6, but not ghrelin or MK-0677, can engage the brain ghrelin signaling system.

Factors affecting hormonal outcomes in patients undergoing surgery for non-functioning pituitary neuroendocrine tumors: a prospective observational study.

Surgical resection of non-functioning pituitary neuroendocrine tumors (NF-PitNET) is associated with new onset hormonal axis (HA) dysfunction, and factors predicting HA dysfunction are controversial, especially in large and giant NF-PitNET. Thus, we evaluated the postoperative hormonal function and assessed factors affecting HA dysfunction in patients with NF-PitNET. This prospective observational study involved 50 patients who underwent endoscopic surgical resection of NF-PitNET in the Department of Neurosurgery (April 2023-March 2024). The preoperative tumor diameter and volume were calculated radiologically. Hormonal evaluation was performed preoperatively, and again postoperatively at 7-days and 90-days. At 90-days, 36% patients recovered HA function, 34% remained unchanged, while 30% worsened. Serum cortisol (p < 0.0001), adrenocorticotropic hormone (p = 0.012), growth hormone (p = 0.013), and luteinizing hormone (p = 0.020) levels increased significantly; serum prolactin (p = 0.016) decreased significantly; while serum thyroid-stimulating hormone, follicle-stimulating hormone, and testosterone levels remained unchanged (all p > 0.05). Overall, there was no significant change in grade of HA dysfunction (p > 0.05). Male sex (OR:5.630, 95%CI:1.648-19.232; p = 0.006), tumor volume (OR:3.511, 95%CI:1.308-9.423; p = 0.013) and tumor diameter (OR:9.489, 95%CI:2.916-30.878; p < 0.0001) were significantly associated with postoperative HA dysfunction. Tumor volume and diameter (cut-off: 8.87 cm3 and 2.95cm, respectively) predicted postoperative HA dysfunction with a sensitivity of 96.0% and 92.0%, and a specificity of 88.0% and 76.0%, respectively. New-onset diabetes insipidus (30%) was the predominant complication. Tumor diameter and volume are significant predictors of postoperative HA dysfunction. More than one third of patients improved their HA function, while it worsened in less than a third of patients.

Prolactin Response to a Submaximal Dose of Ghrelin in Different Phases of the Normal Menstrual Cycle.

Background and Objectives: A similar secretory pattern of prolactin (PRL) and growth hormone (GH) during the menstrual cycle has been reported in response to a high dose of ghrelin in adult healthy women. The present study aimed to assess the pattern of PRL and GH secretions in response to a submaximal dose of ghrelin during different menstrual phases in adult healthy women. Materials and Methods: Eight female subjects with normal cyclicity were enrolled. These subjects were either in the early follicular (EF), late follicular (LF), or mid-luteal (ML) phase of their cycles. Each subject received an IV dose of normal saline (2 mL each time) during the first cycle after enrollment, followed by an IV dose of ghrelin (0.30 μg/kg bw) in the second cycle. The blood samples were collected before and after the IV dosage at -15, 0, 15, 30, 45, 60, 75, 90 and 120 min, where 0 min denotes the time of IV dosage. Results: All the enrolled subjects experienced ovulatory cycles as assessed by increased serum progesterone levels. Serum estradiol levels were significantly higher in the LF than in the EF (p < 0.001) and ML phases (p < 0.01); these levels were also significantly higher in the ML than in the EF phase (p < 0.01). The administration of saline did not affect serum GH or PRL levels. Following the administration of ghrelin, plasma ghrelin levels and serum GH levels increased significantly (p < 0.001). The response amplitude of GH was similar in the three stages of cycle 2. In contrast to GH, the ghrelin injection induced a significant increase in serum PRL levels only in the LF phase (p < 0.05). Conclusions: These results show, for the first time, a different pattern of PRL and GH in response to a submaximal dose of ghrelin during the normal menstrual cycle. It is suggested that the ghrelin threshold for pituitary lactotrophs is higher than for somatotrophs and that, unlike GH, ghrelin-stimulated PRL secretion can be influenced by ovarian steroids.

Toxic and histopathological effects induced by exposure to the pesticide dicamba in carp Cyprinus carpio L.

