ABSTRACT

Growth hormone (GH) is an ancestral hormone, secreted episodically from somatotroph cells in the anterior pituitary. Since the recognition of its multiple and complex effects in the early 1960s, the physiology and regulation of GH has become a major area of research interest in the field of endocrinology. In adulthood its main role is to regulate metabolism. Pituitary synthesis and secretion of GH is stimulated by episodic hypothalamic secretion of GH releasing factor and inhibited by somatostatin. Insulin-like Growth Factor I (IGF-I) inhibits GH secretion by a negative loop at both hypothalamic and pituitary levels. In addition, age, gender, pubertal status, food, exercise, fasting, sleep, and body composition play important regulatory roles. GH acts both directly through its own receptors and indirectly through the induced production of IGF-I. Their effects may be synergic (stimulate growth) or antagonistic as for the effect on glucose metabolism: GH stimulates lipolysis and promotes insulin resistance, whereas IGF-I acts as an insulin agonist. The bioactivity of IGF-I is tightly controlled by a multitude of IGF-I binding globulins. The mechanisms to explain the insulin antagonist effect of GH in humans are causally linked to lipolysis and ensuing elevated levels of circulating free fatty acids (FFA). The nitrogen retaining properties of GH predominantly involve stimulation of protein synthesis, which could be either direct or mediated through IGF-I, insulin, or lipid intermediates. In this chapter the normal physiology of GH secretion and the effects of GH on intermediary metabolism throughout adulthood, focusing on human studies, are presented. For complete coverage of all related areas of Endocrinology, please visit our on-line FREE web-text, WWW.ENDOTEXT.ORG.

INTRODUCTION

Harvey Cushing proposed in 1912 in his monograph “The Pituitary Gland” the existence of a “hormone of growth” and was thereby among the first to indicate that the primary action of growth hormone (GH) was to control and promote skeletal growth. In clinical medicine GH (also called somatotrophin) was previously known for its role on promoting growth of hypopituitary children, and for its adverse effects in connection with hypersecretion as observed in acromegaly. The multiple and complex actions of human GH were, however, acknowledged shortly after the advent of pituitary derived preparation of the hormone in the late fifties, as reviewed by Raben in 1962 (1).

In the present chapter we will briefly review the normal physiology of GH secretion and the effects of GH on intermediary metabolism throughout adulthood. Other important physiological effects of GH are presented in the review on GH replacement in adults.

GROWTH HORMONE

GH is a single chain protein with 191 amino-acids and two disulfide bonds. The human GH gene is located on chromosome 17q22 as part of a locus that comprises five genes. In addition to two GH related genes (GH1 that codes for the main adult growth hormone, produced in the somatotrophic cells found in the anterior pituitary gland and, to a minor extent, in lymphocytes, and GH2 that codes for the placental GH), there are three genes coding for chorionic somatomammotropin (CSH1, CSH2 and CSHL) (also known as placental lactogen) genes (2,3). The GH1 gene encodes two distinct GH isoforms (22 kDa and 20 kDa). The principal and most abundant GH form in pituitary and blood is monomeric 22K-GH isoform, representing also the recombinant GH available for therapeutic use (and subsequently for doping purposes) (3). Administration of recombinant 22K-GH exogenously leads to a decrease in the 20K-GH isoform and testing both isoforms is used to detect GH doping in sports (4).

As already mentioned, GH is secreted by the somatotroph cells located primarily in the lateral wings of the anterior pituitary. A recent single cell RNA sequencing study performed in mice showed that GH-expressing cells, representing the somatotrophs, are the most abundant cell population in adult pituitary gland (5). The differentiation of somatotroph cell is governed by the pituitary transcription factor 1 (Pit-1). Data in mice suggests that the pituitary holds regenerative competence, the GH-producing cells being regenerated from the pituitary’s stem cells in young animals after a period of 5 months (6).

Physiological Regulation of GH Secretion

The morphological characteristics and number of somatotrophs are remarkably constant throughout life, while the secretion pattern changes. GH secretion occurs in a pulsatile fashion, and in a circadian rhythm with a maximal release in the second half of the night. So, sleep is an important physiological factor that increases GH release. Interestingly, the maximum GH levels occur within minutes of the onset of slow wave sleep and there is marked sexual dimorphism of the nocturnal GH increase in humans, constituting only a fraction of the total daily GH release in women, but the bulk of GH output in men (7).

