Recent insights into the role of hormones during development and their functional regulation.

Introduction: Hormones play a vital role in development from conception to birth and throughout the human lifespan. These periods are logically divided into fetal development, pre-pubertal growth, puberty, and adulthood. Deviations from standard physiological levels and release patterns of constituent hormones can lead to pathology affecting the normal developmental trajectory. Research is ongoing to better understand the mechanisms of these hormones and how their modulation affects development. Methods: This article focuses on recent developments in understanding the role hormones play in development. We also cover recent discoveries in signaling pathways and hormonal regulation. Results: New and continuing research into functional hormone regulation focuses on sex hormones, gonadotropic hormones, growth hormones, insulin-like growth factor, thyroid hormone, and the interconnectedness of each of these functional axes. Currently, the abundance of work focuses on fertility and correction of sex hormone levels based on an individual's condition and stage in life. Discussion: Continuing research is needed to fully understand the long-term effects of hormone modulation in growth and sexual development. The role of each hormone in parallel endocrine axes should also be more thoroughly investigated to help improve the safety and efficacy in endocrine pharmacotherapeutics.

Impact of Growth Hormone on Microglial and Astrocytic Function.

The role of growth hormone (GH) in the central nervous system (CNS) involves neuroprotection, neuroregeneration, formation of axonal projections, control of cognition, and regulation of metabolism. As GH induces insulin-like growth factor-1 (IGF-1) expression in many tissues, differentiating the specific functions of GH and IGF-1 in the organism is a significant challenge. The actions of GH and IGF-1 in neurons have been more extensively studied than their functions in nonneuronal cells (e.g., microglial cells). Glial cells are fundamentally important to CNS function. Microglia, astrocytes, oligodendrocytes, and tanycytes are essential to the survival, differentiation, and proliferation of neurons. As the interaction of the GH/IGF-1 axis with glial cells merits further exploration, our objective for this review was to summarize and discuss the available literature regarding the genuine effects of GH on glial cells, seeking to differentiate them from the role played by IGF-1 action whenever possible.

Growth Hormone, Atherosclerosis and Peripheral Arterial Disease: Exploring the Spectrum from Acromegaly to Growth Hormone Deficiency.

Growth hormone (GH) and insulin-like growth factor 1 (IGF-1) are increasingly recognised for their role in cardiovascular (CV) physiology. The GH-IGF-1 axis plays an essential role in the development of the CV system as well as in the complex molecular network that regulates cardiac and endothelial structure and function. A considerable correlation between GH levels and CV mortality exists even among individuals in the general population without a notable deviation in the GHIGF- 1 axis functioning. In addition, over the last decades, evidence has demonstrated that pathologic conditions involving the GH-IGF-1 axis, as seen in GH excess to GH deficiency, are associated with an increased risk for CV morbidity and mortality. A significant part of that risk can be attributed to several accompanying comorbidities. In both conditions, disease control is associated with a consistent improvement of CV risk factors, reduction of CV mortality, and achievement of standardised mortality ratio similar to that of the general population. Data on the prevalence of peripheral arterial disease in patients with acromegaly or growth hormone deficiency and the effects of GH and IGF-1 levels on the disease progression is limited. In this review, we will consider the pivotal role of the GH-IGF-1 axis on CV system function, as well as the far-reaching consequences that arise when disorders within this axis occur, particularly in relation to the atherosclerosis process.

The physiology of growth hormone (GH) in adults: translational journey to GH replacement therapy.

The fact that growth hormone (GH) plays an important role in health after the cessation of growth requiring replacement therapy in adult life has only been recognised in the last three decades. This has only been made possible by recombinant technology providing GH supplies required to undertake investigations in the physiology of GH action and the benefits of replacement therapy in patients identified by rigorously validated diagnostic tests for GH deficiency (GHD). Human studies have revealed important regulatory roles in substrate metabolism, sodium homeostasis, body composition, and physical function. GH-induced anabolism is achieved by stimulating amino acid incorporation into protein while reducing oxidative loss simultaneously enhancing lipid utilisation by stimulating fatty acid oxidation and reducing lipid storage. Sodium and fluid retention are enhanced by activating the renin-angiotensin system and distal renal tubular reabsorption. GH stimulates the aerobic and anaerobic energy systems that underpin muscle and cardiovascular function. These pleiotropic actions explain the clinical picture of increased adiposity, reduced lean mass, and impaired physical and psychological function in the GHD adult, all of which are reversed when GH is replaced. Women require a greater replacement dose of GH than men. This is because androgens enhance while oestrogens attenuate GH action. The oestrogen effect is route-dependent, occurring with oral delivery blunting the liver-mediated actions of GH by directly inhibiting GH receptor signalling, global experience spanning over 30 years has attested to the safety, efficacy, and benefits of replacement therapy for adults with GHD.

