Acromegaly management in the Nordic countries: A Delphi consensus survey.

OBJECTIVE: Acromegaly is associated with increased morbidity and mortality if left untreated. The therapeutic options include surgery, medical treatment, and radiotherapy. Several guidelines and recommendations on treatment algorithms and follow-up exist. However, not all recommendations are strictly evidence-based. To evaluate consensus on the treatment and follow-up of patients with acromegaly in the Nordic countries. METHODS: A Delphi process was used to map the landscape of acromegaly management in Denmark, Sweden, Norway, Finland, and Iceland. An expert panel developed 37 statements on the treatment and follow-up of patients with acromegaly. Dedicated endocrinologists (n = 47) from the Nordic countries were invited to rate their extent of agreement with the statements, using a Likert-type scale (1-7). Consensus was defined as ≥80% of panelists rating their agreement as ≥5 or ≤3 on the Likert-type scale. RESULTS: Consensus was reached in 41% (15/37) of the statements. Panelists agreed that pituitary surgery remains first line treatment. There was general agreement to recommend first-generation somatostatin analog (SSA) treatment after failed surgery and to consider repeat surgery. In addition, there was agreement to recommend combination therapy with first-generation SSA and pegvisomant as second- or third-line treatment. In more than 50% of the statements, consensus was not achieved. Considerable disagreement existed regarding pegvisomant monotherapy, and treatment with pasireotide and dopamine agonists. CONCLUSION: This consensus exploration study on the management of patients with acromegaly in the Nordic countries revealed a relatively large degree of disagreement among experts, which mirrors the complexity of the disease and the shortage of evidence-based data.

Growth hormone-receptor disruption in mice reduces osteoarthritis and chondrocyte hypertrophy.

Excessive growth hormone (GH) has been shown to promote joint degeneration in both preclinical and clinical studies. Little is known about the effect of disrupted GH or GH receptor (GHR) on joint health. The goal of this study is to investigate joint pathology in mice with either germline (GHR-/-) or adult inducible (iGHR-/-) GHR deficiency. Knee joints from male and female GHR-/- and WT mice at 24 months of age were processed for histological analysis. Also, knee joints from male and female iGHR-/- and WT mice at 22 months of age were scanned by micro-CT (µCT) for subchondral bone changes and characterized via histology for cartilage degeneration. Joint sections were also stained for the chondrocyte hypertrophy marker, COLX, and the cartilage degeneration marker, ADAMTS-5, using immunohistochemistry. Compared to WT mice, GHR-/- mice had remarkably smooth articular joint surfaces and an even distribution of proteoglycan with no signs of degeneration. Quantitatively, GHR-/- mice had lower OARSI and Mankin scores compared to WT controls. By contrast, iGHR-/- mice were only moderately protected from developing aging-associated OA. iGHR-/- mice had a significantly lower Mankin score compared to WT. However, Mankin scores were not significantly different between iGHR-/- and WT when males and females were analyzed separately. OARSI scores did not differ significantly between WT and iGHR-/- in either individual or combined sex analyses. Both GHR-/- and iGHR-/- mice had fewer COLX+ hypertrophic chondrocytes compared to WT, while no significant difference was observed in ADAMTS-5 staining. Compared to WT, a significantly lower trabecular thickness in the subchondral bone was observed in the iGHR-/- male mice but not in the female mice. However, there were no significant differences between WT and iGHR-/- mice in the bone volume to total tissue volume (BV/TV), bone mineral density (BMD), and trabecular number in either sex. This study identified that both germline and adult-induced GHR deficiency protected mice from developing aging-associated OA with more effective protection in GHR-/- mice.

Medical treatment of functional pituitary adenomas, trials and tribulations.