GH secretion is also gender, pubertal status, and age dependent (Figure 1) (8). Integrated 24 h GH concentration is significantly greater in women than in men and greater in the young than in the old adults. The serum concentration of free estradiol, but not free testosterone, correlates with GH and when correcting for the effects of estradiol, neither gender nor age influence GH concentration. This suggests that estrogens play a crucial role in modulating GH secretion (8). During puberty, a 3-fold increase in pulsatile GH secretion occurs that peaks around the age of 15 years (yr) in girls and 1 yr later in boys (9).

Figure 1.

The secretory pattern of GH in young and old females and males. In young individuals the GH pulses are larger and more frequent and females secrete more GH than men (modified from (8)).

Pituitary synthesis and secretion of GH is stimulated by episodic hypothalamic hormones. Growth hormone releasing hormone (GHRH) stimulates while somatostatin (SST) inhibits GH production and release. GH stimulates IGF-I production which in turn inhibits GH secretion at both hypothalamic and pituitary levels. The gastric peptide ghrelin is also a potent GH secretagogue, which acts to boost hypothalamic GHRH secretion and synergize with its pituitary GH-stimulating effects (Figure 2) (10). Interestingly, recently germline or somatic duplication of GPR101 constitutively activates the cAMP pathway in the absence of a ligand, leading to GH release. Although GPR101 physiology is unclear it is worth mentioning it since it clearly has an effect on GH physiology (11).

In addition, a multitude of other factors may impact the GH axis most probably due to interaction with GHRH, somatostatin, and ghrelin. Estrogens stimulate the secretion of GH but inhibit the action of GH on the liver by suppressing GH receptor (GHR) signaling. In contrast, androgens enhance the peripheral actions of GH (12). Exogenous estrogens potentiate pituitary GH responses to submaximal effective pulses of exogenous GHRH (13) and mutes inhibition by exogenous SST (14). Also, exogenous estrogen potentiates ghrelin action (15).

GH release correlates inversely with intraabdominal visceral adiposity via mechanisms that may depend on increased FFA flux, elevated insulin, or free IGF-I.

Figure 2.

Factors that stimulate and suppress GH secretion under physiological conditions.

GROWTH HORMONE RELEASING HORMONE (GHRH)

GHRH is a 44 amino-acid polypeptide produced in the arcuate nucleus of the hypothalamus. These neuronal terminals secrete GHRH to reach the anterior pituitary somatotrophs via the portal venous system, which leads to GH transcription and secretion. Moreover, animal studies have demonstrated that GHRH plays a vital role in the proliferation of somatotrophs in the anterior pituitary, whereas the absence of GHRH leads to anterior pituitary hypoplasia (16). In addition, GHRH upregulates GH gene expression and stimulates GH release (17). The secretion of GHRH is stimulated by several factors including depolarization, α2-adrenergic stimulation, hypophysectomy, thyroidectomy, and hypoglycemia and it is inhibited by somatostatin, IGF-I, and activation of GABAergic neurons.

GHRH acts on the somatotrophs via a seven trans-membrane G protein-coupled stimulatory cell-surface receptor. This receptor has been extensively studied over the last decade leading to the identification of several important mutations. Point mutations in the GHRH receptors, as illustrated by studies done on the lit/lit dwarf mice, showed a profound impact on subsequent somatotroph proliferation leading to anterior pituitary hypoplasia (18). Unlike the mutations in the Pit-1 and PROP-1 genes, which lead to multiple pituitary hormone deficiencies and anterior pituitary hypoplasia, mutations in the GHRH receptor leads to profound GH deficiency with anterior pituitary hypoplasia. Subsequently to the first GHRH receptor mutation described in 1996 (19) an array of familial GHRH receptor mutations have been recognized over the last decade. These mutations account for almost 10% of the familial isolated GH deficiencies. An affected individual will present with short stature and a hypoplastic anterior pituitary. However, they lack certain typical features of GH deficiency such as midfacial hypoplasia, microphallus, and neonatal hypoglycemia (20).

