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.

Factors affecting prepubertal and pubertal bone age progression.

Bone age (BA) is a clinical marker of bone maturation which indicates the developmental stage of endochondral ossification at the epiphysis and the growth plate. Hormones that promote the endochondral ossification process include growth hormone, insulin-like growth factor-1, thyroid hormone, estrogens, and androgens. In particular, estrogens are essential for growth plate fusion and closure in both sexes. Bone maturation in female children is more advanced than in male children of all ages. The promotion of bone maturation seen in females before the onset of puberty is thought to be an effect of estrogen because estrogen levels are higher in females than in males before puberty. Sex hormones are essential for bone maturation during puberty. Since females have their pubertal onset about two years earlier than males, bone maturation in females is more advanced than in males during puberty. In the present study, we aimed to review the factors affecting prepubertal and pubertal BA progression, BA progression in children with hypogonadism, and bone maturation and deformities in children with Turner syndrome.

Reduced Growth Hormone Response to Anaerobic Exercise Among Children With Overweight and Obesity.

ABSTRACT: Hejla, D, Dror, N, Pantanowitz, M, Nemet, D, and Eliakim, A. Reduced growth hormone response to anaerobic exercise among children with overweight and obesity. J Strength Cond Res 36(8): 2194-2197, 2022-The aim of the present study was to examine the effect of an anaerobic exercise test on growth hormone (GH) secretion in children with overweight and obesity compared with children with normal weight. Fifteen children with overweight (body mass index percentile [BMI%ile] ≥85 < 95) and obesity (BMI%ile ≥95) and 10 children with normal weight (BMI%ile >5 < 85) participated in the study. Subjects performed a modification of the Wingate anaerobic test (WAnT), with 10 bouts of 15-second cycling separated by 1 minute of rest. Blood samples for GH and lactate were collected before and 15, 30, 45, and 60 minutes after the beginning of the exercise test. There was a significant increase in GH levels following the modified repeated WAnT in both groups, but the increase in GH levels was significantly greater among the normal weight children compared with those with overweight and obesity ( p < 0.003). Seven of the 10 subjects with normal weight had GH increase above the threshold for GH sufficiency compared with only 2 subjects with overweight and obesity. Growth hormone response to the modified repeated WAnT was significantly reduced among children with overweight and obesity compared with those with normal weight. Anaerobic interval-type training may not be a sufficient exercise alternative to stimulate appropriate GH levels among children with obesity.

The heart in growth hormone (GH) deficiency and the cardiovascular effects of GH.

Besides its effects on longitudinal growth in childhood and its metabolic effects with consequences on body composition and lipid levels, growth hormone (GH) has important roles on maintaining the structure and function of the normal adult heart. GH/insulin like growth factor-I (IGF-I) also interacts with the vascular system and plays a role in the regulation of vascular tone. GH deficiency (GHD) in adulthood is associated with increased fat mass (particularly visceral) and abnormal lipid profile, which may contribute to the excess cardiovascular mortality observed in patients with panhypopituitarism. Treatment with GH improved body composition (by increasing lean mass and decreasing fat mass) and improved lipid profile. It also has beneficial effects on vascular walls. The improvement in cardiovascular morbidity and mortality induced by GH is less clear as data are scarce and obtained on small populations. The importance of alteration in cardiac morphology and function observed in GHD is debated, particularly when cardiac magnetic resonance is used rather than echocardiography. The effects of treatment with GH on heart function and morphology are modest when studied by echocardiography.

Role of the GH-IGF1 system in progression of cancer.

Emerging evidence links the growth hormone (GH)-insulin-like growth factor-1 (IGF1) endocrine axis to cancer development. While this putative correlation is of major translational relevance, most clinical and epidemiological reports to date found no causal linkage between GH therapy and enhanced cancer risk. Thus, it is generally agreed that GH therapy constitutes a safe pharmacological intervention. The present review focuses on a number of issues in the area of GH-IGF1 action in cancer development. Emphasis is given to the idea that GH and IGF1 do not conform to the definition of oncogenic factors. Specifically, these hormones, even at high pharmacological doses, are unable to induce malignant transformation. However, the GH-IGF1 axis is capable of 'pushing' already transformed cells through the various phases of the cell cycle. Viral and cellular oncogenes require an intact IGF1 signaling pathway in order to elicit transformation; in other words, oncogenic agents adopt the IGF1 pathway. This universal mechanism of action of oncogenes has broad implications in oncology. Our review provides an in-depth analysis of the interplay between the GH-IGF1 axis and cancer genes, including tumor suppressors p53 and BRCA1. Finally, the safety of GH therapy in both children and adults needs further long-term follow-up studies.

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.

Disorders caused by genetic defects associated with GH-dependent genes: PAPPA2 defects.

