Growth Hormone Secretion Research Articles

P-50 Plurihormonal cystic pituitary adenoma: Case report

Abstract Introduction Pituitary adenomas account for 10-15% of all intracranial neoplasms. Around 1/3 of cases are cystic pituitary adenomas presented by non-staining tumors, usually being prolactinomas and rarely – somatotropinomas. Combined prolactin and growth hormone-secreting adenomas are uncommon and clinical diagnosis can be deferred due to symptoms specific for only one of the excess secreted hormones. Clinical Case A 47-years-old woman was referred to our clinic in November 2022, her only complaint being headaches in the occipital region that persisted for the last 7 years. The patient had a history of taking various SSRI/SNRI antidepressants and benzodiazepines continuously for the same period of time (7 years). She presented outpatient prolactin test results from August 2022 showing a level of 3180 µUI/ml [N 17-637 µUI/ml], 10 fold dilution - 2947 µUI/ml and a pituitary scan that revealed a 13.3×9.6×11.1 mm tumor with a cystic component, invading the suprasellar cistern and the left cavernous sinus. Anamnesis determined that she had two children, a regular menstrual cycle and no heredocolateral antecedents. Clinical examination revealed milky white breast discharge and mild changes in the face, hands, and feet structure that were suggestive of acromegaly. Before admission the patient was started on 0.5 mg cabergoline weekly. On admission, prolactin levels were still elevated, and the cabergoline dose was increased. Of all the pituitary axes the only out-of-range value was IGF-1 – which was elevated to 53.1 nmol/l [N 10.3-28.57]. The patient refused surgery for the moment, and no pharmacological treatment options were available in the country. The patient was lost to follow up and had returned in August 2023 with complaints of general fatigue and malaise. History revealed that in May 2023 she suffered from severe headaches and was admitted to the neurosurgery department of a local hospital, where she underwent transsphenoidal surgery for the pituitary adenoma. The histology showed chromophobe adenoma tissue, no follow-up immunohistology was done. After the surgery, cabergoline was stopped. During our exploration of the pituitary function – there were no deficits or excesses registered. Considering that co-secreting pituitary adenomas are common for MEN syndromes, she was tested for presence of thyroid, parathyroid, adrenal tumors, but no imagistic or laboratory findings were detected. Conclusion In the light of global increased use of antidepressant and anxiety relieving medication, this clinical case underlines the importance of a thorough assessment in these patients, before and during treatment. Additionally, prolactin and growth hormone co-secreting pituitary adenomas often have a silent clinical presentation and may be challenging in diagnosis. A multimodal management is necessary as plurihormonal adenomas require both control of hormone excess and tumor growth.

Assessment of adenohypophysis function and ghrelin level in children with biologically inactive growth hormone syndrome

Background. Mutations in the growth hormone (GH) gene cause various forms of biologically inactive growth hormone (BIGH) syndrome. Ghrelin potentiates the secretion of GH. Ade­nohypophysis hormones take part in human growth mechanisms. Insulin-like growth factor 1 (IGF-1) level is a criterion of GH activity. The purpose of the study was to assess the adenohypo­physis functions and to determine the role of ghrelin in patients with BIGH syndrome to optimize the diagnosis and treatment. Materials and methods. Anthropometric parameters were evalua­ted in 158 children with BIGH syndrome whose average age was 7.83 ± 1.23 years. The function of the adenohypophysis was evalua­ted accor­ding to the levels of somatotropin, thyroid-sti­mulating, adrenocorticotropic, luteinizing, follicle-stimulating hormone and their corresponding peripheral hormones, which were determined by radioimmunological methods and chemiluminescent immunoassay. A statistical analysis of the results was carried out. Results. The release of GH against the background of clonidine and insulin tests in patients with BIGH syndrome was higher than 10 ng/ml, the basal level of IGF-1 was significantly lower than the reference values. After a 4-day test for sensitivity to GH, the level of IGF-1 increased more than 2 times. Against the background of treatment with recombinant GH, serum thyroid-stimulating, adrenocorticotropic hormone, and cortisol indicators changed significantly, but their levels fluctuated within the reference values. Significant changes in ghrelin content were detected 120 minutes after falling asleep. Most children with BIGH syndrome had timely sexual development, precocious puberty was revealed in 19 children, the smallest was the group with delayed puberty (5 children). Gonadotropin-releasing hormone ana­logues were added to the GH treatment in case of unsatisfactory final growth. Conclusions. Normal/high levels of GH and reduced IGF-1 are characteristic of children with BIGH syndrome. In addition, these children have a significant increase in ghrelin in the first hours after falling asleep. The test for sensitivity to GH is a reliable diagnostic method. Thyroid and adrenal disorders were not found in patients with BIGH syndrome. Children with BIGH syndrome have normal sexual development with a tendency to precocious puberty. The simultaneous use of gonadotropin-releasing hormone analogues in combination with GH preparations significantly improves patients’ final growth.