SOMATOSTATIN (SST)

SST is a cyclic peptide, encoded by a single gene in humans, which mostly exerts inhibitory effects on endocrine and exocrine secretions. Many cells in the body, including specialized cells in the anterior periventricular nucleus and arcuate nucleus, produce SST. These neurons secrete SST into the adenohypophyseal portal venous system, via the median eminence, to exert effect on the anterior pituitary. SST has a short half-life of approximately 2 minutes as it is rapidly inactivated by tissue peptidase in humans. The secretion of SST by the hypothalamic neurons is inhibited by high blood glucose and is stimulated by serum GH/IGF-I level, exercise, and immobilization (21).

SST acts via a seven trans-membrane, G protein coupled receptor and, thus far, five subtypes of the receptor have been identified in humans (SSTR1-5). Although all five receptor subtypes are expressed in the human fetal pituitary, adult pituitary only express 4 subtypes (SSTR1, SSTR2, SSTR3, SSTR5). Out of these four subtypes, somatotrophs exhibit more sensitivity to SSTR2 and SSTR5 ligands in inhibiting the secretion of GH in a synergistic manner (22).

GHRELIN

Ghrelin is a 28 amino-acid peptide that is the natural ligand for the GH secretagogue receptor. In fact, ghrelin and GHRH have a synergistic effect in increasing circulating GH levels (7). Ghrelin is primarily secreted by stomach and may be involved in the GH response to fasting and food intake.

Clinical Implications

GH LEVELS- INFLUENCE ON BODY COMPOSISTION, PHYSICAL FITNESS, AND AGE

With the introduction of dependable radioimmunological assays, it was recognized that circulating GH is blunted in obese subjects, and that normal aging is accompanied by a gradual decline in GH levels (23,24). It has been hypothesized that many of the senescent changes in body composition and organ function are related to or caused by decreased GH (25), also known as “the somatopause”.

Studies done in the late 90s have uniformly documented that adults with severe GH deficiency are characterized by increased fat mass and reduced lean body mass (LBM) (26). It is also known that normal GH levels can be restored in obese subjects following massive weight loss (27), and that GH substitution in GH-deficient adults normalizes body composition. What remains unknown is the cause-effect relationship between decreased GH levels and senescent changes in body composition. Is the propensity for gaining fat and losing lean body mass initiated or preceded by a primary age-dependent decline in GH secretion and action? Alternatively, accumulation of fat mass secondary to non-GH dependent factors (e.g., lifestyle, dietary habits) results in a feedback inhibition of GH secretion. Moreover, little is known about possible age-associated changes in GH pharmacokinetics and bioactivity.

Cross sectional studies done to assess the association between body composition and stimulated GH release in healthy subjects show that, adult people (mean age 50 yr) have a lower peak GH response to secretagogues (clonidine and arginine), and females had a higher response to arginine when compared to males. Multiple regression analysis, however, reveal that intra-abdominal fat mass is the most important and negative predictor of peak GH levels as previously mentioned (Figure 3) (28). In the same population, 24-h spontaneous GH levels also predominantly correlated inversely with intra-abdominal fat mass (29).

Figure 3.

Correlation between intra-abdominal fat mass and 24-hour GH secretion.

A detailed analysis of GH secretion in relation to body composition in elderly subjects has, to our knowledge, not been performed. Instead, serum IGF-I has been used as a surrogate or proxy for GH status in several studies of elderly men (30-32). These studies comprise large populations of ambulatory, community-dwelling males aged between 50-90 yr. As expected, the serum IGF-I declined with age (Figure 4), but IGF-I failed to show any significant association with body composition or physical performance.

Figure 4.

Changes in serum IGF-I with age; modified from (33).