This study investigated the effects of dicamba (DIC), a widely used auxinic pesticide in agriculture, on carp fish as an experimental model, especially examining serum adrenocorticotropic hormone (ACTH), cortisol (CORT), growth hormone (GH), and insulin-like growth factor-1 (IGF-1) levels. Additionally, it analyzed serum tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6) levels, as well as histopathological changes in gill and liver tissues. Fish were exposed to varying doses (1.35 and 13.5ppm) and durations (4 and 30days). Sixty fish were randomly assigned to six groups (10 fish/group) and exposed to the specified DIC concentrations and durations. Following exposure, stress, growth, and immune parameters were assessed, along with pathological changes. Analyses revealed dose-dependent increases in ACTH, CORT, and TNF-α levels in both exposure periods compared to controls. Conversely, decreases in GH, IGF-1, IL-1β, and IL-6 levels were observed. A significant difference (p < 0.05) was noted in the changes of ACTH, CORT, TNF-α, GH, IGF-1, IL-1β, and IL-6 levels between the exposure periods in the subchronic phase for both dose groups. Histopathological examination identified significant alterations in gill and liver tissues across all dose groups. Gill pathology included epithelial separation (aneurysm), shortening and fusion of secondary lamellae, clubbing, reduced interlamellar space, and cartilage tissue damage. Liver histopathology showed hepatocellular degeneration, passive hyperemia, mononuclear cell infiltration, and hepatocyte vacuolization. In conclusion, dicamba exposure induced significant stress, growth, immune, and histopathological changes in carp, highlighting its potential harmful effects on aquatic organisms, especially at higher concentrations and prolonged exposure durations.

Regulatory Effects of Copper on Ghrelin Secretion in Rat Fundic Glands.

Copper (Cu) is an effective additive in feed for promoting growth. Growth dan axis comprising growth hormone (GH), somatostatin (SS) and GH-releasing hormone (GHRH), with ghrelin regulating their release. The growth-promoting effects of Cu are closely related to ghrelin, but the specific mechanism behind the relationship remains unknown. We investigated the adjustment of ghrelin synthesis and secretion by Cu. Sprague-Dawley rats were fed basal diets with an addition of 0, 120 or 240 mg/kg Cu sulfate for 28 day to establish a growth-promoting model. Signalling molecules relevant to ghrelin synthesis and secretion were detected and mechanistically explored using enzyme-linked immunosorbent assay, quantitative reverse-transcription polymerase chain reaction and Western blot analysis. The 120 mg/kg supplement improved growth performance; significantly increased the serum levels of ghrelin, ghrelin O-acyltransferase (GOAT), acylated ghrelin (AG), GH, and reactive oxygen species (ROS) and decreased those of SS; significantly increased the mRNA and protein expression of ghrelin, GOAT, ghrelin receptor (GHS-R1α), and activator protein 1 (AP-1); increased the phosphorylation ratio of JNK and p38 MAPK; and inhibited the mRNA and protein expression of SS and SS receptor subtype 2 (SSTR2) in gastric fundic gland tissues. Thus, Cu may affect gastric ghrelin synthesis at the transcriptional level by activating the JNK/p38 MAPK pathway through increased ROS levels and regulating the activation of the downstream redox-sensitive transcription factor AP-1. SS plays a crucial determinant role in ghrelin regulation via intragastric Cu. Cu promotes GOAT activity and ghrelin secretion by inhibiting SS secretion, affecting AG levels, and promoting ghrelin acylation through ghrelin/GOAT/GHS-R1α system, modulating ghrelin secretion.

The effects of laparoscopic sleeve gastrectomy on serum levels of growth hormone and insulin-like growth factor 1

Background. It is unclear exactly how bariatric surgery affects the body’s metabolic and physiological functions. The purpose of the study was to assess the activity of growth hormone (GH) and insulin-like growth factor 1 (IGF-1) levels in obese individuals before and six months after laparoscopic sleeve gastrectomy. Materials and methods. This study included 52 patients with a body mass index (BMI) ranging from 35 to 56 kg/m2 who qualified for laparoscopic sleeve gastrectomy and had completed data at the 6-month postoperative follow-up. All patients were clinically examined by a team of surgeons and a physician before operation. The serum levels of GH and IGF-1 were assessed pre- and post-operatively. Results. The study included 52 patients with obesity who were undergoing laparoscopic gastric sleeve surgery. Their mean age was 32.04 ± 6.90 years. More than half of the patients, 27 (51.9 %), were aged 19 to 32 years, 32 (61.5 %) patients were females, and 38 (73.1 %) had a BMI of 35–49.9 kg/m2. There was a significant increase in the serum GH after the sleeve gastrectomy compared to the pre-operative level (0.95 ± 0.30 vs 0.62 ± 0.40 ng/ml, p = 0.0001). IGF-1 also significantly increased after the surgery: 117.13 ± 32.40 vs 102.63 ± 33.90 ng/ml (p = 0.0001). Concerning BMI, there was no significant difference in the GH mean for patients with a BMI of 35–49.9 and 50–56 kg/m2 pre- and post-operatively: 0.6 vs 0.8 (p = 0.07) and 0.9 vs 1 (p = 0.5), respectively. On the other hand, IGF-1 exhibited a significant difference before and after surgery: 107.7 vs 88.9 ng/ml (p = 0.02) and 123.2 vs 100.7 (p = 0.03). Conclusions. This study concludes that sleeve gastrectomy significantly increases the serum level of both GH and IGF-1 and, consequently, their effects on disturbed lipid and protein metabolism in morbidly obese patients.