Growth and Growth Hormone through the Ages: Art and Science.

BACKGROUND: People have long been fascinated with the size and growth of living things, from the giants of classic mythology and art to the little people who also have appeared in classical art, as well as the courts of European monarchs, and were exploited in "shows." Serious medical evaluation began in the late 19th century with the description of acromegaly and its association with pituitary tumors. In the early 20th century, multiple investigators attempted to extract a growth-promoting factor from the anterior pituitary and then, over the decades, to purify it and distinguish it from other anterior pituitary hormones. With relatively pure growth hormone (GH), its biological activity in growth promotion and as a metabolic hormone were studied, and species specificity became apparent: primate GH was the only GH active in man. Human GH was prepared from cadaveric pituitaries and distributed by the NIH to treat children with GH deficiency, but there was never enough pituitary hGH for all of the children who required it. When Creutzfeldt-Jakob disease was found in some patients who received pituitary GH, the production and FDA approval of biosynthetic hGH dramatically accelerated. With a large supply, one could treat those who were GH deficient and test its efficacy in other causes of short stature; longer acting versions of hGH have now been developed, tested, and in a few instances received FDA approval. SUMMARY: It has been a long journey from the description of over- and underproduction of GH in animals to the production and clinical use of the biosynthetic hormones. KEY MESSAGES: The efforts of basic scientists led to the extraction and purification of GH. Clinical scientists have expanded the appropriate use of hGH for short children with conditions in addition to GH deficiency.

Growth Hormone and Counterregulation in the Pathogenesis of Diabetes.

PURPOSE OF REVIEW: Canonical growth hormone (GH)-dependent signaling is essential for growth and counterregulatory responses to hypoglycemia, but also may contribute to glucose homeostasis (even in the absence of hypoglycemia) via its impact on metabolism of carbohydrates, lipids and proteins, body composition, and cardiovascular risk profile. The aim of this review is to summarize recent data implicating GH action in metabolic control, including both IGF-1-dependent and -independent pathways, and its potential role as target for T2D therapy. RECENT FINDINGS: Experimental blockade of the GHR can modulate glucose metabolism. Moreover, the soluble form of the GH receptor (GHR, or GHBP) was recently identified as a mediator of improvement in glycemic control in patients with T2D randomized to bariatric surgery vs. medical therapy. Reductions in GHR were accompanied by increases in plasma GH, but unchanged levels of both total and free IGF-1. Likewise, hepatic GHR expression is reduced following both RYGB and VSG in rodents. Emerging data indicate that GH signaling is important for regulation of long-term glucose metabolism in T2D. Future studies will be required to dissect tissue-specific GH signaling and sensitivity and their contributions to systemic glucose metabolism.

Small molecules to regulate the GH/IGF1 axis by inhibiting the growth hormone receptor synthesis.

Growth hormone (GH) and insulin-like growth factor-1 (IGF1) play an important role in mammalian development, cell proliferation and lifespan. Especially in cases of tumor growth there is an urgent need to control the GH/IGF1 axis. In this study we screened a 38,480-compound library, and in two consecutive rounds of analogues selection, we identified active lead compounds based on the following criteria: inhibition the GH receptor (GHR) activity and its downstream effectors Jak2 and STAT5, and inhibition of growth of breast and colon cancer cells. The most active small molecule (BM001) inhibited both the GH/IGF1 axis and cell proliferation with an IC50 of 10-30 nM of human cancer cells. BM001 depleted GHR in human lymphoblasts. In preclinical xenografted experiments, BM001 showed a strong decrease in tumor volume in mice transplanted with MDA-MB-231 breast cancer cells. Mechanistically, the drug acts on the synthesis of the GHR. Our findings open the possibility to inhibit the GH/IGF1 axis with a small molecule.