GH ACTION - INFLUENCE OF AGE, SEX, AND BODY COMPOSITION

Considering the great interest in the actions of GH in adults, surprisingly few studies have addressed possible age associated differences in the responsiveness or sensitivity to GH. In normal adults the senescent decline in GH levels is paralleled by a decline in serum IGF-I, suggesting a down-regulation of the GH-IGF-I axis. Administration of GH to elderly healthy adults has generally been associated with predictable, albeit modest, effects on body composition and side effects in terms of fluid retention and modest insulin resistance (34). Whether this reflects an unfavorable balance between effects and side effects in older people or employment of excessive doses of GH is uncertain, but it is evident that older subjects are not resistant to GH. Short-term dose response studies clearly demonstrate that older patients require a lower GH dose to maintain a given serum IGF-I level (35,36), and it has been observed that serum IGF-I increases in individual patients on long-term therapy if the GH dosage remains constant. Moreover, patients with GH deficiency older than 60 yr are highly responsive to even a small dose of GH (37). Interestingly, there is a gender difference in response to GH treatment with men being more responsive in terms of IGF-I generation and fat loss during therapy, most probably due to men having lower estrogen levels that negatively impact the effect of GH on IGF-I generation in the liver (38).

The pharmacokinetics and short-term metabolic effects of a near physiological intravenous GH bolus (200 micrograms) were compared in a group of young (30 yr) and older (50 yr) healthy adults (39). The area under the GH curve was significantly lower in older subjects, whereas the elimination half-life was similar in the two groups, suggesting both an increased metabolic clearance rate and apparent distribution volume of GH in older subjects. Both parameters showed a strong positive correlation with fat mass, although multiple regression analysis revealed the age to be an independent positive predictor. The short-term lipolytic response to the GH bolus was higher in young as compared to older subjects. Interestingly, the same study showed that the GH binding protein (GHBP) correlated strongly and positively with abdominal fat mass (40).

A prospective long-term study of normal adults with serial concomitant estimations of GH status and adiposity would provide useful information about the cause-effect relationship between GH status and body composition as a function of age. In the meantime, the following hypothesis is proposed (Figure 5): 1.Changes in life-style and genetic predispositions promote accumulation of body fat with aging; 2. The increased fat mass increases FFA availability, inducing insulin resistance and hyperinsulinemia; 3. High insulin levels suppress IGF binding protein (BP)-1 resulting in a relative increase in free IGF-I levels; 4. Systemic elevations of FFA, insulin, and free IGF-I suppresses pituitary GH release, which further increases fat mass; 5. Endogenous GH is cleared more rapidly in subjects with high amount of fat tissue.

At present it is not justified to treat the age-associated deterioration in body composition and physical performance with GH also due to concern that the ensuing elevation of IGF-I levels may increase the risk for the development of neoplastic disease.

Figure 5.

Hypothetical model for the association between low GH levels and increased visceral fat adults.

LIFE- LONG GH DEFICIENCY

A real-life model for the GH effects in human physiology is provided by the subjects with life-long severe reduction in GH signaling due to GHRH or GHRH receptor mutations, combined deficiency of GH, prolactin, and TSH, or global deletion of GHR. They show short stature, doll facies, high-pitched voices, central obesity, and are fertile (41). Despite central obesity and increased liver fat, they are insulin sensitive, partially protected from cancer, and present a major reduction in pro-aging signaling and perhaps increased longevity (42). The decrease in cancer risk in life-long GH deficiency together with reports on the GH permissive role for neoplastic colon growth (43), preneoplastic mammary lesions (44), and progression of prostate cancer (45) demands, at least, a careful tailoring of GH substitution dosage in the GH deficient patients. However, recent evidence suggests that the GH produced locally by the colon tumor cells, and not pituitary GH, acts in an autocrine and paracrine manner to suppress the tumor suppressor proteins and to increase nuclear β-catenin accumulation and epithelial–mesenchymal transition potentially participating in tumor progression (46,47).

GH AND IMMUNE SYSTEM

Although the majority of data on the relation between GH and the immune system are from animal studies, it seems that GH may pose immunomodulatory actions. Immune cells express receptors for growth hormone, and respond to GH stimulation (48). The GHR is expressed by several lymphocyte subpopulations. GH stimulates in vitro T and B-cell proliferation and immunoglobulin synthesis, enhances human myeloid progenitor cell maturation, and modulates in vivo Th1/Th2 (8) and humoral immune responses (49). It has been shown that GH can induce de novo T cell production and enhance CD4 recovery in HIV+ patients. Another study with possible clinical relevance showed that sustained GH expression reduced prodromal disease symptoms and eliminated progression to overt diabetes in mouse model of type 1 diabetes, a T-cell–mediated autoimmune disease. GH altered the cytokine environment, triggered anti-inflammatory macrophage (M2) polarization, maintained activity of the suppressor T-cell population, and limited Th17 cell plasticity (49). JAK/STAT signaling, the principal mediator of GHR activation, is well-known to be involved in the modulation of the immune system, so it is tempting to assume that GH may have a role too, but clear data in humans are needed.