7394 Testicular Function in Young Adults with Growth Hormone (GH) Deficiency Previously Treated with GH: Comparison with Normal Controls

Abstract Disclosure: R. Cannarella: None. A. Crafa: None. S. Sapienza: None. M.M. Caruso: None. A.E. Calogero: None. Background: We have previously reported that treatment with recombinant human growth hormone (rhGH) can influence testicular growth and puberty onset in children with GH deficiency (GHD), and suggested GH as a determinant of testicular growth in childhood (doi: 10.3389/fendo.2021.619895). Limited evidence is available on testicular function in post-pubertal GHD patients. Objective: This prospective controlled study was undertaken to evaluate testicular function in young GHD adults previously undergone to GH treatment. Patients and Methods: Post-pubertal patients with non-syndromic GHD (&amp;gt;18 years), in whom GH therapy was discontinued after reaching the therapeutic goal, were required to have a complete evaluation of testicular function. Those who agreed were enrolled in our study. Age-matched healthy men older than 18 years served as controls. Exclusion criteria were: the presence of varicocele, urogenital infections, cryptorchidism, hypospadias, hypogonadism, testicular trauma or torsion, and other congenital or acquired disorders capable of interfering with testicular function. The study outcomes were: serum gonadotropins and total testosterone (TT), conventional sperm parameters, and testicular volume (TV) measured by ultrasound examination. Between-group analysis was performed using the Student’s t-test for independent samples or the Mann-Whitney test, for normally or non-normally distributed variables, respectively. Data were reported as mean±standard deviation for non-skewed data and median (interquartile range) for skewed data. Results: 26 patients with GHD and 25 age-matched controls (18.8±3.3 years vs. 20.1±3.6 years; p=0.18) were enrolled. Patients and controls did not differ for serum luteinizing hormone [2.6 (1.5-4.9) IU/L vs. 3.5 (2.8-4.8) IU/L); p=0.2], follicle-stimulating hormone [3.4 (2.2-4.3) IU/L vs. 3.1 (2.3-4.3) IU/L); p=1.0], and TT [5.7 (4.7-6.8) ng/dL vs. 6.0 (5.1-7.4) ng/dL); p=0.4] levels. At semen analysis, GHD patients had lower semen volume (2.1±1.4 mL vs. 3.5±1.5 mL; p=0.002), total sperm count [135.0 miL/ejaculate (54.3-229.0) vs. 231.3 miL/ejaculate (124.8-285.0); p=0.03], progressive motility [25.5% (15.0-34.0%) vs. 32.0% (30.0-36.5); p=0.02], and total motility [56.0% (49.0-62.0) vs. 66.5% (62.5-70.0); p=0.0001] compared to controls. No difference was found in sperm concentration [73.0 miL/mL (45.0-92.0) vs. 68.0 miL/mL (39.0-90.0); p=1.0] and normal morphology [8.5% (7.0-12.0) % vs. 10.0% (7.5-14.0); p=0.3]. Importantly, GHD patients had lower right (13.3±3.4 mL vs. 16.9±4.1 mL; p=0.001) and left (12.5±3.4 mL vs. 16.3±3.8 mL; p=0.0005) TV. Conclusion: This study provides the first evidence of lower TV and slightly worse semen parameters in patients with GHD compared to healthy controls. Serum GH levels during growth may be important for achieving normal testicular volume and spermatogenesis in adulthood. Presentation: 6/2/2024

9277 Testicular Function in Young Adults with Growth Hormone (GH) Deficiency Previously Treated with GH: Comparison with Normal Controls