Brain morphometric changes in children born as small for gestational age without catch up growth.

Most infants born as small for gestational age (SGA) demonstrate catch up growth by 2-4 years, but some fail to do so. This failure is associated with several health risks, including neuropsychological development issues. However, data on the morphological characteristics of the brains of infants born as SGA without achieving catch up growth are lacking. This study aims to determine the structural aspects of the brains of children born as SGA without catch up growth. We conducted voxel- and surface-based morphometric analyses of 1.5-T T1-weighted brain images scanned from eight infants born as SGA who could not achieve catch up growth by 3 years and sixteen individuals with idiopathic short stature (ISS) to exclude body size effects. Growth hormone (GH) secretion stimulation tests were used to rule out GH deficiency in all SGA and ISS cases. The magnetic resonance imaging data were assessed using Levene's test for equality of variances and a two-tailed unpaired t-test for equality of means. The Benjamini-Hochberg procedure was used to apply discovery rate correction for multiple comparisons. Morphometric analyses of both t-statical map and surface-based analyses using general linear multiple analysis determined decreased left insula thickness and volume in SGA without catch up growth compared with ISS. The brain scans of patients with SGA who lack catch up growth indicated distinct morphological disparities when compared to those with ISS. The discernible features of brain morphology observed in patients born as SGA without catch up growth may improve understanding of the association of SGA without catch up growth with both intellectual and psychological outcomes.

Nedostatak hormona rasta kod odraslih - dijagnoza i lečenje

Growth hormone deficiency (GHD) in adults is a rare clinical syndrome with an incidence of 1.4-4.2 per 100,000 persons per year and a prevalence of 350/million. It is characterized by unfavorable body composition, reduced muscle, and bone mass, lower capacity to endure physical effort, abnormal lipid profile, increased cardiovascular risk and poor quality of life. Despite these clinical manifestations, GHD is often unrecognized, so its diagnosis is often missed or delayed. The reason is the non-specific and subtle clinical characteristics, which require the testing of growth hormone (GH) secretion with stimulation tests. Two tests are in use, the insulin tolerance test and the glucagon test, which require the experience of the team performing them. Recently, an oral secretagogue of growth hormone - macimorelin has been used, which is simple test to perform and is safe for the patient. Insufficient secretion of GH in adults can be manifested as isolated or in combination with deficits of other pituitary hormones. However, GH is the most frequently detected hormonal deficit in adults as part of hypopituitarism. Causes of GHD can be congenital or acquired. Congenital reasons are the result of disorders of the embryogenic development of the pituitary gland and hypothalamus, and acquired are the most common complications of tumors of the sellar region and head trauma. Patients with GHD have an increased mortality rate compared to the general population. The causes of the shortened life span of these patients depend on the etiology of hypopituitarism, the applied therapy of tumors of the hypothalamus/pituitary region (surgery, radiotherapy), and the replacement of other missing pituitary hormones. During the last two decades, growth hormone therapy in adults has entered routine clinical practice. The beneficial effects of this substitution are reflected in the body composition, skeletal system, metabolic status, and improvement of the quality of life. GH replacement in adults returns the mortality rate to that expected for age in the general population. Due to the known proliferative, angiogenic, and anti-apoptotic properties of GH, there is still some caution regarding the recurrence of hypopituitarism-causing tumors or the appearance of new tumors during GH replacement. However, large and long-term follow-up studies of adults on GH therapy have shown a high safety profile of this treatment. Daily injections of GH were until recently the only way of its application, and now longacting weekly forms have been marketed, which will significantly improve adherence to this therapy.