INSULIN-LIKE GROWTH FACTOR-I

Physiology of IGF-I

GH acts both directly through its own receptor and indirectly through the induced production of IGF-I. GH stimulates synthesis of IGF-I in the liver and many other GH target tissues (Figure 6); about 75% of circulating IGF-I is liver-derived. IGF-I is a 70 amino-acid peptide, found in the circulation, 99% bound to transport proteins.

Following the initial discovery of IGF-I, it was thought, that GH governs somatic growth only by IGF-I produced by the liver (67). However, in the 1980s this hypothesis was changed by the identification of IGF-I production in numerous tissues (Figure 6). IGF-I is known as a global and tissue-specific growth factor as well as an endocrine factor. In some tissues IGF-I acts as a potent inhibitor of cellular apoptosis.

Figure 6.

GH is produced in the pituitary gland. In the periphery, GH acts directly and indirectly through stimulation of IGF-I production. In the circulation, the liver is the most important source of IGF-I (75%) but other tissues (e.g. brain, adipose tissue, kidney, bone, and muscles) may contribute. Under GH stimulation the muscle, adipose tissue, and bone have been shown to secrete IGF-I that has a paracrine/autocrine effect.

Interestingly, insulin and IGF-I share many structural and functional similarities implying that they have originated from the same ancestral molecule. Both molecules could have been part of the cycle of food intake and consequent tissue growth. The IGF-I gene is a member of the insulin gene family and the IGF-I receptor is structurally similar to the insulin receptor in its tetrametric structure, with 2 alpha and 2 beta subunits (68). The alpha subunit binds IGF-I, IGF-II, and insulin; however, the subunit has a higher affinity towards IGF-I compared to IGF-II and insulin. Although insulin and IGF-I share many similarities, during evolution, the functionality of the two molecules has become more divergent, where insulin plays a more metabolic role and IGF-I plays a role in cell growth.

The IGF-I receptor is expressed in many tissues in the body. However, the receptor number on each cell is strictly regulated by several systemic and tissue factors including circulating GH, iodothyronines, platelet-derived growth factor, and fibroblast growth factor. Following the binding of the IGF-I molecule, the receptor undergoes a conformational change, which activates tyrosine kinase, leading to auto-phosphorylation of tyrosine. The activated receptor phosphorylates “insulin receptor substrate-2” (IRS-2), which in-turn activates the RAS activating protein SOS. This complex activates the mitogen activated protein kinase (MAP kinase) pathway. Thus activation of the MAP kinase pathway becomes vital in the stimulation of cell growth by IGF-I (69,70).

IGF-I is bound almost 100% to a family of binding proteins (IGFBP) in the circulation. The IGFBP family comprises six binding proteins (IGFBP 1-6) with a high affinity towards IGF-I and II. Apart from regulating the free plasma IGF fraction, IGFBPs also play an important role in the transport of IGF into different tissues and extravascular space. IGFBP-3 and IGFBP-2 are the most abundant forms seen in plasma and are saturated with IGF-I due to their high affinity. 75% of IGF-I is bound to IGFBP-3. Interestingly, similar to IGF-I, IGFBP-3 production is also regulated by GH. In the plasma, IGFBP-3 is bound to a protein called acid labile subunit (ALS), which stabilizes the “IGFBP3-IGF-I” complex, prolonging its half-life to approximately 16 hours (71). IGFBP-1, on the other hand, is present in lower concentration in plasma than IGFBP-2 and 3. However, due to lower affinity for IGF-I, IGFBP-1 is usually in an unsaturated state and changing plasma concentrations of IGFBP-1 becomes important in determining the unbound fraction of IGF-I. A recently new discovered player in the regulation of IGF-I bioavailability is the pregnancy-associated plasma protein-A2 (PAPP-A2) that cleaves IGFBP3 and 5 and releases IGF-I. Homozygous mutations in PAPP-A2 result in growth failure with elevated total but low free IGF-I (72). Low IGF-I bioavailability impairs growth and glucose metabolism in a mouse model of human PAPP-A2 deficiency and treatment with recombinant human IGF-I in PAPP-A2 deficient patients improves growth and bone mass and ameliorates glucose metabolism (72,73).