Abstract Disclosure: R. Cannarella: None. A. Crafa: None. S. Sapienza: None. M.M. Caruso: None. A.E. Calogero: None. Background: We have previously reported that treatment with recombinant human growth hormone (rhGH) can influence testicular growth and puberty onset in children with GH deficiency (GHD), and suggested GH as a determinant of testicular growth in childhood (doi: 10.3389/fendo.2021.619895). Limited evidence is available on testicular function in post-pubertal GHD patients. Objective: This prospective controlled study was undertaken to evaluate testicular function in young GHD adults previously undergone to GH treatment. Patients and Methods: Post-pubertal patients with non-syndromic GHD (&amp;gt;18 years), in whom GH therapy was discontinued after reaching the therapeutic goal, were required to have a complete evaluation of testicular function. Those who agreed were enrolled in our study. Age-matched healthy men older than 18 years served as controls. Exclusion criteria were: the presence of varicocele, urogenital infections, cryptorchidism, hypospadias, hypogonadism, testicular trauma or torsion, and other congenital or acquired disorders capable of interfering with testicular function. The study outcomes were: serum gonadotropins and total testosterone (TT), conventional sperm parameters, and testicular volume (TV) measured by ultrasound examination. Between-group analysis was performed using the Student’s t-test for independent samples or the Mann-Whitney test, for normally or non-normally distributed variables, respectively. Data were reported as mean±standard deviation for non-skewed data and median (interquartile range) for skewed data. Results: 26 patients with GHD and 25 age-matched controls (18.8±3.3 years vs. 20.1±3.6 years; p=0.18) were enrolled. Patients and controls did not differ for serum luteinizing hormone [2.6 (1.5-4.9) IU/L vs. 3.5 (2.8-4.8) IU/L); p=0.2], follicle-stimulating hormone [3.4 (2.2-4.3) IU/L vs. 3.1 (2.3-4.3) IU/L); p=1.0], and TT [5.7 (4.7-6.8) ng/dL vs. 6.0 (5.1-7.4) ng/dL); p=0.4] levels. At semen analysis, GHD patients had lower semen volume (2.1±1.4 mL vs. 3.5±1.5 mL; p=0.002), total sperm count [135.0 miL/ejaculate (54.3-229.0) vs. 231.3 miL/ejaculate (124.8-285.0); p=0.03], progressive motility [25.5% (15.0-34.0%) vs. 32.0% (30.0-36.5); p=0.02], and total motility [56.0% (49.0-62.0) vs. 66.5% (62.5-70.0); p=0.0001] compared to controls. No difference was found in sperm concentration [73.0 miL/mL (45.0-92.0) vs. 68.0 miL/mL (39.0-90.0); p=1.0] and normal morphology [8.5% (7.0-12.0) % vs. 10.0% (7.5-14.0); p=0.3]. Importantly, GHD patients had lower right (13.3±3.4 mL vs. 16.9±4.1 mL; p=0.001) and left (12.5±3.4 mL vs. 16.3±3.8 mL; p=0.0005) TV. Conclusion: This study provides the first evidence of lower TV and slightly worse semen parameters in patients with GHD compared to healthy controls. Serum GH levels during growth may be important for achieving normal testicular volume and spermatogenesis in adulthood. Presentation: 6/2/2024

8686 scRNA-seq of pituitary from letrozole-induced PCOS mouse model reveals abnormal prolactin secretion

Abstract Disclosure: G. De Robles: None. N. Ujagar: None. Z. Del Mundo: None. D. Nicholas: None. Polycystic ovary syndrome (PCOS) has a complex pathophysiology and is the most common endocrine disorder among reproductive-aged women. Ovarian hormonal dynamics are regulated via the secretion of the gonadotropin-releasing hormone (GnRH), which stimulates the release of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) from the anterior pituitary gland. High serum levels of LH in PCOS patients indicate an increase in GnRH levels, but the mechanisms within the anterior pituitary at a cellular level are unclear. We performed single-cell mRNA sequencing (scRNA-seq) on the pituitaries of the letrozole-induced (LET) mouse model of PCOS to profile the functional genomics of endocrine cell populations relative to serum hormone levels. The population percentage of lactotropes significantly decreased; in contrast, two gonadotrope populations significantly increased in the LET mice compared to the placebo-treated mice. Consistent with these changes, an increasing trend of serum LH levels and a decreasing trend of serum prolactin (PRL) levels were observed in the LET mice, while no change occurred in serum growth hormone levels. A gene set enrichment analysis (GSEA) on the differentially expressed genes (DEGs) from the lactotropes revealed an association with negative regulation of protein kinase activity. These DEGs included Hspb1, Park7, Pcp4, and Ppia, which all share the function of mediating stress-induced apoptosis. A GSEA on the DEGs between the two gonadotrope clusters in the LET mice also confirmed a variation in biological pathways linked to ribosomal subunits, transcription regulation, and the regulation of steroid metabolic processes. Based on the scRNA-seq results of the anterior pituitaries of LET mice, alterations in the proportions of hormone-secreting cells may be a response to hyperandrogenism, in which functionally diverse gonadotropes could contribute to heterogeneity in reproductive phenotypes. Changes in the lactotrope population and PRL serum levels also support further research on the lactation hormone and its role in PCOS. PRL is involved in metabolic homeostasis and reproduction, and understanding its dysregulations may provide additional insight into the pathophysiology of PCOS. Presentation: 6/3/2024