The New Trends in Physiological and Pathological Actions of Ghrelin (Brain-Heart Axis) on the Heart and Cardiovascular System

Background: Ghrelin increased significantly the Left Ventriculus Eject Fraction and end-systolic volume after 30 minutes of intra-venous injection and without alterations heart rate and blood pressure. Ghrelin was discovered in 1999 as an only one 28 amino acid peptides (with octanoyl serine group) located on the short arm of chromosome 3 (position 3p25-26) having six exons, two are noncoding and four introns and encodes a 511 bp mRNA. Ghrelin is synthesized by the endocrine X/A-like cells located from the gastric fundus mucosa through the whole mucosa of the medium right vertical side of the stomach until to the 1 inch before anatomical pylorus. These cells are responsible to produced 80% of the whole ghrelin produced in the human body. Furthermore, other place of this production occurs at the hypothalamus, the pituitary, second portion of duodenum, pancreas, heart and other tissues. Bibliographic references also demonstrate the importance of ghrelin’s action in the main cardiovascular activities. Related to cardiovascular activities, ghrelin plays multitudinous beneficial and thereby help during cardiovascular diseases. Several studies demonstrated that ghrelin cause an anti-inflammatory activity by the inhibition of proinflammatory cytokines which can diminish inflammatory diseases in the heart, pericardium and specific innervations, for instance, vagus nerve and inhibited sympathetic nerves. Outcomes of this review emphasize these important actions of ghrelin. Methods: A systematic review of ghrelin activities over the heart and cardiovascular system with the inclusion of papers in review involved the physiological and physio pathological activities of ghrelin in vivo and in vitro studies. Results: Ghrelin is a natural tide with the growth hormone secretagogue (GHS) receptor (GHS-R) which cloned in 1996. The processes which generate this peptide and ghrelin-related peptides are transcriptional, translational and posttranslational. Homo and heterodimers of GHS-R and other yet unidentified receptors mediate the biological actions of acyl ghrelin and desacyl ghrelin. However, the main biological functions of ghrelin involve the secretion of growth hormone, stimulation of appetite and food intake at the hypothalamus, modulate acid secretion and motility, endocrine and exocrine pancreas secretion, blockaded insulin activity, heart functions and cardiovascular responses and other. Conclusion: One of the main occurrences in acute heart infarction is an increase activation of cardiac sympathetic nerve activity (CSNA) which is one of the causes of chronic cardiac dysfunction (CCD). Ghrelin is an effective for obtain a better cardiac function and by the suppression of renal sympathetic nerve activity which also have an important benefit to the acute myocardial infarction. Therefore, the physiological effects of ghrelin are very important to the body homeostasis even in the grave heart and cardiovascular diseases and in the immunological system.

Clinical Pharmacology of Oral Octreotide Capsules for the Treatment of Acromegaly.

The primary goal of acromegaly treatment is to normalize biochemical parameters as it significantly reduces the risks of complications and comorbidities associated with the disease. First-line medical treatment is commonly represented by injectable somatostatin analogues (SRLs) after surgery. In June 2020, with the integration of Transient Permeation Enhancer® technology, oral octreotide capsules (OOCs) received regulatory approval from the US Food and Drug Administration for long-term maintenance treatment in patients with acromegaly who have responded to and tolerated treatment with octreotide or lanreotide. We reviewed the clinical pharmacological data on the development and clinical use of OOCs. The pharmacokinetic and pharmacodynamic data on OOCs showed a dose-dependent increase in octreotide levels and remarkable suppression of growth hormone secretion. The efficacy and safety of OOCs were investigated in four clinical trials conducted on patients with complete or partially controlled acromegaly. The trials resulted in the maintenance of biochemical control after switching from injectable SRLs to OOCs, with a comparable side-effect profile. Moreover, the acromegaly symptoms improved in patients on OOC. The data showed a patient preference to continue in the OOC arm for the extension phase of the trials. From the clinical pharmacological perspective, oral formulation of octreotide has the advantage of efficacy and safety with respect to injectable octreotide.

Dorsomedial Ventromedial Hypothalamic Nucleus Growth Hormone-Releasing Hormone Neuron Steroidogenic Factor-1 Gene Targets in Female Rat.