CONTEXT: Functioning pituitary adenomas (FPAs) include most frequently prolactinomas, somatotroph or corticotroph adenomas, while thyrotroph and gonadotroph adenomas are very rare. Despite their benign histological nature (aggressive tumors are rare and malignant ones exceptional), FPAs could cause significant morbidity and increased mortality due to complications associated with hormonal excess syndromes and/or mass effect leading to compression of adjacent structures. This mini review will focus on the increasing role of medical therapy in the multimodal treatment, which also includes transsphenoidal surgery (TSS) and radiotherapy. EVIDENCE SYNTHESIS: Most patients with prolactinomas are treated only with medications, but surgery could be considered for some patients in a specialized pituitary center, if higher chances of cure. Dopamine agonists, especially cabergoline, are efficient in reducing tumor size and normalizing prolactin. TSS is the first-line treatment for all other FPAs, but most patients require complex adjuvant treatment, including a combination of therapeutic approaches. Medical therapy is the cornerstone of treatment in all patients after unsuccessful surgery or when surgery cannot be offered and includes somatostatin receptor ligands and dopamine agonists (almost all FPAs), growth hormone receptor antagonists (acromegaly), adrenal steroidogenesis inhibitors and glucocorticoid receptor blockers (Cushing's disease). Novel medical treatments, especially for acromegaly and Cushing's disease are under research. CONCLUSIONS: An enlarged panel of effective drugs available with increased knowledge of predictive factors for response and/or adverse effects will enhance the possibility to offer a more individualized treatment. This would not only improve disease control and prognosis, but also quality of life.

Normal or improved cardiovascular risk factors in IGF-I-deficient adults with growth hormone receptor deficiency.

BACKGROUND: Human subjects with generalized growth hormone (GH) insensitivity due to GH receptor deficiency (GHRD)/Laron syndrome display a very low incidence of insulin resistance, diabetes, and cancer, as well as delayed age-related cognitive decline. However, the risk of cardiovascular disease (CVD) in these subjects is poorly understood. Here, we have assessed cardiovascular function, damage, and risk factors in GHRD subjects and their relatives. METHODS: We measured markers of CVD in two phases: one in a cohort of 30 individuals (GHRD = 16, control relatives = 14) brought to USC (in Los Angeles, CA) and one in a cohort including additional individuals examined in Ecuador (where the subjects live) for a total of 44 individuals (GHRD = 21, control relatives = 23). Data were collected on GHRD and control groups living in similar geographical locations and sharing comparable environmental and socio-economic circumstances. RESULTS: Compared to controls, GHRD subjects displayed lower serum glucose, insulin, blood pressure, smaller cardiac dimensions, similar pulse wave velocity, lower carotid artery intima-media thickness, lower creatinine, and a non-significant but major reduction in the portion of subjects with carotid atherosclerotic plaques (7% GHRDs vs. 36%, Controls p = 0.1333) despite elevated low-density lipoprotein cholesterol levels. CONCLUSION: The current study indicates that individuals with GHRD have normal or improved levels of cardiovascular disease risk factors as compared to their relatives. FUNDING: This study was funded in part by NIH/NIA grant P01 AG034906 to V.D.L.

A Clinical Trial of High Dose Growth Hormone in a Patient with a Dominant Negative Growth Hormone Receptor Mutation.

CONTEXT: Rare patients with short stature and growth hormone (GH) resistance have dominant-negative variants in the GH receptor. We describe a patient with GH resistance due to elevated levels of GH binding protein and demonstrate the potential for a precision medicine intervention. OBJECTIVE: To determine whether high dose GH can overcome GH resistance in this specific patient resulting in normal IGF-1 levels and improved growth rates. DESIGN: Single patient trial of ascending doses of GH followed by dose stable phase; total 12 months of treatment. PATIENT: Patient has a heterozygous variant in GH receptor resulting in elevated levels of GH binding protein manifesting as GH resistance and severe short stature. INTERVENTIONS: Daily subcutaneous GH starting at 50 micrograms/kg/day and escalating to 250 micrograms/kg/day until goal IGF-1 achieved. Subject continued 250 micrograms/kg/day for a total treatment duration of 12 months. OUTCOME MEASURES: The primary outcome measure was the dose of GH required to achieve an IGF-1 level above the mid-point of the normal range. Secondary endpoints included height velocity and the change in height SDS during the 1st year of treatment. RESULTS: A dose of GH of 250 micrograms/kg/day achieved the target IGF-1 level. The patient's annualized height velocity was 8.7 cm/year, an increase of 3.4 cm/year from baseline, resulting in a 0.81 SD gain in height. CONCLUSIONS: A precision medicine approach of extremely high dose GH was able to overcome GH resistance in a patient with a dominant-negative variant in the GH receptor resulting in elevated GH binding protein levels.

Association of the GHRd3 polymorphism with adult height and type 2 diabetes in a Saudi Arabian population from Jazan Province: A case-control study.