6509 IGF-1 receptor and insulin receptor in LepRb neurons coordinates body growth, reproduction, and metabolism

Abstract Disclosure: M. Wang: None. J.W. Hill: None. Growth and reproduction are tightly linked. Growth hormone (GH) deficiency results in a profound suppression of postnatal growth accompanied by severely delayed puberty and reproductive senescence, while GH excess is correlated with the reverse. The specific mechanism underlying this delay is undefined. Although leptin receptor (LepRb)-expressing neurons are known to link body growth and reproduction, the role of insulin-like growth factor 1 receptor (IGF1R) signaling in LepRb neuron function is unknown. Previous studies have shown that IGF-1 and insulin can bind to each other’s receptor, permitting IGF-1 signaling in the absence of IGF1R. Therefore, we created mice lacking IGF1R exclusively in LepRb neurons (IGF1RLepRb mice) and mice simultaneously lacking IGF1R and IR in LepRb neurons (IGF1R/IRLepRb mice) to test if IGF1R and insulin receptor (IR) cooperatively regulate metabolic and reproductive functions. IGF1RLepRb and IGF1R/IRLepRb mice displayed delayed onset of puberty and impaired fertility in both sexes, which suggested that both IGF1R and IR in LepRb neurons are required for normal reproduction. Additionally, we found transient growth retardation in IGF1RLepRb and IGF1R/IRLepRb mice. Loss of IGF1R in LepRb neurons led to lower serum IGF-1 and GH levels in male mice and impaired trabecular and cortical bone development in mice of both sexes. Only transient and mild changes were noticed in the body weight. However, we found IGF1R and IR in LepRb neurons jointly regulate body mass composition, energy homeostasis and glucose homeostasis, as shown by elevated fat mass composition, low energy expenditure and low physical activity in IGF1R/IRLepRb mice. Taken together, these studies identify the unique and cooperative role of LepRb IGF1R and IRs in the regulation of body growth, reproduction, and metabolism. Presentation: 6/3/2024

8386 The Evolving Face of The Great Masquerader - Panhypopituitarism Associated with Neurosyphilis

Abstract Disclosure: M. Yabe: None. Z. Lin: None. F. Joseph: None. G. Philip: None. R. Silver: None. L. Callejas: None. J. Giunta: None. Untreated syphilis is on the rise in the United States. The CDC reported syphilis cases in newborns have increased 10-fold over a decade in November 2023, signifying the emergence of untreated infections. Pituitary involvement in syphilis is a very rare phenomenon, and endocrinological investigation is often overlooked. This will be the second reported case of neurosyphilis with pituitary involvement in a non-HIV infected patient. A 45-year-old female with no significant past medical history was admitted to the hospital with progressive neurological symptoms of intermittent left-side headache, hearing loss with tinnitus, and gait instability. Postcontrast MRI Brain revealed multifocal leptomeningeal enhancement involving supratentorial and infratentorial regions. Thickening of the enhanced pituitary infundibulum was also noted. Subsequent RPR titer showed 1:16 and lumbar puncture revealed CSF-VDRL titer 1:32, with pleocytosis 83 cells/uL, CSF-glucose 19 mg/dL, and CSF-protein 370 mg/dL. The patient completed Penicillin G 4 million/units intravenous every 4 hours for 14 days, with repeat MRI showing significant interval decrease in previously described extensive supratentorial and infratentorial leptomeningeal enhancement. However, there is no record of her sexual partner receiving treatment. The patient was readmitted one year later after a fall while displaying dysmetria. MRI Brain with contrast revealed a small subacute infarct along the right frontal corona radiata and pituitary gland measuring up to 1.2 cm in craniocaudal dimension compared to 0.4 cm on the prior exam. This prompted evaluation of pituitary hormones: FSH 0.8 IU/L, LH &amp;lt;0.3 IU/L, and ACTH 6.3 pg/mL, with normal serum growth hormone and prolactin levels. Further investigation revealed morning cortisol 2.5 ug/dL, thyrotropin &amp;lt; 0.2 uIU/mL, and free thyroxine 0.63 ng/dL. Radiological evidence is suspicious of inflammatory etiology of the pituitary gland. The patient was discharged with endocrinology follow-up and plan to perform a pituitary gland biopsy as an outpatient for confirmatory result. The association of neurosyphilis and hypophysitis leading to panhypopituitarism in a non-HIV infected patient was first reported in 2015. Since then, there remains limited research regarding their association due to rarity of pituitary involvement in neurosyphilis. With untreated syphilis on the rise and increased availability of MRI, clinicians should expect to encounter more cases of neurosyphilis with pituitary involvement in the future. Early detection of panhypopituitarism in those with positive CSF-VDRL titer could lead to better clinical outcomes. It is paramount that these cases are documented to emphasize pituitary involvement in neurosyphilis and encourage a low threshold to initiate endocrinological testing in the future. Presentation: 6/3/2024

8649 Ablation of Leptin Receptors in Somatotropes Impacts Transcriptomic Plasticity in the Pou1f1 Lineage of Female Pituitary Cells