The prospect that the ventromedial hypothalamic nucleus (VMN) transcription factor steroidogenic factor-1/NR5A1 (SF-1) may exert sex-dimorphic control of glucose counterregulation is unresolved. Recent studies in male rats show that SF-1 regulates transcription of co-expressed hypoglycemia-sensitive neurochemicals in dorsomedial VMN growth hormone-releasing hormone (Ghrh) neurons. Gene knockdown and laser-catapult-microdissection/single-cell multiplex qPCR techniques were used here in a female rat model to determine if SF-1 control of Ghrh neuron transmitter marker, energy sensor, and estrogen receptor (ER) variant mRNAs varies according to sex. Data show that in females, hypoglycemia elicits a gain of SF-1 inhibitory control of VMNdm Ghrh neuron Ghrh and Ghrh-receptor gene profiles and loss of augmentation of glutaminase transcription; SF-1 gene silencing diminished eu- and hypoglycemic patterns of neuronal nitric oxide gene transcription. SF-1 imposes divergent control of baseline and hypoglycemic glutamate decarboxylase65 (GAD)-1 (stimulatory) versus GAD2 (inhibitory) mRNAs in that sex. SF-1 stimulates baseline VMNdm Ghrh neuron PRKAA1/AMPKα1 and PRKAA2/AMPKα2 gene expression, yet causes opposite changes in these gene profiles during hypoglycemia. SF-1 exerts glucose-dependent control of ER-alpha and G-protein-coupled ER-1 transcription, but blunts ER-beta gene profiles during eu- and hypoglycemia. In females, SF-1 knockdown did not affect hypercorticosteronemia or hyperglucagonemia, but blunted hypoglycemic suppression of growth hormone secretion. Results show that SF-1 expression is critical for female rat VMNdm Ghrh neuron counterregulatory neurochemical, AMPK catalytic subunit, and ER gene transcription responses to hypoglycemia. Sex differences in direction of SF-1 control of distinctive gene profiles may result in observed disparities in SF-1 regulation of counterregulatory hormone secretion between sexes.

Characterization of the somatostatin system in tilapia: implications for growth and reproduction.

Somatostatin (SST) plays diverse physiological roles in vertebrates, particularly in regulating growth hormone secretion from the pituitary. While the function of SST as a neuromodulator has been studied extensively, its role in fish and mammalian reproduction remains poorly understood. To address this gap, we investigated the involvement of the somatostatin system in the regulation of growth and reproductive hormones in tilapia. RNA sequencing of mature tilapia brain tissue revealed the presence of three SST peptides: SST6, SST3, and low levels of SST1. Four different isoforms of the somatostatin receptor (SSTR) subfamily were also identified in the tilapia genome. Phylogenetic and synteny analysis identified tiSSTR2-like as the root of the tree, forming two mega clades, with SSTR1 and SSTR4 in one and SSTR2a, SSTR3a, and SSTR5b in the other. Interestingly, the tiSSTR-5 isoforms 5x1, 5x2, and 5x3 were encoded in the sstr3b gene and were an artifact of misperception in the nomenclature in the database. RNA-seq of separated pituitary cell populations showed that SSTRs were expressed in gonadotrophs, with sstr3a enriched in luteinizing hormone (LH) cells and sstr3b significantly enriched in follicle-stimulating hormone (FSH) cells. Notably, cyclosomatostatin, an SSTR antagonist, induced cAMP activity in all SSTRs, with SSTR3a displaying the highest response, whereas octreotide, an SSTR agonist, showed a binding profile like that observed in human receptors. Binding site analysis of tiSSTRs from tilapia pituitary cells revealed the presence of canonical binding sites characteristic of peptide-binding class A G-protein-coupled receptors. Based on these findings, we explored the effect of somatostatin on gonadotropin release from the pituitary in vivo. Whereas cyclosomatostatin increased LH and FSH plasma levels at 2h post-injection, octreotide decreased FSH levels after 2h, but the LH levels remained unaffected. Overall, our findings provide important insights into the somatostatin system and its mechanisms of action, indicating a potential role in regulating growth and reproductive hormones. Further studies of the complex interplay between SST, its receptors, and reproductive hormones may advance reproductive control and management in cultured populations.

GNAS mutations suppress cell invasion by activating MEG3 in growth hormone-secreting pituitary adenoma.