Objectives: This study investigated the association of the GHRd3 polymorphism with height and type-2 diabetes mellitus (T2DM) in Saudi Arabia. Methods: This case-control study included a total of 284 participants, divided into healthy controls (n = 142) and patients with T2DM (n = 142), recruited from Jazan University Hospital, southwest of Saudi Arabia in the period between January to September 2022. The GHRd3 polymorphism was genotyped using multiplex PCR. The correlation between height and genotypes was analyzed using one-way analysis of variance. The association between GHRd3 polymorphism and T2DM was assessed using logistic regression analysis. Results: The data showed a significant difference between the means of heights associated with each GHRd3 genotype, flfl, fld3, and d3d3. Logistic regression analysis showed no association between GHRd3 variants and T2DM. Conclusion: Homozygous GHRd3 polymorphism carriers, d3d3 genotype, were taller than fld3 or flfl carriers in our population. None of the GHRd3 variants were associated with T2DM. Thus, the GHRd3 polymorphism has growth-related actions with a minor contribution to T2DM. However, more studies with a larger sample size are required to confirm these findings.

Tmem263 deletion disrupts the GH/IGF-1 axis and causes dwarfism and impairs skeletal acquisition.

Genome-wide association studies (GWAS) have identified a large number of candidate genes believed to affect longitudinal bone growth and bone mass. One of these candidate genes, TMEM263, encodes a poorly characterized plasma membrane protein. Single nucleotide polymorphisms in TMEM263 are associated with bone mineral density in humans and mutations are associated with dwarfism in chicken and severe skeletal dysplasia in at least one human fetus. Whether this genotype-phenotype relationship is causal, however, remains unclear. Here, we determine whether and how TMEM263 is required for postnatal growth. Deletion of the Tmem263 gene in mice causes severe postnatal growth failure, proportional dwarfism, and impaired skeletal acquisition. Mice lacking Tmem263 show no differences in body weight within the first 2 weeks of postnatal life. However, by P21 there is a dramatic growth deficit due to a disrupted growth hormone (GH)/insulin-like growth factor 1 (IGF-1) axis, which is critical for longitudinal bone growth. Tmem263-null mice have low circulating IGF-1 levels and pronounced reductions in bone mass and growth plate length. The low serum IGF-1 in Tmem263-null mice is associated with reduced hepatic GH receptor (GHR) expression and GH-induced JAK2/STAT5 signaling. A deficit in GH signaling dramatically alters GH-regulated genes and feminizes the liver transcriptome of Tmem263-null male mice, with their expression profile resembling wild-type female, hypophysectomized male, and Stat5b-null male mice. Collectively, our data validates the causal role for Tmem263 in regulating postnatal growth and raises the possibility that rare mutations or variants of TMEM263 may potentially cause GH insensitivity and impair linear growth.

Evaluation of the expression of growth hormone and its receptor during the resumption of postpartum ovarian follicle development in dairy cows.

Growth hormone is a key endocrine factor for metabolic adaptations to lactation and optimal reproductive function of the dairy cow. This study aimed to analyze the expression of GH and its receptor (GHR) in ovarian follicles, along with metabolic biomarkers, during the resumption of the postpartum follicular development, and to analyze the immunolocalization and protein expression of GH and GHR in preovulatory follicles. Thirty-six dairy cows were grouped according to the postpartum days (PPD) until the establishment of the first dominant follicle in: cows that established their first dominant follicle at fewer postpartum days (FPPD group; n = 15) and cows that established their first dominant follicle at more postpartum days (MPPD group; n = 22). For a second analysis, the same cows were regrouped according to the calving season (S), into cows calving in autumn (n = 20) and cows calving in winter (n = 17). During the PP, blood and follicular aspirates were obtained at two timepoints (T): when the first dominant follicle was established (T1, day 9 ± 2), and when the preovulatory follicle was established (T2, day 45 ± 2). Also, six dairy cows were ovariectomized in proestrus and ovarian histological sections were obtained. Growth hormone mRNA was detected in granulose cells from ovarian follicle sampled during PP. A PPD × T interaction was observed for GHR mRNA, where it was greater in the FPPD cows than in the MPPD cows at T1. Metabolic biomarkers and reproductive hormones showed differences or interaction between PPD, T, S, depending on the case. Also, GH and GHR were immunolocalized in granulosa and theca interna cells of preovulatory follicles. These results confirm the expression of GH and GHR in the mature ovarian follicles of dairy cows and show a possible association between greater GHR expression and an earlier resumption of postpartum follicular development.