Abstract Disclosure: T.K. Miles: None. A.K. Odle: None. S. Byrum: None. A. Lagasse: None. A. Haney: None. V.G. Ortega: None. A. Herdman: None. M.C. MacNicol: None. A.M. MacNicol: None. G.V. Childs: None. Anterior pituitary somatotropes produce growth hormone (GH) to optimize body composition, receiving tropic signals from leptin about the metabolic state. When leptin receptors are ablated in somatotropes, GH proteins, serum GH and GHRH receptors are reduced. Unexpectedly, POU1F1, Prolactin, and TSH-beta proteins are also reduced in pituitaries of Somatotrope LEPR-null females (mutants), suggesting a tropic role for leptin in differentiation. To test this hypothesis, single cell RNA-seq analysis compared the pituitary transcriptome of 6-month-old control and mutant female mice housed under thermoneutral conditions (28°C). Following scRNA-seq, cells were clustered computationally with the use of Seurat; all cell types were identified in separate UMAP clusters. Mutants showed increases in cell numbers in somatotrope (4.7X) and Pou1f1 (5.7x) clusters, but no change in thyrotrope or lactotrope clusters. In LEPR-null female somatotropes, the 516 differentially expressed genes (DEGs; adj p&amp;lt;0.05) included upregulated Pomc, Prl, Lhb, Tshb and Cga (Log2FC+0.5-1.7) and downregulated Pou1f1, Ghrhr, and Gh (Log2FC -0.5—1.5). In the lactotrope cluster from mutants, Pomc, Cga, and Gh were upregulated (Log2FC+1.1-1.5) and Pou1f1 and Prl were downregulated. The thyrotrope cluster was unchanged. Prl, Pomc, and Gh were upregulated in the Pou1f1 cluster. The down regulation of Gh, Pou1f1, and Ghrhr in somatotropes and Prl in lactotropes correlates with the lower serum levels of GH and Prl in mutant females. However, the upregulated DEGs do not correlate with increased secretory activity suggesting that the multihormonal cells are not fully functional. This was confirmed with Ingenuity Pathway Analysis (IPA) showing downregulation of canonical pathways involved in secretion in mutant somatotropes. Unexpectedly, mutant females exposed to a HFD (60% fat) for 16 weeks (+16.6g) showed a reversal of the changes in somatotrope cell numbers and multihormonal expression seen in control fed mutants. The increase in genes belonging to IPA canonical cytoplasmic translation pathways in mutant somatotropes were also completely reversed following a HFD. Furthermore, the downregulated secretory/signaling pathways seen in control fed mutant female somatotropes and lactotropes (endocytosis, vesicle transport, Gaq, GnRH) were upregulated modestly following a HFD. The high serum leptin in the HFD fed mutant mice may activate signaling pathways in cells still expressing LEPR. Collectively, these results confirm a role for leptin in maintaining differentiated somatotropes. They also suggest that leptin may limit expansion of multihormonal progenitor cells. The decreased multihormonal expression and protein synthesis in lactotrope clusters from mutant mice exposed to a HFD are also seen in lactotropes from control mice on a HFD, which suggests that a HFD may compromise pituitary plasticity. Presentation: 6/3/2024

Secondary diabetes mellitus in acromegaly: Case report and literature review.

Acromegaly, predominantly resulting from a pituitary adenoma, is marked by excessive secretion of growth hormone (GH) and insulin-like growth factor-1 (IGF-1). However, normalization of blood glucose levels posttreatment is rarely achieved. This case study aims to highlight the diagnostic challenges posed by overlapping symptoms of acromegaly and diabetes, emphasizing the importance of precise diagnosis and effective treatment strategies for optimal patient outcomes. A 22-year-old male was hospitalized for diabetic ketoacidosis and exhibited classic signs of acromegaly, such as enlarged hands and feet, and distinct facial changes. The patient's diagnosis of acromegaly, attributed to a pituitary adenoma, was confirmed through clinical observations, laboratory findings (notably raised serum GH and IGF-1 levels, and absence of GH suppression after glucose load during an OGTT), and pituitary MRI scans. The patient underwent 2 surgical tumor resections followed by gamma knife radiosurgery (GKRS). After treatment, GH, IGF-1, and blood glucose levels normalized without further need for hypoglycemic intervention. Posttreatment, the patient achieved stable GH, IGF-1, and blood glucose levels. The hyperglycemia was attributed to the GH-secreting tumor, and its resolution followed the tumor's removal. This case emphasizes the need for comprehensive assessment in patients with acromegaly to address coexisting diabetic complications. Surgical and radiotherapeutic management of acromegaly can lead to significant metabolic improvements, highlighting the importance of interdisciplinary care in managing these complex cases.