Approximately 30%-40% of growth hormone-secreting pituitary adenomas (GHPAs) harbor somatic activating mutations in GNAS (α subunit of stimulatory G protein). Mutations in GNAS are associated with clinical features of smaller and less invasive tumors. However, the role of GNAS mutations in the invasiveness of GHPAs is unclear. GNAS mutations were detected in GHPAs using a standard polymerase chain reaction (PCR) sequencing procedure. The expression of mutation-associated maternally expressed gene 3 (MEG3) was evaluated with RT-qPCR. MEG3 was manipulated in GH3 cells using a lentiviral expression system. Cell invasion ability was measured using a Transwell assay, and epithelial-mesenchymal transition (EMT)-associated proteins were quantified by immunofluorescence and western blotting. Finally, a tumor cell xenograft mouse model was used to verify the effect of MEG3 on tumor growth and invasiveness. The invasiveness of GHPAs was significantly decreased in mice with mutated GNAS compared with that in mice with wild-type GNAS. Consistently, the invasiveness of mutant GNAS-expressing GH3 cells decreased. MEG3 is uniquely expressed at high levels in GHPAs harboring mutated GNAS. Accordingly, MEG3 upregulation inhibited tumor cell invasion, and conversely, MEG3 downregulation increased tumor cell invasion. Mechanistically, GNAS mutations inhibit EMT in GHPAs. MEG3 in mutated GNAS cells prevented cell invasion through the inactivation of the Wnt/β-catenin signaling pathway, which was further validated in vivo. Our data suggest that GNAS mutations may suppress cell invasion in GHPAs by regulating EMT through the activation of the MEG3/Wnt/β-catenin signaling pathway.

Brain Natriuretic Peptide in Patients with Acromegaly: A Comparative Study between those with and without Obstructive Sleep Apnea

Abstract Background: Acromegaly is a rare endocrine disorder; it has an incidence of 4 per million annually and a prevalence of 40 per million. It is due to growth hormone-secreting pituitary adenoma. The objective of our study is to evaluate the levels of brain natriuretic peptide (BNP) in patients with acromegaly with and without obstructive sleep apnea (OSA). Materials and Methods: One hundred five registered patients with acromegaly in the National Diabetes Center-Mustansiriyah University were enrolled in the study. Out of 105 patients with acromegaly, 81 have OSA while the remaining 24 have no OSA. OSA affects 81.8% of males and 72% of females. All recruited patients have given oral consent to participate in the study which was conducted during the period from January to October 2023. Results: Males with OSA had a mean age of 52 years while those without OSA had a mean age of 46 years. Epworth Sleepiness Scale is higher among those with OSA. BNP is found to be higher in females with OSA (905.54 pg/ml) while in males with OSA, it drops down to 878.76 pg/ml. In no OSA group, the BNP level was 355.33 ± 30.1 pg/ml while in those with OSA, it jumped to 890.66 ± 205.63 pg/ml. Conclusions: The results showed that BNP was elevated in patients with acromegaly and OSA versus those without OSA, OSA is more common in males particularly when they get older.

Delineating the Spectrum of Pituitary Adenoma Based on the WHO 2017 Classification.

The WHO 2017 classification of endocrine tumors incorporates lineage-specific transcription factors (TF) and hormone expression for the classification of pituitary adenoma (PA). There is paucity of reports describing the spectrum of PA based on this classification. The aim of this study was to delineate the spectrum of PA based on WHO 2017 classification of endocrine tumors. PA diagnosed in the year 2018 were studied. H and E and hormonal immunohistochemistry (IHC) for GH, PRL, ACTH, TSH, FSH, LH, CK, T-Pit and MIB-1 were performed and the results were analyzed. The cohort included 88 cases. M: F ratio was 2:1. Clinically, 22 (25%) were functional and 66 (75%) were non-functional adenomas. Amongst the clinically functional adenomas, GH secreting adenomas were the commonest (68%). Majority (83%) of non-functional adenomas were hormone positive with gonadotroph adenomas being the commonest (72.7%). Eleven (12.5%) PA were clinically and hormonally silent. Three of these showed intense nuclear T-Pit positivity, classifying them under silent corticotroph adenoma. Lineage of the remaining eight adenomas remained undetermined, since, IHC for Pit-1 and SF-1 was not performed. The aggressive adenomas identified by IHC included sparsely granulated somatotroph adenoma, Crooke cell adenoma, silent corticotroph adenoma, densely granulated lactotroph adenoma in men and constituted 17% of the PA. Four (4/88) cases were clinically invasive. A large majority of PA including aggressive adenomas can be identified by IHC. Addition of T-Pit helped to identify silent corticotroph adenoma. Pit -1 and SF-1 TF would help identify plurihormonal Pit-1 PA and null cell adenomas.