Growth hormone directly stimulates GATA2 expression.

OBJECTIVE: GATA2 is a key transcription factor involved in the differentiation and determination of thyrotrophs and gonadotrophs in pituitary and hematopoietic development. However, studies on the upstream ligands of the GATA2 signal transduction pathway have been limited. To identify upstream ligands, we examined growth hormone (GH) as a plausible stimulator. DESIGN: We evaluated GH-induced GATA2 expression in murine TtT/GF thyrotrophic pituitary tumor cells and its direct impact on the GHR/JAK/STAT5 pathway using a combination of a reporter assay, real-time quantitative polymerase chain reaction, and western blotting. RESULTS: GATA2 expression increased with activated STAT5B in a dose-dependent manner and was inhibited by a STAT5 specific inhibitor. Moreover, we found functional STAT5B binding site consensus sequences at -359 bp in the GATA2 promoter region. CONCLUSION: These findings suggest that GH directly stimulates GATA2 via the GHR/JAK/STAT pathway and participates in various developmental phenomena mediated by GATA2.

Effective Long-term Pediatric Pegvisomant Monotherapy to Final Height in X-linked Acrogigantism.

X-linked acrogigantism (X-LAG) is characterized by extreme tall stature from early childhood resulting from duplication of the GPR101 gene, in turn resulting in GH excess. Most cases present with pituitary tumors secreting GH and prolactin. Diffuse pituitary hyperplasia is uncommon and normal prolactin is rare. We present a girl with tall stature from 3 years of age; her height was +4.25 SD score at 5 years, with no signs of syndromic disease. She had significant GH excess, serum IGF-1 4 times the upper limit of normal and normal circulating GHRH, with normal pituitary magnetic resonance imaging over 13 years. No abnormalities were found in either the AIP or MEN1 genes. Treatment with somatostatin analogues and dopamine agonists showed minimal therapeutic benefit, but significant side effects. She tested positive for duplication of GPR101 6 years after the initial diagnosis. She was then initiated on pegvisomant aged 12 years, achieving prompt IGF-1 normalization and growth cessation. Aged 16.5 years, she showed escape from IGF-1 control, and height velocity increased, but this responded well to a dose increase in pegvisomant, with reassuring long-term pediatric safety over 7 years. Her final height is +2.9 SD score. Currently, life-long pegvisomant treatment is planned with genetic counselling regarding future offspring.

Growth Axis Somatostatin, Growth Hormone Receptor, and Insulin-like Growth Factor-1 Genes Express and Are Affected by the Injection of Exogenous Growth Hormone in Chinemys reevesii.

In this study, to explore the effect of growth hormone changes on the related genes and regulatory roles of the turtle, PCR amplification, real-time fluorescence quantitative analysis, and enzyme cutting technology were used to clone and sequence the somatostatin (SS) gene, growth hormone receptor (GHR), and insulin-like growth factor-1 (IGF-I) sequence of Chinemys reevesii. The effects of human growth hormone on the mRNA expression of growth-axis-related genes SS, GHR, and IGF-1 in different sexes were observed. The study of the SS gene in turtles using real-time fluorescence quantitative PCR showed that the SS gene was mainly expressed in the nervous system and the digestive system, with the highest expression found in the brain, while the GHR gene and the IGF-I gene were expressed in all tissues of Chinemys reevesii. The SS gene was expressed in the brain, pituitary, liver, stomach, and intestine, with the highest expression in the brain and the lowest expression in the liver. Within 4 weeks of the injection of exogenous growth hormone, the expression level of the SS gene in the brain of both sexes first increased and then decreased, showing a parabolic trend, and the expression level of the experimental group was lower than that of the control group. After the injection of growth hormone (GH), the expression of the GHR gene in the liver of both sexes showed a significant increase in the first week, decreasing to the control group level in the second week, and then gradually increasing. Finally, a significant level of difference in the expression of the GHR gene was reached at 3 and 4 weeks. In terms of the IGF-I gene, the changing trend of the expression level in the liver was the same as that of the GHR gene. After the injection of exogenous growth hormone, although the expression of the SS gene increased the inhibition of the secretion of the GHR gene by the Reeves' turtle, exogenous growth hormone could replace the synthesis of GH and GHR, accelerating the growth of the turtle. The experiments showed that the injection of recombinant human growth hormone affects the expression of SS, GHR, and IGF-1 genes, and promotes the growth of the Reeves' turtle.