The Modulatory Role of Growth Hormone in Inflammation and Macrophage Activation.

Inflammation is a body's response to remove harmful stimuli and heal tissue damage, which is involved in various physiology and pathophysiology conditions. If dysregulated, inflammation may lead to significant negative impacts. Growth hormone (GH) has been shown responsible for not only body growth but also critical in the modulation of inflammation. In this review, we summarize the current clinical and animal studies about the complex and critical role of GH in inflammation. Briefly, GH excess or deficiency may lead to pathological inflammatory status. In inflammatory diseases, GH may serve as an inflammatory modulator to control the disease progression and promote disease resolution. The detailed mechanisms and signaling pathways of GH on inflammation, with a focus on the modulation of macrophage polarization, are carefully discussed with potential direction for future investigations.

Regulation of 11ß-HSD1 by GH/IGF-1 in key metabolic tissues may contribute to metabolic disease in GH deficient patients.

Patients with growth hormone deficiency (GHD) have many clinical features in common with Cushing's syndrome (glucocorticoid excess) - notably visceral obesity, insulin resistance, muscle myopathy and increased vascular mortality. Within key metabolic tissues, 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) converts cortisone to the active glucocorticoid, cortisol (11-dehydrocorticosterone and corticosterone in rodents respectively), and thus amplifies local glucocorticoid action. We hypothesize that 11ß-HSD1 expression is negatively regulated by growth hormone (GH), and that GHD patients have elevated 11ß-HSD1 within key metabolic tissues (leading to increased intracellular cortisol generation) which contributes to the clinical features of this disease. To identify the impact of GH excess/resistance on 11ß-HSD1 in vivo, we measured mRNA expression in key metabolic tissues of giant mice expressing the bovine GH (bGH) gene, dwarf mice with a disrupted GH receptor (GHRKO) gene and mice expressing a gene encoding a GH receptor antagonist (GHA). Additionally, we assessed urine steroid markers of 11ß-HSD1 activity in both GHRKO and bGH animals. 11ß-HSD1 expression was decreased in gastrocnemius muscle (0.43-fold, p < 0.05), subcutaneous adipose (0.53-fold, p < 0.05) and epididymal adipose tissue (0.40-fold, p < 0.05), but not liver, in bGH mice compared to WT controls. This was paralleled by an increased percentage of 11-DHC (inactive glucocorticoid) present in the urine of bGH mice compared to WT controls (2.5-fold, p < 0.01) - consistent with decreased systemic 11ß-HSD1 activity. By contrast, expression of 11ß-HSD1 was increased in the liver of GHRKO (2.7-fold, p < 0.05) and GHA mice (2.0-fold, p < 0.05) compared to WT controls, but not gastrocnemius muscle, subcutaneous adipose tissue or epididymal adipose tissue. In summary, we have demonstrated a negative relationship between GH action and 11ß-HSD1 expression which appears to be tissue specific. These data provide evidence that increased intracellular cortisol production within key tissues may contribute to metabolic disease in GHD patients.

Role of growth hormone in hepatic and intestinal triglyceride-rich lipoprotein metabolism.

BACKGROUND: Elevated plasma concentrations of hepatic- and intestinally-derived triglyceride-rich lipoproteins (TRL) are implicated in the pathogenesis of atherosclerotic cardiovascular disease and all-cause mortality. Excess of TRL is the driving cause of atherogenic dyslipidemia commonly occurring in insulin-resistant individuals such as patients with obesity, type 2 diabetes and metabolic syndrome. Interestingly, growth hormone (GH)-deficient individuals display similar atherogenic dyslipidemia, suggesting an important role of GH and GH deficiency in the regulation of TRL metabolism. OBJECTIVE: We aimed to examine the direct and/or indirect role of GH on TRL metabolism. METHODS: We investigated the effect on fasting and postprandial hepatic-TRL and intestinal-TRL metabolism of short-term (one month) withdrawal of GH in 10 GH-deficient adults. RESULTS: After GH withdrawal, we found a reduction in fasting plasma TRL concentration (significant decrease in TRL-TG, TRL-cholesterol, TRL-apoB-100, TRL-apoC-III and TRL-apoC-II) but not in postprandial TRL response. This reduction was due to fewer fasting TRL particles without a change in TG per particle and was not accompanied by a change in postprandial TRL-apoB-48 response. Individual reductions in TRL correlated strongly with increases in insulin sensitivity and decreases in TRL-apoC-III. CONCLUSION: In this relatively short term 'loss of function' human experimental model, we have shown an unanticipated reduction of hepatic-TRL particles despite increase in total body fat mass and reduction in lean mass. These findings contrast with the atherogenic dyslipidemia previously described in chronic GH deficient states, providing a new perspective for the role of GH in lipoprotein metabolism.