Growth hormone (GH) and its mediator, insulin-like growth factor-1 (IGF-1), have long been recognized as central to human growth physiology. IGF-1 is known to complex with IGF binding proteins as well as with the acid labile subunit (ALS) in order to prolong its half-life in circulation. Factors regulating the bioavailability of IGF-1 (i.e. the balance between free and bound IGF-1) were less well understood. Recently, pregnancy-associated plasma protein-A2 (PAPP-A2) was discovered as a protease which specifically cleaves IGF-binding protein (IGFBP)-3 and -5. PAPP-A2 deficient patients present with characteristic findings including growth failure, elevated total IGF-1 and -2, IGFBPs, and ALS, but decreased percentage of free to total IGF-1. Additionally, patients with PAPP-A2 deficiency have impairments in glucose metabolism and bone mineral density (BMD). Treatment with recombinant human IGF-1 (rhIGF-1) improved height SD scores, growth velocity, body composition, and dysglycemia. Mouse models recapitulate many of the human findings of PAPP-A2 deficiency. This review summarizes the function of PAPP-A2 and its contribution to the GH-IGF axis through an examination of PAPP-A2 deficient patients and mouse models, thereby emphasizing the importance of the regulation of IGF-1 bioavailability in human growth.

Insulin signaling in the whole spectrum of GH deficiency

ABSTRACT GH is one of the insulin counterregulatory hormones which acts in the opposite way to insulin, increasing the glucose production by the liver and kidneys and decreasing glucose uptake from peripheral tissues, thus being a hyperglycemic hormone. When in excess, as in acromegaly, it induces glucose intolerance and diabetes. As expected, patients with GH deficiency (GHD) have hypoglycemia, especially in early childhood, but as GH is also a lipolytic hormone, these patients are becoming obese with higher percentages of body fat. Although obesity in general is directly related to insulin resistance, in patients with GH secretion disorders this relationship may be altered. In acromegaly there is a decrease in fat mass with worsening insulin sensitivity and mice with isolated GHD are characterized by greater insulin sensitivity despite excess fat mass. In humans with GHD, body composition shows increased body fat and decreased free fat mass, but the results regarding insulin sensitivity are still controversial in these patients. These discrepant results regarding insulin sensitivity in patients with GHD suggest the existence of other variables influencing these results. In the present review, we will try to follow the path of the different researches conducted on this subject, both in animal and human models, with the goal of understanding the current knowledge of insulin sensitivity across the spectrum of GHD. Arch Endocrinol Metab. 2019;63(6):582-91

Growth hormone in the tumor microenvironment

ABSTRACT Tumor development is a multistep process whereby local mechanisms enable somatic mutations during preneoplastic stages. Once a tumor develops, it becomes a complex organ composed of multiple cell types. Interactions between malignant and non-transformed cells and tissues create a tumor microenvironment (TME) comprising epithelial cancer cells, cancer stem cells, non-tumorous cells, stromal cells, immune-inflammatory cells, blood and lymphatic vascular network, and extracellular matrix. We review reports and present a hypothesis that postulates the involvement of growth hormone (GH) in field cancerization. We discuss GH contribution to TME, promoting epithelial-to-mesenchymal transition, accumulation of unrepaired DNA damage, tumor vascularity, and resistance to therapy. Arch Endocrinol Metab. 2019;63(6):568-75

Resistance exercise-induced hormonal response promotes satellite cell proliferation in untrained men but not in women.

The purpose of this work was to determine the effect of resistance exercise (RE)-induced hormonal changes on the satellite cell (SC) myogenic state in response to muscle damage. Untrained men (n = 10, 22 ± 3 yr) and women (n = 9, 21 ± 4 yr) completed 2 sessions of 80 unilateral maximal eccentric knee extensions followed by either an upper body RE protocol (EX) or a 20-min rest (CON). Muscle samples were collected and analyzed for protein content of Pax7, MyoD, myogenin, cyclin D1, and p21 before (PRE), 12 h, and 24 h after the session was completed. Serum testosterone, growth hormone, cortisol, and myoglobin concentrations were analyzed at PRE, post-damage, immediately after (IP), and 15, 30, and 60 min after the session was completed. Testosterone was significantly (P < 0.05) higher immediately after the session in EX vs. CON for men. A significant time × sex × condition interaction was found for MyoD with an increase in EX (men) and CON (women) at 12 h. A significant time × condition interaction was found for Pax7, with a decrease in EX and increase in CON at 24 h. A significant time effect was found for myogenin, p21, and cyclin D1. Myogenin and p21 were increased at 12 and 24 h, and cyclin D1 was increased at 12 h. These results suggest that the acute RE-induced hormonal response can be important for men to promote SC proliferation after muscle damage but had no effect in women. Markers of SC differentiation appeared unaffected by the hormonal response but increased in response to muscle damage.

[Aging and growthhormone: assumptions and facts (review of literature).]