A cluster of X-linked miRNAs are de-repressed with age in mouse liver and target growth hormone signaling.

Growth hormone (GH) signaling influences lifespan in a wide variety of mammalian species. We previously reported that a cluster of miRNAs located on the X-chromosome are de-repressed with age in male mouse liver, and a subset, the mir-465 family, can directly attenuate expression of the growth hormone receptor (GHR) in vitro leading to a reduction in GH signaling. Here we show that this cluster of miRNAs is also upregulated in the liver with age in females, and that calorie restriction and the Ames dwarf genotype, both known to delay aging, attenuate the upregulation of the miRNA cluster. Upregulation of mir-465 in vivo leads to a reduction in GHR mRNA in the liver and an attenuation of GH signaling, indicated by a reduction in GHR, IGF-1, IGFBP3, and ALS mRNA expression. There is a corresponding reduction in IGF-1 protein levels in the liver and plasma. These results suggest that the age-associated upregulation of the X-chromosomal cluster of miRNAs could influence lifespan.

Effect of IGF-1 C472T, GH C2141G, and GHR T914A polymorphisms on growth performance and feed efficiency in young Kazakh white-headed cattle.

Background and Aim: Improving the feed efficiency of beef cattle is necessary to increase the profitability of meat production. Implementing marker-assisted selection breeding systems can improve the genetic potential of beef cattle for increased productivity. This research aimed to study the effects of insulin-like growth factor (IGF)-1 C472T, growth hormone (GH) C2141G, and GH receptor (GHR) T914A polymorphisms on growth performance and feed efficiency in young Kazakh white-headed cattle. Materials and Methods: Young Kazakh white-headed cattle (n = 50) were grouped after weaning according to sex (28 bulls and 22 heifers) and they were genotyped according to the IGF-1 C472T, GH C2141G, and GHR T914A polymorphisms. The test period was conducted from 8 to 15 months of age. The experimental animals were evaluated for live weight (LW) at the beginning and end of the test period. They were also assessed for average daily gain, hip height, metabolic mid-weight (MMWT), actual dry matter intake (DMI), and residual feed intake (RFI). Results: Significant differences in MMWT were found between the bulls with the IGF-1TT and IGF-1CT genotypes, which was a 2.2 kg increase in heterozygous cattle (p < 0.05). Heterozygous IGF-1CT bulls differed with a higher DMI of 0.087 kg/day (p < 0.05) compared to IGF-1TT homozygotes. Carriers of the IGF-1TT genotype had the greatest feed efficiency at 0.068 kg/day (p < 0.05). Heifers with the GHCC genotype differed in their maximum DMI with an increase of 1.17%-1.57% (p < 0.05) relative to the other genotypes. The G allele in the GH C2141G polymorphism was associated with better (p < 0.05) feed efficiency in the Kazakh white-headed breed. The minimum DMI and RFI in GHR T914A heterozygous heifers were significantly inferior (p < 0.05) to the other genotypes. Conclusion: Association studies of the IGF-1 C472T, GH C2141G, and GHR T914A polymorphisms indicate a relationship between growth, development, and feed efficiency with the genetic characteristics of young Kazakh white-headed cattle. A significant (p < 0.05) dominant effect was found in the IGF-1 gene in bulls and in the GHR gene in heifers, which should be considered when breeding with heterogeneous parental pairs. The negative effect of the allele substitution in the IGF-1 C472T polymorphism was observed in the LW of heifers (-3.25 kg) at the age of 8 months and bulls (-6.05 kg) at 15 months. The substitution in the GH C2141G polymorphism was associated with a significant reduction in DMI by 0.036 kg (p < 0.05) and an increase in feed efficiency by 0.023 kg (p < 0.05) during the rearing of heifers. These results can improve the production efficiency of mature herds of Kazakh white-headed cattle.

Growth hormone receptor gene disruption.