GH directly inhibits steatosis and liver injury in a sex-dependent and IGF1-independent manner.

A reduction in hepatocyte growth hormone (GH)-signaling promotes non-alcoholic fatty liver disease (NAFLD). However, debate remains as to the relative contribution of the direct effects of GH on hepatocyte function vs indirect effects, via alterations in insulin-like growth factor 1 (IGF1). To isolate the role of hepatocyte GH receptor (GHR) signaling, independent of changes in IGF1, mice with adult-onset, hepatocyte-specific GHR knockdown (aHepGHRkd) were treated with a vector expressing rat IGF1 targeted specifically to hepatocytes. Compared to GHR-intact mice, aHepGHRkd reduced circulating IGF1 and elevated GH. In male aHepGHRkd, the shift in IGF1/GH did not alter plasma glucose or non-esterified fatty acids (NEFA), but was associated with increased insulin, enhanced systemic lipid oxidation and reduced white adipose tissue (WAT) mass. Livers of male aHepGHRkd exhibited steatosis associated with increased de novo lipogenesis, hepatocyte ballooning and inflammation. In female aHepGHRkd, hepatic GHR protein levels were not detectable, but moderate levels of IGF1 were maintained, with minimal alterations in systemic metabolism and no evidence of steatosis. Reconstitution of hepatocyte IGF1 in male aHepGHRkd lowered GH and normalized insulin, whole body lipid utilization and WAT mass. However, IGF1 reconstitution did not reduce steatosis or eliminate liver injury. RNAseq analysis showed IGF1 reconstitution did not impact aHepGHRkd-induced changes in liver gene expression, despite changes in systemic metabolism. These results demonstrate the impact of aHepGHRkd is sexually dimorphic and the steatosis and liver injury observed in male aHepGHRkd mice is autonomous of IGF1, suggesting GH acts directly on the adult hepatocyte to control NAFLD progression.

Cholinergic neurons in the hypothalamus and dorsal motor nucleus of the vagus are directly responsive to growth hormone.

AIMS: Cholinergic neurons are distributed in brain areas containing growth hormone (GH)-responsive cells. We determined if cholinergic neurons are directly responsive to GH and the metabolic consequences of deleting the GH receptor (GHR) specifically in choline acetyltransferase (ChAT)-expressing cells. MAIN METHODS: Mice received an acute injection of GH to detect neurons co-expressing ChAT and phosphorylated STAT5 (pSTAT5), a well-established marker of GH-responsive cells. For the physiological studies, mice carrying ablation of GHR exclusively in ChAT-expressing cells were produced and possible changes in energy and glucose homeostasis were determined when consuming regular chow or high-fat diet (HFD). KEY FINDINGS: The majority of cholinergic neurons in the arcuate nucleus (60%) and dorsomedial nucleus (84%) of the hypothalamus are directly responsive to GH. Approximately 34% of pre-ganglionic parasympathetic neurons in the dorsal motor nucleus of the vagus also exhibited GH-induced pSTAT5. GH-induced pSTAT5 in these ChAT neurons was absent in GHR ChAT knockout mice. Mice carrying ChAT-specific GHR deletion, either in chow or HFD, did not exhibit significant changes in body weight, body adiposity, lean body mass, food intake, energy expenditure, respiratory quotient, ambulatory activity, serum leptin levels, glucose tolerance, insulin sensitivity and metabolic responses to 2-deoxy-d-glucose. However, GHR deletion in ChAT neurons caused decreased hypothalamic Pomc mRNA levels in HFD mice. SIGNIFICANCE: Cholinergic neurons that regulate the metabolism are directly responsive to GH, although GHR signaling in these cells is not required for energy and glucose homeostasis. Thus, the physiological importance of GH action on cholinergic neurons still needs to be identified.