Growth hormone is a powerful metabolic hormone with pleiotropic effects, which is positioned as a "source of youth". Somatotropin has various functions: stimulation of bone growth, regulation of carbohydrate, protein, lipid metabolism, metabolic function of the liver and energy balance. At the cellular level, somatotropic hormone regulates cell growth, differentiation, apoptosis, and cytoskeleton reorganization. The review article presents the results of topical studies that reflect the relationship of growth hormone deficiency or resistance to it with the development of aging and diseases associated with age, as well as with an increase in life expectancy.

Insulin signaling in the whole spectrum of GH deficiency.

GH is one of the insulin counterregulatory hormones which acts in the opposite way to insulin, increasing the glucose production by the liver and kidneys and decreasing glucose uptake from peripheral tissues, thus being a hyperglycemic hormone. When in excess, as in acromegaly, it induces glucose intolerance and diabetes. As expected, patients with GH deficiency (GHD) have hypoglycemia, especially in early childhood, but as GH is also a lipolytic hormone, these patients are becoming obese with higher percentages of body fat. Although obesity in general is directly related to insulin resistance, in patients with GH secretion disorders this relationship may be altered. In acromegaly there is a decrease in fat mass with worsening insulin sensitivity and mice with isolated GHD are characterized by greater insulin sensitivity despite excess fat mass. In humans with GHD, body composition shows increased body fat and decreased free fat mass, but the results regarding insulin sensitivity are still controversial in these patients. These discrepant results regarding insulin sensitivity in patients with GHD suggest the existence of other variables influencing these results. In the present review, we will try to follow the path of the different researches conducted on this subject, both in animal and human models, with the goal of understanding the current knowledge of insulin sensitivity across the spectrum of GHD. Arch Endocrinol Metab. 2019;63(6):582-91.

Growth hormone in the tumor microenvironment.

Tumor development is a multistep process whereby local mechanisms enable somatic mutations during preneoplastic stages. Once a tumor develops, it becomes a complex organ composed of multiple cell types. Interactions between malignant and non-transformed cells and tissues create a tumor microenvironment (TME) comprising epithelial cancer cells, cancer stem cells, non-tumorous cells, stromal cells, immune-inflammatory cells, blood and lymphatic vascular network, and extracellular matrix. We review reports and present a hypothesis that postulates the involvement of growth hormone (GH) in field cancerization. We discuss GH contribution to TME, promoting epithelial-to-mesenchymal transition, accumulation of unrepaired DNA damage, tumor vascularity, and resistance to therapy. Arch Endocrinol Metab. 2019;63(6):568-75.

The Use and Abuse of Human Growth Hormone in Sports.

CONTEXT: Recombinant human growth hormone (rHGH) has become a target of abuse in the sporting world. Conversely, sports medicine clinicians may encounter athletes using rHGH to achieve normalcy in the context of growth hormone (GH) deficiency. EVIDENCE ACQUISITION: Medline and PubMed databases were queried using the following keywords: GH, GH physiology, GH deficiency, acromegaly, GH athlete, GH sports, GH athletic performance, and GH deficiency concussion. Articles focusing on GH physiology, deficiency, excess, and its effects in both deficient and healthy patients were included. STUDY DESIGN: Clinical review. LEVEL OF EVIDENCE: Level 3. RESULTS: GH is a naturally occurring hormone with important roles in human physiology. Patients with GH deficiency (GHD) present variably, and GHD has numerous etiologies. rHGH treatment has substantial therapeutic benefits for patients with GHD. The benefits of rHGH treatment in otherwise-healthy adults are uncertain. GH excess may cause health problems such as acromegaly. Professional, collegiate, and international sports leagues and associations have banned rHGH use to maintain athlete health, safety, and fair play. Athletes misusing GH may face prolonged suspensions from competition. Implementing GH abuse testing is challenging, but new methods, such as the biomarker testing procedure, are being finalized. CONCLUSION: rHGH is not only an important therapeutic agent for GH-deficient patients but also a target of abuse in competitive athletics. Its benefits in a healthy, adult population are uncertain. A safe exercise and competition plan, developed with a physician knowledgeable of GH use, physiology, and abuse potential, should be of benefit to a longitudinal clinician-patient relationship.

MECHANISMS IN ENDOCRINOLOGY: Lessons from growth hormone receptor gene-disrupted mice: are there benefits of endocrine defects?

Growth hormone (GH) is produced primarily by anterior pituitary somatotroph cells. Numerous acute human (h) GH treatment and long-term follow-up studies and extensive use of animal models of GH action have shaped the body of GH research over the past 70 years. Work on the GH receptor (R)-knockout (GHRKO) mice and results of studies on GH-resistant Laron Syndrome (LS) patients have helped define many physiological actions of GH including those dealing with metabolism, obesity, cancer, diabetes, cognition and aging/longevity. In this review, we have discussed several issues dealing with these biological effects of GH and attempt to answer the question of whether decreased GH action may be beneficial.