Ідіопатична низькорослість: особливості поліморфізму Taql гена VDR рецептора вітаміну D

The causes of idiopathic short stature (IS) are diverse and not well understood, including polymorphisms of the vitamin D receptor (VDR) gene, dysfunction of growth hormone (GH) secretion, or certain structural abnormalities of the GH cannot be denied. The Taql polymorphism is located at the exon-intron junction and can potentially affect the stability of the VDR gene mRNA and, consequently, the child's height. Purpose - to study of the influence of the Taql polymorphism of the VDR gene in children with IS on certain indicators of bone metabolism. Materials and methods. We studied 22 children aged 10.68±3.28 years diagnosed with idiopathic short stature. The following data were taken into account: sex and age of the patient, anthropometric data, blood vitamin D level, bone age, basal and after stimulation tests, and Taql polymorphism of the VDR gene. All data were analyzed by non-parametric methods of variational statistics using the computer program MedCals (2006). Results. All children with IS had low vitamin D levels, regardless of the Taql polymorphic locus of the vitamin D receptor gene. All children with IS, regardless of the Taql polymorphic locus of the vitamin D receptor gene, were found to have low vitamin D levels. The basal level of GH in all patients was low, while the stimulated level of GH was normal in all patients. Conclusions. In the group of patients with IS, the frequency of the T/C (TaqI T/C, g.65058 T>C) genotype is 1.63 times higher than in the group of healthy subjects. Carriage of allele C of the polymorphic locus rs731236 Tagl of the VDR gene is significantly associated with the risk of developing idiopathic short stature - OR (Odds ratio) =1.68 (95% CI (confidence interval): 1.41-2.01; p<0.001), and in the presence of the T/C genotype the risk of this pathology is significantly high - OR=3.78 (95% CI: 1.23-11.63; p<0.02). Vitamin D deficiency was found in children with the T/T polymorphism, and vitamin D deficiency was found in patients with the T/C and C/C polymorphisms. The research was carried out in accordance with the principles of the Helsinki Declaration. The study protocol was approved by the Local Ethics Committee of the participating institution. The informed consent of the patient was obtained for conducting the studies. No conflict of interests was declared by the authors.

Basal interaction of the orphan receptor GPR101 with arrestins leads to constitutive internalization

GPR101 is an orphan G protein-coupled receptor that promotes growth hormone secretion in the pituitary. The microduplication of the GPR101 gene has been linked with the X-linked acrogigantism, or X-LAG, syndrome. This disease is characterized by excessive growth hormone secretion and abnormal rapid growth beginning early in life. Mechanistically, GPR101 induces growth hormone secretion through constitutive activation of multiple heterotrimeric G proteins. However, the full scope of GPR101 signaling remains largely elusive. Herein, we investigated the association of GPR101 to multiple transducers and uncovered an important basal interaction with Arrestin 2 (β-arrestin 1) and Arrestin 3 (β-arrestin 2). By using a GPR101 mutant lacking the C-terminus and cell lines with an Arrestin 2/3 null background, we show that the arrestin association leads to constitutive clathrin- and dynamin-mediated GPR101 internalization. To further highlight GPR101 intracellular fate, we assessed the colocalization of GPR101 with Rab protein markers. Internalized GPR101 was mainly colocalized with the early endosome markers, Rab5 and EEA-1, and to a lesser degree with the late endosome marker Rab7. However, GPR101 was not colocalized with the recycling endosome marker Rab11. These findings show that the basal arrestin recruitment by GPR101 C-terminal tail drives the receptor constitutive clathrin-mediated internalization. Intracellularly, GPR101 concentrates in the endosomal compartment and is degraded through the lysosomal pathway. In conclusion, we uncovered a constitutive intracellular trafficking of GPR101 that potentially represents an important layer of regulation of its signaling and function.

Increased IGFBP Proteolysis, IGF-I Bioavailability, and Pappalysin Levels in Children With Prader-Willi Syndrome.