Spexin level in growth hormone deficiency Iraqi children

Spexin (SPX) is a newly discovered brain adipokine implicated in various homeostatic functions including metabolism, energy balance, endocrine processes and growth hormone (GH) production in particular. At the same time, the growth-promoting effects of GH are influenced by Insulin-like growth factor-1 (IGF‑1) and vitamin D3. The aim of this study was to investigate the possible involvement of SPX in growth hormone deficiency (GHD) in children. The research involved 90 children (40 with growth hormone deficiency and 50 healthy controls aged 5-14). Serum levels of GH, IGF and vitamin D3 were tested using a chemiluminescent immunoassay, that of SPX – by Elabscience ELISA Kit. The results revealed that children with GHD had significantly higher SPX levels compared to the control group. No significant difference in IGF-1 and vitamin D3 levels between patients and control groups was observed. In the GHD group, we found a significant negative correlation between SPX and GH levels; at the same time, there was no correlation between SPX and D3 levels. These findings suggest that the changes in SPX levels may contribute to growth hormone deficiency. Keywords: growth hormone deficiency, IGf-1, Iraqi children, spexin, vitamin D3

Effects of GH L127V and TG5 C422T polymorphisms on the hormonal profile, slaughter traits, and meat quality of Hereford bulls.

The creation of objective methods for the evaluation and improvement of quantitative and qualitative indicators of meat productivity in farm animals should be based on a comprehensive analysis of the genetic, physiological, and biochemical parameters of the animal. This study aimed to investigate the effects of growth hormone (GH) and thyroglobulin (TG5) gene polymorphisms on the hormonal status, slaughter traits, and chemical, amino acid, and fatty acid composition of meat in Hereford bulls. Hereford bulls (n = 9) were reared under the same feeding and housing conditions until the age of 21 months, after which they were slaughtered. Polymerase chain reaction-restriction fragment length polymorphism was performed for genotyping GH L127V and TG5 C422T polymorphisms. The experimental animals were evaluated to determine slaughter traits (including pre-slaughter weight, carcass, and internal fat weight and yield), chemical, fatty acid, and amino acid composition of ground beef, and hormonal status using serum concentrations of GH, triiodothyronine, and thyroxine. Animals with the valine homozygous (VV) genotype of GH had the maximum serum GH level of 9.33 mIU/mL (p = 0.10) higher than leucine homozygous (LL) genotype carriers. Individuals with the LL genotype outperformed V-allele carriers in serum thyroxine (T4) concentration by 21.3-30.5 nmol/L (16.15%-24.86%; p < 0.01-0.05). Genetic differentiation induced by TG5 C422T polymorphism was determined to a lesser extent by the hormonal status of the Hereford animals. The V-allele was associated with increased carcass weight, with VV homozygotes significantly outperforming LL individuals by 45.0 kg (13.61%; p < 0.05). The T allele at the TG5 gene polymorphism was associated with more intense lipogenesis and less protein synthesis in muscle tissue and these effects were enhanced in the homozygous state. Young animals with the TT variant of the TG5 gene exhibited a significantly superior polyunsaturated fatty acid/saturated fatty acid ratio of 0.012 units (p < 0.01). Carriers of the LL genotype were characterized by minimum amino acid content in muscle tissue. Heterozygous bulls exceeded LL homozygotes in the sum of essential amino acids by 3.09% (p = 0.10) and non-essential amino acids by 1.9% (p < 0.05). The development of breeding programs for the Hereford breed should be carried out considering genetic features that determine the formation of economic traits in animals. Analysis of polymorphisms in the TG5 gene is a promising method for the early diagnosis of the fatty acid composition of beef. Identification of polymorphisms in the GH gene allows the prediction of higher productivity potential and amino acid composition of meat. The different effects of the GH and TG5 genes on the development of various economic traits allowed us to determine further vectors for scientific research on their complex associations in Hereford cattle, which will be useful for planning effective breeding schemes.

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.

A review of complex hormone regulation in thyroid cancer: novel insights beyond the hypothalamus-pituitary-thyroid axis.

Like the ovaries and prostate, the thyroid exhibits characteristic hormone secretion and regulation. Thyroid cancer (TC), especially differentiated thyroid carcinoma, has typical sex-specific and age-specific hormone-driven clinical features. Previous research has primarily focused on the effects of thyroid stimulating hormone, thyroid hormones, and estrogens on the onset and progression of TC, while the roles of growth hormone (GH), androgens, and glucocorticoids have largely been overlooked. Similarly, few studies have investigated the interactions between hormones and hormone systems. In fact, numerous studies of patients with acromegaly have shown that serum levels of GH and insulin-like growth factor-1 (IGF-1) may be associated with the onset and progression of TC, although the influences of age, sex, and other risk factors, such as obesity and stress, remain unclear. Sex hormones, the GH/IGF axis, and glucocorticoids are likely involved in the onset and progression of TC by regulating the tumor microenvironment and metabolism. The aim of this review was to clarify the roles of hormones and hormone systems in TC, especially papillary thyroid carcinoma, as references for further investigations.