METABOLIC EFFECTS OF GROWTH HORMONE

Nutritional status dictates GH effects. In the state of feast and sufficient nutrient intake where insulin is increased in the liver and IGF-I production is stimulated, GH promotes protein anabolism. Whereas, in the state with decreased nutrient intake and during sleep and exercise, the direct effect of GH are more predominant and this is mainly characterized by stimulation of lipolysis.

Interaction of Glucose and Lipid Metabolism

Relatively few studies have scrutinized the exact modes of action of GH on glucose metabolism. There is no evidence of a GH effect on insulin binding to the receptor (91,98), which obviously implies post receptor metabolic effects. The effect of FFA on the partitioning of intracellular glucose fluxes was originally described by Randle et al. (99). According to his hypothesis (the glucose/fatty acid cycle), oxidation of FFA initiates an upstream, chain-reaction-like inhibition of glycolytic enzymes, which ultimately inhibits glucose uptake (Figure 7).

Figure 7.

The glucose fatty-acid cycle.

Randle proposed in 1963 that increased FFA compete with and displace glucose utilization leading to a decreased glucose uptake. The hypothesis stated that an increase in fatty acid oxidation in muscle and fat results in higher acetyl CoA in mitochondria leading to inactivation of two rate-limiting enzymes of glycolysis (i.e., phosphofructokinase (PFK) and pyruvate dehydrogenase (PDH) complex). A subsequent increase in intracellular glucose-6-phosphate (glucose 6-P) results in high intracellular glucose concentrations and decreased glucose uptake by muscle and fat.

However, in contrast to the proposed hypothesis by Randle, studies using MR spectroscopy have shown reductions in intramyocellular glucose 6-P and glucose concentrations and have led to an alternative hypothesis. The new hypothesis proposes that a transient increase of intracellular diacylglycerol (DAG) activates theta isoform of protein kinase C (PKCθ) that causes increased serine phosphorylation of IRS-1/2 and consecutively decrease PI3K activation and glucose-transport activity leading to decrease intracellular glucose concentrations.

When considering the pronounced lipolytic effects of GH the Randle hypothesis remains an appealing model to explain the insulin-antagonistic effects of GH. In support of this, experiments have shown that co-administration of anti-lipolytic agents and GH reverses GH-induced insulin resistance. Similar conclusions were drawn from a recent study in GH deficient adults, which showed that insulin sensitivity was restored when acipimox (a nicotinic acid derivative) was co-administered with GH (100). We have also shown that GH-induced insulin resistance is associated with suppressed pyruvate dehydrogenase activity in skeletal muscle (101). It has, however, also been reported that GH-induced insulin resistance precedes the increase in circulating levels of fatty acids and forearm uptake of lipid intermediates (102). This early effect of GH on muscular glucose uptake could reflect intramyocytic FFA release and oxidation and thus be compatible with the Randle hypothesis. According to the Randle hypothesis the fatty acid-induced insulin resistance will result in elevated intracellular levels of both glucose and glucose-6-phosphate (Figure 7). By contrast, muscle biopsies from GH deficient adults after GH treatment have revealed increased glucose but low-normal glucose-6-phosphate levels (103). Moreover, NMR spectroscopy studies in healthy adults indicate that FFA infusion results in a drop in the levels of both glucose and glucose-6-phosphate (104). The latter study, which did not involve GH administration, reported that FFA suppressed the activity of PI-3 kinase, an enzyme stimulated by insulin, which is considered essential for glucose transportation into skeletal muscle via translocation of glucose transporter activity (GLUT 4). A more recent study showed that GH infusion does not impact insulin-stimulated PI-3 kinase activity (65).