Classical and novel GH receptor signaling pathways.

In this review, I summarize historical and recent features of the classical pathways activated by growth hormone (GH) through the cell surface GH receptor (GHR). GHR is a cytokine receptor superfamily member that signals by activating the non-receptor tyrosine kinase, JAK2, and members of the Src family kinases. Activation of the GHR engages STATs, PI3K, and ERK pathways, among others, and details of these now-classical pathways are presented. Modulating elements, including the SOCS proteins, phosphatases, and regulated GHR metalloproteolysis, are discussed. In addition, a novel physical and functional interaction of GHR with IGF-1R is summarized and discussed in terms of its mechanisms, consequences, and physiological and therapeutic implications.

Nutrition and growth in children.

The well-balanced nourishment during "the first 1000 days," the period between conception (day 18) and the age of two years, is quite important for two main reasons. Firstly, the nutritive requirement is high due to the rapid physiological growth and functional development. Then, this period is characterized by extreme susceptibility to external stimuli such as inadequate maternal and infant nutritional status which they can interfere with the different stages of the development process leading to short and long-term consequences for health. Linear growth and brain development are particularly impaired from not sufficient nutrition. In consideration of the irreversible damage of malnutrition, especially on developing brain, an adequate nutrition during the first 1000 days of life is paramount. The aim of this review was to overview the latest scientific evidences on the relationship between nutrition and growth, focusing on nutritional requirements during the first 1000 days, and the impact of inadequate nutrition on brain development and linear growth.

Regulatory role of NF-κB in growth plate chondrogenesis and its functional interaction with Growth Hormone.

Nuclear Factor kappa B (NF-kB) is a family of transcription factors that participates in the regulation of cell proliferation, migration, and apoptosis. Impaired NF-kB activity appears to be involved in the pathophysiology of inflammatory states, autoimmune diseases, and cancer. Genetic manipulation in mice leading to impaired NF-kB function is associated with abnormal limb development and delayed bone growth. We have previously shown in rodent cultured chondrocytes and cultured metatarsal bones that NF-kB promotes longitudinal bone growth and growth plate chondrocyte function. These NF-kB growth-promoting effects appear to be facilitated by Growth Hormone (GH) and Insulin-like Growth factor-1 (IGF-1). These stimulatory effects of GH and IGF-1 on NF-kB activity are supported by observational evidence in humans; a number of individuals carrying mutations that alter NF-kB function exhibit growth failure and GH insensitivity.

Functional changes of the liver in the absence of growth hormone (GH) action - Proteomic and metabolomic insights from a GH receptor deficient pig model.

OBJECTIVE: The liver is a central target organ of growth hormone (GH), which stimulates the synthesis of insulin-like growth factor 1 (IGF1) and affects multiple biochemical pathways. A systematic multi-omics analysis of GH effects in the liver has not been performed. GH receptor (GHR) deficiency is a unique model for studying the consequences of lacking GH action. In this study, we used molecular profiling techniques to capture a broad spectrum of these effects in the liver of a clinically relevant large animal model for Laron syndrome. METHODS: We performed holistic proteome and targeted metabolome analyses of liver samples from 6-month-old GHR-deficient (GHR-KO) pigs and GHR-expressing controls (four males, four females per group). RESULTS: GHR deficiency resulted in an increased abundance of enzymes involved in amino acid degradation, in the urea cycle, and in the tricarboxylic acid cycle. A decreased ratio of long-chain acylcarnitines to free carnitine suggested reduced activity of carnitine palmitoyltransferase 1A and thus reduced mitochondrial import of fatty acids for beta-oxidation. Increased levels of short-chain acylcarnitines in the liver and in the circulation of GHR-KO pigs may result from impaired beta-oxidation of short-chain fatty acids or from increased degradation of specific amino acids. The concentration of mono-unsaturated glycerophosphocholines was significantly increased in the liver of GHR-KO pigs without morphological signs of steatosis, although the abundances of several proteins functionally linked to non-alcoholic fatty liver disease (fetuin B, retinol binding protein 4, several mitochondrial proteins) were increased. Moreover, GHR-deficient liver samples revealed distinct changes in the methionine and glutathione metabolic pathways, in particular, a significantly increased level of glycine N-methyltransferase and increased levels of total and free glutathione. Several proteins revealed a sex-related abundance difference in the control group but not in the GHR-KO group. CONCLUSIONS: Our integrated proteomics/targeted metabolomics study of GHR-deficient and control liver samples from a clinically relevant large animal model identified a spectrum of biological pathways that are significantly altered in the absence of GH action. Moreover, new insights into the role of GH in the sex-related specification of liver functions were provided.