Much of our understanding of growth hormone's (GH)'s numerous activities stems from studies utilizing GH receptor (GHR) knockout mice. More recently, the role of GH action has been examined by creating mice with tissue-specific or temporal GHR disruption. To date, 37 distinct GHR knockout mouse lines have been created. Targeted tissues include fat, liver, muscle, heart, bone, brain, macrophage, intestine, hematopoietic stem cells, pancreatic ß cells, and inducible multi-tissue "global" disruption at various ages. In this chapter, a summary of each mouse line is provided with background information on the generation of the mouse line as well as important physiological outcomes resulting from GHR gene disruption. Collectively, these mouse lines provide unique insights into GH action and have resulted in the development of new hypotheses about the functions ascribed to GH action in particular tissues.

The Exon 3-Deleted Growth Hormone Receptor (d3GHR) Polymorphism-A Favorable Backdoor Mechanism for the GHR Function.

Growth hormone (GH) is a peptide hormone that plays a crucial role in controlling growth, development, and lifespan. Molecular regulation of GH is accomplished via the GH receptor (GHR), which is the main factor influencing human development and is essential to optimal functioning of the GH/IGF-I axis. Two GHR isoforms have been studied, according to the presence (flGHR) or absence (d3GHR) of exon 3. The d3GHR isoform, which lacks exon 3 has recently been related to longevity; individuals carrying this isoform have higher receptor activity, improved signal transduction, and alterations in the treatment response and efficacy compared with those carrying the wild type (WT) isoform (flGHR). Further, studies performed in patients with acromegaly, Prader-Willi syndrome, Turner syndrome, small for gestational age (SGA), and growth hormone deficiency (GHD) suggested that the d3GHR isoform may have an impact on the relationship between GH and IGF-I levels, height, weight, BMI, and other variables. Other research, however, revealed inconsistent results, which might have been caused by confounding factors, including limited sample sizes and different experimental methods. In this review, we lay out the complexity of the GHR isoforms and provide an overview of the major pharmacogenetic research conducted on this ongoing and unresolved subject.

Effect of Growth Hormone Receptor Deficiency on Androgen-Associated Gene Expression of Hepatic Drug Metabolizing Enzymes and Drug Transporters in Pigs.

Growth hormone receptor (GHR)-deficient pigs were generated using the CRISPR/Cas9 system to investigate the involvement of GHR-mediated growth hormone (GH) signaling in androgen-associated gene expression of hepatic drug metabolizing enzymes (DMEs) and drug transporters. We initially confirmed that no wild-type GHR mRNA was present in GHR-/- (GHR-KO) pigs; in addition, as previously reported, those pigs exhibited decreases in body weight and serum insulin-like growth factor-1 concentration and an increase in serum GH concentration compared with the levels in GHR-/+ and GHR+/+ pigs with a wild-type GHR mRNA. The real-time RT-PCR results on the mRNA levels of hepatic DMEs and drug transporters in the GHR-KO pigs and the pigs with a wild-type GHR mRNA revealed that, among the examined hepatic DMEs, the mRNA levels of CYP1A2, CYP2A19, sulfotransferase (SULT) 1A1, and SULT2A1 were higher in GHR-KO pigs than in the pigs with a wild-type GHR mRNA, whereas the opposite trend was observed for the mRNA level of uridine 5'-diphospho-glucuronosyltransferase 1A6. No such significant differences in the mRNA levels of three hepatic drug transporters including multidrug resistance protein 1 were observed. In addition, the mRNA level of hepatic cut-like homeobox 2 (CUX2), which is expressed in an androgen-dependent manner and associated with the hepatic mRNA expression of several DMEs, was significantly decreased in GHR-KO pigs. The present findings strongly suggest that not only serum androgen but also GHR-mediated GH signaling contributes to the mRNA expression of several DMEs and CUX2, but not transporters, in the pig liver.

Growth hormone proteoformics atlas created to promote predictive, preventive, and personalized approach in overall management of pituitary neuroendocrine tumors.

Human growth hormone (GH) is the indispensable hormone for the maintenance of normal physiological functions of the human body, including the growth, development, metabolism, and even immunoregulation. The GH is synthesized, secreted, and stored by somatotroph cells in adenohypophysis. Abnormal GH is associated with various GH-related diseases, such as acromegaly, dwarfism, diabetes, and cancer. Currently, some studies found there are dozens or even hundreds of GH proteoforms in tissue and serum as well as a series of GH-binding protein (GHBP) proteoforms and GH receptor (GHR) proteoforms were also identified. The structure-function relationship of protein hormone proteoforms is significantly important to reveal their overall physiological and pathophysiological mechanisms. We propose the use of proteoformics to study the relationship between every GH proteoform and different physiological/pathophysiological states to clarify the pathogenic mechanism of GH-related disease such as pituitary neuroendocrine tumor and conduct precise molecular classification to promote predictive preventive personalized medicine (PPPM / 3P medicine). This article reviews GH proteoformics in GH-related disease such as pituitary neuroendocrine tumor, which has the potential role to provide novel insight into pathogenic mechanism, discover novel therapeutic targets, identify effective GH proteoform biomarker for patient stratification, predictive diagnosis, and prognostic assessment, improve therapy method, and further accelerate the development of 3P medicine.