Effect of Adenotonsillectomy on Symptomatology and Growth of Children with Obstructive Adenotonsillar Enlargement

Background: Obstructive adenotonsillar enlargement, a common childhood disorder in Ear, Nose and Throat (ENT) practice, is associated with obstructive sleep apnea syndrome (OSAS) and growth failure. Objective: To assess the effect of adenotonsillectomy on symptomatology and somatic and biochemical markers of growth in children with obstructive adenotonsillar enlargement. Setting and design: A prospective interventional and controlled study was conducted among children 2-8 years old with the diagnosis of adenotonsillar enlargement who attended the ENT Clinic of a Teaching Hospital in Nigeria. Methods: The study group consisted of 43 children who underwent adenotonsillectomy, while the control group consisted of 43 age and sex-matched children without features of obstructive adenotonsillar enlargement. The symptomatology score, weight, height, serum growth hormone (GH), and insulin-like growth factor-1 (IGF-1) were measured pre-surgery and six months post-surgery among the study and the control groups. Results: There was a statistically significant difference in symptomatology scores among the study group six months post-surgery (p &lt;0.001). The weight, height, and serum levels of GH and IGF-1 significantly increased in the study group six months after the surgery. Conclusion: Adenotonsillectomy positively affects the symptomatology, somatic growth and biochemical markers of growth in children with obstructive adenotonsillar enlargement.

Growth hormone increase by luteinizing hormone-releasing hormone reflects gonadotroph-related characteristics in acromegaly

PurposeWe previously showed the clinical characteristics of acromegaly with a paradoxical growth hormone (GH) response to oral glucose or thyrotropin-releasing hormone. However, the clinical characteristics of acromegaly with an increased GH response to luteinizing hormone-releasing hormone (LHRH responders) remain unclear. The aim of the present study was to evaluate the clinical characteristics, especially gonadotroph-related characteristics of LHRH responders in acromegaly.MethodsThe clinical characteristics of 33 LHRH responders and 81 LHRH nonresponders were compared.ResultsNo differences in age, sex or basal serum levels of GH, insulin-like growth factor-1 (IGF-1), and gonadotropin were observed between the two groups. Steroidogenic factor 1 (SF-1), gonadotropin-releasing hormone receptor (GnRHR), and LH expression was more frequently observed in LHRH responders (P < 0.05). In addition, a greater increased rate of GH after LHRH loading, and the proportion of GnRHR and gonadotropin expression was observed in pituitary tumor with SF-1 expression than that without the expression (P < 0.01). LHRH responders showed a greater GH decrease in the octreotide test and a greater IGF-1 decrease after first-generation somatostatin ligand than LHRH nonresponders (P < 0.05). Furthermore, the proportion of hypointense pituitary tumors on T2-weighted magnetic resonance imaging and tumors with densely granulated type was higher in LHRH responders than in LHRH nonresponders, respectively (P < 0.05). No difference between the two groups was observed in either somatostatin receptor 2 or 5 expression.ConclusionsThe increased GH response to LHRH is associated with the gonadotroph-related characteristics. This response may reflect the biological characteristics of somatotroph tumors.

Effects of Fermented Navel Orange Pulp on Growth Performance, Carcass Characteristics, Meat Quality, Meat Nutritional Value, and Serum Biochemical Indicators of Finishing Tibetan Pigs.

In order to cope with the limited supply of feed for global animal production, there is a pressing need to explore alternative feed resources. Orange pulp, a by-product of agriculture and industry, has shown potential to positively or neutrally impact pig productive performance when included in their diet. However, there is a lack of research on the effects of fermented navel orange pulp (FNOP) on pig growth and productive performance. This study aimed to investigate the effects of FNOP as a dry matter substitute on pig's growth performance, carcass characteristics, meat quality, meat nutritional value, and serum biochemical indicators. The experiment involved 128 finishing Tibetan pigs, divided into four feed treatment groups, with varying levels (0%, 5%, 10% and 15%) of FNOP replacing dry matter in the basal diet. The results indicate that substituting 5% to 15% FNOP had no adverse effects on pig growth performance. However, at a 15% substitution rate, there was a decrease in serum growth hormone and IGF-1 levels, along with an increase in the feed-to-gain ratio. A 10% FNOP replacement notably increased the loin-eye muscle area of pigs. Additionally, 5% and 10% FNOP substitutions reduced the drip loss of pork. The study also found that substituting 5% to 15% FNOP increased unsaturated fatty acids and umami nucleotide contents in pork and raised serum total protein and uric acid (nucleotide-metabolism-related product) levels. These findings suggest that moderate FNOP substitution might improve meat quality, nutritional value, and maintain growth and productive performance in Tibetan pigs by improving protein synthesis and nucleotide metabolism, while also reducing feed costs. The optimal substitution ratio identified was 10%.