Normal and Abnormal Growth in the Pediatric Patient.

Proper growth is a marker of the overall health of a child. Growth monitoring in infancy and childhood is a central part of preventative child health programs. For early recognition of pathological causes of growth failure, accurate measurements of height and weight using standardized methods is fundamental. The general pediatrician is a key participant, as he/she provides the auxological data to determine if further testing is needed. This review provides an outline for the general pediatrician for proper auxological measurements, normal variants versus abnormal growth, initial testing for abnormal growth, and when to refer to a pediatric endocrinologist.

Growth Hormone(s), Testosterone, Insulin-Like Growth Factors, and Cortisol: Roles and Integration for Cellular Development and Growth With Exercise.

Hormones are largely responsible for the integrated communication of several physiological systems responsible for modulating cellular growth and development. Although the specific hormonal influence must be considered within the context of the entire endocrine system and its relationship with other physiological systems, three key hormones are considered the "anabolic giants" in cellular growth and repair: testosterone, the growth hormone superfamily, and the insulin-like growth factor (IGF) superfamily. In addition to these anabolic hormones, glucocorticoids, mainly cortisol must also be considered because of their profound opposing influence on human skeletal muscle anabolism in many instances. This review presents emerging research on: (1) Testosterone signaling pathways, responses, and adaptations to resistance training; (2) Growth hormone: presents new complexity with exercise stress; (3) Current perspectives on IGF-I and physiological adaptations and complexity these hormones as related to training; and (4) Glucocorticoid roles in integrated communication for anabolic/catabolic signaling. Specifically, the review describes (1) Testosterone as the primary anabolic hormone, with an anabolic influence largely dictated primarily by genomic and possible non-genomic signaling, satellite cell activation, interaction with other anabolic signaling pathways, upregulation or downregulation of the androgen receptor, and potential roles in co-activators and transcriptional activity; (2) Differential influences of growth hormones depending on the "type" of the hormone being assayed and the magnitude of the physiological stress; (3) The exquisite regulation of IGF-1 by a family of binding proteins (IGFBPs 1-6), which can either stimulate or inhibit biological action depending on binding; and (4) Circadian patterning and newly discovered variants of glucocorticoid isoforms largely dictating glucocorticoid sensitivity and catabolic, muscle sparing, or pathological influence. The downstream integrated anabolic and catabolic mechanisms of these hormones not only affect the ability of skeletal muscle to generate force; they also have implications for pharmaceutical treatments, aging, and prevalent chronic conditions such as metabolic syndrome, insulin resistance, and hypertension. Thus, advances in our understanding of hormones that impact anabolic: catabolic processes have relevance for athletes and the general population, alike.

Regulation of gene expression by growth hormone.

Growth hormone (GH) plays a pivotal role in many physiological processes in humans, and in other mammalian and non-mammalian vertebrate species, through actions on somatic growth, tissue development and repair, and intermediary metabolism. This review will focus on mechanisms of GH actions on gene expression, primarily from the perspective of the genes that encode proteins stimulated by GH to regulate somatic growth, especially insulin-like growth factor 1 (IGF-I), but also others that are induced or repressed by GH. Topics to be discussed will include a brief overview of GH-mediated signal transduction pathways and how these cascades alter the functions of responsive transcription factors, with a specific focus on STAT5B, a key member of the signal transducers and activators of transcription family, characterization of essential GH-regulated genes, and elucidation of mechanisms of their regulation from biochemical, genetic, and genomic perspectives.