The GH/IGF1 axis in the kidney of young goats fed a protein-reduced diet.

Feeding approaches for ruminants are changing to reduce N excretion as a major source of pollution. Based on the ruminohepatic cycle of N, it was assumed that the metabolism of ruminants could tolerate a reduced-protein diet well. However, metabolic changes such as a reduction in hepatic IGF1 mRNA expression, resulting in lower blood IGF1 levels due to decreased hepatic growth hormone receptor (GHR) expression, were found. Therefore, the aim of the present study was to determine the effect of a low-protein diet on the expression of GHR and subsequent IGF1 signalling in the renal cortex of young male goats to verify whether organ-specific synthesis of IGF1 mRNA expression occurs. Kidney cortex samples were obtained from eight goats fed a control diet (20% CP) and nine animals fed a reduced-protein diet (9% CP). The expression of GHR in the kidneys was reduced, whereas the expression of Janus kinase 2 (JAK2), suppressor of cytokine signalling 3 and signal transducers and activators of transcription 3 (STAT3) increased significantly. The stimulated JAK2 expression could modulate the expression of STAT3, which led to increased renal IGF1 mRNA expression. These results suggest that this increase in IGF1 mRNA expression in the kidneys is tissue-specific. This could be due to the autocrine/paracrine IGF1 effect on renal cell metabolism during a protein-reduced diet. These signalling pathways need further investigation to understand how and why low levels of protein stimulate IGF1 synthesis differently in the kidney than in the liver.

Deletion of hepatic growth hormone receptor (GHR) alters the mouse gut microbiota by affecting bile acid metabolism.

Both growth hormone (GH) and gut microbiota play significant roles in diverse physiological processes, but the crosstalk between them is poorly understood. Despite the regulation of GH by gut microbiota, study on GH's influence on gut microbiota is limited, especially on the impacts of tissue specific GH signaling and their feedback effects on the host. In this study, we profiled gut microbiota and metabolome in tissue-specific GHR knockout mice in the liver (LKO) and adipose tissue (AKO). We found that GHR disruption in the liver rather than adipose tissue affected gut microbiota. It changed the abundance of Bacteroidota and Firmicutes at phylum level as well as abundance of several genera, such as Lactobacillus, Muribaculaceae, and Parasutterella, without affecting α-diversity. Moreover, the impaired liver bile acid (BA) profile in LKO mice was strongly associated with the change of gut microbiota. The BA pools and 12-OH BAs/non-12-OH BAs ratio were increased in the LKO mice, which was due to the induction of CYP8B1 by hepatic Ghr knockout. Consequently, the impaired BA pool in cecal content interacted with gut bacteria, which in turn increased the production of bacteria derived acetic acid, propionic acid, and phenylacetic acid that were possible to participate in the impaired metabolic phenotype of the LKO mice. Collectively, our findings suggested that the liver GH signaling regulates BA metabolism by its direct regulation on CYP8B1, which is an important factor influencing gut microbiota. Our study is significant in exploring gut microbiota modification effects of tissue-specific GH signaling as well as its involvement in gut microbiota-host interaction.

Targeting growth hormone in cancer: future perspectives.

Decades of published research support a role for growth hormone (GH) in cancer. Accordingly, there is increasing interest in targeting GH in oncology, with GH antagonists exhibiting efficacy in xenograft studies as single agents and in combination with anticancer therapy or radiation. Here we discuss challenges associated with using growth hormone receptor (GHR) antagonists in preclinical models and considerations for translation, such as the identification of predictive biomarkers for selecting patients and for monitoring drug efficacy. Ongoing research will determine whether suppressing GH signalling pharmacologically will also reduce the risk of developing cancer. An increase in GH-targeted drugs in preclinical development will ultimately provide new tools to test anticancer efficacy of blocking the GH signalling pathway.