Prader-Willi syndrome (PWS) is associated with impaired growth hormone (GH) secretion and decreased insulin-like growth factor (IGF)-I levels. Pappalysins (PAPP-A, PAPP-A2) and stanniocalcins (STC-1, STC-2) regulate IGF binding-protein (IGFBP) cleavage and IGF bioavailability, but their implication in PWS is unknown. We determined serum levels of PAPP-As and STCs in association with IGF axis components in prepubertal and pubertal patients with PWS, also analyzing the effect of GH treatment. Forty children and adolescents with PWS and 120 sex- and age-matched controls were included. The effect of GH was evaluated at 6 months of treatment in 11 children. Children with PWS had lower levels of total IGF-I, total and intact IGFBP-3, acid-labile subunit, intact IGFBP-4, and STC-1, and they had higher concentrations of free IGF-I, IGFBP-5, and PAPP-A. Patients with PWS after pubertal onset had decreased total IGF-I, total and intact IGFBP-3, and intact IGFBP-4 levels, and had increased total IGFBP-4, and STCs concentrations. GH treatment increased total IGF-I, total and intact IGFBP-3, and intact IGFBP-4, with no changes in PAPP-As, STCs, and free IGF-I levels. Standardized height correlated directly with intact IGFBP-3 and inversely with PAPP-As and the free/total IGF-I ratio. The increase in PAPP-A could be involved in increased IGFBP proteolysis, promoting IGF-I bioavailability in children with PWS. Further studies are needed to establish the relationship between growth, GH resistance, and changes in the IGF axis during development and after GH treatment in these patients.

A novel somatostatin receptor ligand for human ACTH - and GH -secreting pituitary adenomas.

Somatostatin receptor ligands have come to play a pivotal role in the treatment of both ACTH- and GH-secreting pituitary adenomas. Clinical efficacy averages 30-50%, thus a considerable number of patients with Cushing's disease or acromegaly remain unresponsive to this therapeutic approach. HTL0030310 is a new somatostatin receptor ligand selective for subtype 5 over subtype 2, thus with a different receptor profile compared to clinical somatostatin receptor ligands. Assessment of the effect of HTL0030310 on hormone secretion in human ACTH- and GH-secreting pituitary adenomas in vitro. Primary cultures from 3 ACTH-secreting and 5 GH-secreting pituitary adenomas were treated with 1, 10 and 100 nM HTL0030310 alone or with 10 nM CRH or GHRH, respectively. Parallel incubations with 10 nM pasireotide were also carried out. ACTH and GH secretion were assessed after 4 and 24 hour incubation; SSTR2, SSTR3, SSTR5, GH and POMC expression were evaluated after 24 hours. HTL0030310 reduced unchallenged ACTH and POMC levels up to 50% in 2 ACTH-secreting adenomas and blunted CRH-stimulated ACTH/POMC by 20-70% in all 3 specimens. A reduction in spontaneous GH secretion was observed in 4 GH-secreting adenomas and in 2 specimens during GHRH co-incubation. SSTRs expression was detected in all specimens. This first study on a novel somatostatin receptor 5-preferring ligand indicates that HTL0030310 can inhibit hormonal secretion in human ACTH- and GH-secreting pituitary adenomas. These findings suggest a potential new avenue for somatostatin ligands in the treatment of Cushing's disease and acromegaly.

A Novel Preoperative Score to Predict Long-Term Biochemical Remission in Patients with Growth-Hormone Secreting Pituitary Adenomas

Transsphenoidal surgery (TSS) is considered the treatment of choice in most patients with growth hormone (GH)-secreting pituitary adenomas. Several preoperative factors have been studied to predict postsurgical remission. Our objective was to design a score that could be used in the preoperative setting to identify patients that will achieve long-term biochemical remission after TSS. A retrospective analysis of consecutive patients with GH-secreting pituitary adenomas that underwent TSS in our institution from 2000 to 2015 who fulfilled prespecified criteria were included. Logistic regression methods were used to evaluate independent preoperative variables predicting long-term remission. Beta coefficients were used to create a scoring system for clinical practice. Sixty-eight patients were included, with a mean follow-up time of 87months. Twenty (29%) patients had tumors with a Knosp grade ≥ 3A. Gross-total resection was achieved in 43 (63%) patients. Thirty-three (48%) patients had long-term biochemical remission after TSS. In a multivariate analysis, the following variables were statistically significantly associated with long-term biochemical remission: age, adenoma size (diameter), Knosp grade, GH level, and insulin growth-factor 1index 1 at diagnosis. A score of <3 out of 8 total points was identified as a cutoff associated with long-term remission, with a sensitivity of 91.4% and specificity of 72.7% (AUC 0.867, OR 28.44, 95% CI 6.94-116.47, P=<0.001). A novel, simple, easy-to-use scoring system was created to identify patients with the highest chances of long-term biochemical remission following TSS. This scale should be prospectively validated in a multicenter study before widespread adoption.