IMPLICATIONS FOR GH REPLACEMENT

Regardless of the exact mechanisms, the insulin antagonistic effects may cause concern when replacing adult GH deficient patients with GH, since some of these patients are insulin resistant in the untreated state. There is evidence to suggest that the direct metabolic effects on GH may be balanced by long-term beneficial effects on body composition and physical fitness, but some studies report impaired insulin sensitivity in spite of favorable changes in body composition. There is little doubt that these effects of GH are dose-dependent and may be minimized or avoided if an appropriately low replacement dose is used. Still, the pharmacokinetics of subcutaneous (s.c.) GH administration is unable to mimic the endogenous GH pattern with suppressed levels after meals and elevations only during post absorptive periods, such as during the night. This may be considered the natural domain of GH action, which coincides with minimal beta-cell challenge. This reciprocal association between insulin and GH and its potential implications for normal substrate metabolism was initially described by Rabinowitz & Zierler (105). The problem arises when GH levels are elevated during repeated prandial periods. The classic example is active acromegaly, but prolonged high dose s.c. GH administration may cause similar effects. Administration of GH in the evening probably remains the best compromise between effects and side effects (106), but it is far from physiological.

Long-acting GH analogues have been developed to improve adherence and compliance. The clinical experience is limited now but seem not to impact adversely the glucose metabolism compared with daily GH (107). However, long-term surveillance data are required to consolidate its safety profile (108).

CONCLUSIONS

GH/IGF-I axis is specifically regulated and is involved in a multitude of processes during all aspects of life from intrauterine growth, to childhood and puberty, adulthood, and lastly elderly periods. GH actions directly or via its principal metabolite, IGF-I have a wide range of physiological roles being a metabolic active hormone in adulthood. Nutritional status of an organism dictates the effects of GH, either an impairment of insulin action (fasted state) or promoting protein anabolism (feed state). As our knowledge of the GH normal physiology increases, our ability to understand and specifically target the GH/IGF-I pathway for a diverse range of therapeutic purposes should also increase.

REFERENCES

1.

Raben MS. Growth hormone. 1. Physiologic aspects. The New England journal of medicine. 1962;266:31-35. [PubMed: 14038540]

2.

Petronella N, Drouin G. Gene conversions in the growth hormone gene family of primates: stronger homogenizing effects in the Hominidae lineage. Genomics. 2011;98(3):173-181. [PubMed: 21683133]

3.

Baumann GP. Growth hormone doping in sports: a critical review of use and detection strategies. Endocrine reviews. 2012;33(2):155-186. [PubMed: 22368183]

4.

Holt RIG, Ho KKY. The Use and Abuse of Growth Hormone in Sports. Endocrine reviews. 2019;40(4):1163-1185. [PubMed: 31180479]

5.

Cheung LYM, George AS, McGee SR, et al. Single-Cell RNA Sequencing Reveals Novel Markers of Male Pituitary Stem Cells and Hormone-Producing Cell Types. Endocrinology. 2018;159(12):3910-3924. [PMC free article: PMC6240904] [PubMed: 30335147]

6.

Willems C, Fu Q, Roose H, et al. Regeneration in the pituitary after cell-ablation injury: time-related aspects and molecular analysis. Endocrinology. 2015:en20151741. [PubMed: 26653762]

7.

Ribeiro-Oliveira A, Barkan AL. Growth Hormone Pulsatility and its Impact on Growth and Metabolism in Humans. in K. Ho (ed.), Growth Hormone Related Diseases and Therapy: A Molecular and Physiological Perspective for the Clinician, Contemporary Endocrinology. 2011:33-56.

8.

Ho KY, Evans WS, Blizzard RM, et al. Effects of sex and age on the 24-hour profile of growth hormone secretion in man: importance of endogenous estradiol concentrations. The Journal of clinical endocrinology and metabolism. 1987;64(1):51-58. [PubMed: 3782436]

9.

Leung KC, Johannsson G, Leong GM, Ho KK. Estrogen regulation of growth hormone action. Endocrine reviews. 2004;25(5):693-721. [PubMed: 15466938]

10.