Growth hormone deficiency in the neurocritical patient

Growth hormone (GH) is synthesized in the anterior pituitary, but its production and release are controlled by two neurohormones found in the hypothalamus: somatostatin and growth hormone-releasing hormone (GHRH). GH supports bone growth, regeneration of neurons, astrocytes, endothelial cells, oligodendrocytes, and even neuronal myelination. It is also responsible for stimulating the growth and differentiation of cells from different tissues and cell types, thereby contributing to protein synthesis. Original research papers, case reports, and case series on GH deficiency among neurocritical patients were thoroughly examined in this review. After extensive study, 13 articles were selected for the analysis. Traumatic lesions are defined by distortion of the brain tissue and subsequent biochemical modifications, which can affect GH secretion. The majority of researchers identified fractures, trauma, and bleeding as the mechanical causes of GH deficiency, and subarachnoid haemorrhage (SAH) or traumatic brain injury (TBI) as the etiology. The dysregulation of certain other hormones, including ACTH, Cortisol, Gonadotropin, Prolactin, FSH, TSH, Testosterone, and Hydrocortisone is also related to GH insufficiency. Growth hormone deficiency can cause complications such as hypothyroidism, hypotension, hypoxia, adrenal insufficiency, electrolyte imbalance, hyperprolactinemia, depression, anxiety, concussions, seizures, vomiting, and loss of consciousness. According to previous studies, GH insufficiency is significantly affected by age, body mass index (BMI), pituitary dysfunction, and hypogonadism. GH treatment is widely used in patients with GH deficiency, as it has more benefits than harm. The GH dose should be individualized to minimize side effects and maximize clinical efficacy.

Effects of cooling on thyroid hormone secretion and growth of eastern bluebird (Sialia sialis) nestlings

Achieving endothermic homeothermy is a critical aspect of avian development. In pre-homeothermic altricial nestlings, variation in parental brooding behavior results in variable exposure of nestlings to cooling, with consequences for the developing endocrine system. Nestlings facing repeated cooling challenges may benefit from upregulation of thyroid hormone secretion, allowing for earlier onset of thermoregulatory capability to mitigate the potentially negative effects of exposure to non-optimal temperatures during development. We examined the effects of (1) a single cooling challenge on thyroid hormone secretion in pre-homeothermic nestlings, and (2) repeated cooling challenges prior to the onset of homeothermy on nestling growth and thyroid hormone secretion prior to fledging. We found that pre-homeothermic eastern bluebird nestlings exposed to a single cooling challenge increased circulating triiodothyronine (T3), demonstrating that the thyroid system can be activated by cooling early in life. However, we found no consequences of repeated cooling during the first week of life on nestling growth or baseline T3 levels prior to fledging. This work addresses how the nestling hypothalamic-pituitary-thyroid axis responds to acute cooling challenges prior to the development of endothermic homeothermy; future work will confirm whether such responses allow nestlings to hasten the onset of physiological thermoregulation when conditions demand it.

New findings on brain actions of growth hormone and potential clinical implications.

Growth hormone (GH) is secreted by somatotropic cells of the anterior pituitary gland. The classical effects of GH comprise the stimulation of cell proliferation, tissue and body growth, lipolysis, and insulin resistance. The GH receptor (GHR) is expressed in numerous brain regions. Notably, a growing body of evidence indicates that GH-induced GHR signaling in specific neuronal populations regulates multiple physiological functions, including energy balance, glucose homeostasis, stress response, behavior, and several neurological/cognitive aspects. The importance of central GHR signaling is particularly evident when the organism is under metabolic stress, such as pregnancy, chronic food deprivation, hypoglycemia, and prolonged exercise. These particular situations are associated with elevated GH secretion. Thus, central GH action represents an internal signal that coordinates metabolic, neurological, neuroendocrine, and behavioral adaptations that are evolutionarily advantageous to increase the chances of survival. This review summarizes and discusses recent findings indicating that the brain is an important target of GH, and GHR signaling in different neuronal populations regulates essential physiological functions.

Somapacitan (Sogroya)

&#x0D; CADTH recommends that Sogroya should be reimbursed by public drug plans for the long-term treatment of pediatric patients who have growth failure due to an inadequate secretion of endogenous growth hormone (growth hormone deficiency [GHD]) if certain conditions are met.&#x0D; Sogroya should only be covered to treat children who are at least 2.5 years of age, have not reached puberty yet, and are diagnosed with GHD.&#x0D; Sogroya should only be reimbursed for a patient who is under the care of a pediatric endocrinologist and whose growth plates have not closed if Sogroya does not cost more than somatropin and somatrogon.&#x0D;