Kargi AY, Merriam GR. Diagnosis and treatment of growth hormone deficiency in adults. Nature reviews. Endocrinology. 2013;9(6):335-345. [PubMed: 23629539]

11.

Iacovazzo D, Hernandez-Ramirez LC, Korbonits M. Sporadic pituitary adenomas: the role of germline mutations and recommendations for genetic screening. Expert review of endocrinology & metabolism. 2017;12(2):143-153. [PubMed: 30063429]

12.

Birzniece V, Ho KKY. Sex steroids and the GH axis: Implications for the management of hypopituitarism. Best practice & research. Clinical endocrinology & metabolism. 2017;31(1):59-69. [PubMed: 28477733]

13.

Veldhuis JD, Evans WS, Bowers CY, Anderson S. Interactive regulation of postmenopausal growth hormone insulin-like growth factor axis by estrogen and growth hormone-releasing peptide-2. Endocrine. 2001;14(1):45-62. [PubMed: 11322501]

14.

Bray MJ, Vick TM, Shah N, et al. Short-term estradiol replacement in postmenopausal women selectively mutes somatostatin’s dose-dependent inhibition of fasting growth hormone secretion. The Journal of clinical endocrinology and metabolism. 2001;86(7):3143-3149. [PubMed: 11443179]

15.

Anderson SM, Shah N, Evans WS, Patrie JT, Bowers CY, Veldhuis JD. Short-term estradiol supplementation augments growth hormone (GH) secretory responsiveness to dose-varying GH-releasing peptide infusions in healthy postmenopausal women. The Journal of clinical endocrinology and metabolism. 2001;86(2):551-560. [PubMed: 11158008]

16.

Murray PG, Higham CE, Clayton PE. 60 YEARS OF NEUROENDOCRINOLOGY: The hypothalamo-GH axis: the past 60 years. The Journal of endocrinology. 2015;226(2):T123-140. [PubMed: 26040485]

17.

Bonnefont X, Lacampagne A, Sanchez-Hormigo A, et al. Revealing the large-scale network organization of growth hormone-secreting cells. Proceedings of the National Academy of Sciences of the United States of America. 2005;102(46):16880-16885. [PMC free article: PMC1277257] [PubMed: 16272219]

18.

Le Tissier PR, Carmignac DF, Lilley S, et al. Hypothalamic growth hormone-releasing hormone (GHRH) deficiency: targeted ablation of GHRH neurons in mice using a viral ion channel transgene. Molecular endocrinology. 2005;19(5):1251-1262. [PubMed: 15661833]

19.

Wajnrajch MP, Gertner JM, Harbison MD, Chua SC, Jr., Leibel RL. Nonsense mutation in the human growth hormone-releasing hormone receptor causes growth failure analogous to the little (lit) mouse. Nature genetics. 1996;12(1):88-90. [PubMed: 8528260]

20.

Alatzoglou KS, Dattani MT. Genetic causes and treatment of isolated growth hormone deficiency-an update. Nature reviews. Endocrinology. 2010;6(10):562-576. [PubMed: 20852587]

21.

Giustina A, Veldhuis JD. Pathophysiology of the neuroregulation of growth hormone secretion in experimental animals and the human. Endocrine reviews. 1998;19(6):717-797. [PubMed: 9861545]

22.

Ren SG, Taylor J, Dong J, Yu R, Culler MD, Melmed S. Functional association of somatostatin receptor subtypes 2 and 5 in inhibiting human growth hormone secretion. The Journal of clinical endocrinology and metabolism. 2003;88(9):4239-4245. [PubMed: 12970293]

23.

Copinschi G, Wegienka LC, Hane S, Forsham PH. Effect of arginine on serum levels of insulin and growth hormone in obese subjects. Metabolism: clinical and experimental. 1967;16(6):485-491. [PubMed: 6027286]

24.

Rudman D, Kutner MH, Rogers CM, Lubin MF, Fleming GA, Bain RP. Impaired growth hormone secretion in the adult population: relation to age and adiposity. The Journal of clinical investigation. 1981;67(5):1361-1369. [PMC free article: PMC370702] [PubMed: 7194884]

25.

Rudman D. Growth hormone, body composition, and aging. Journal of the American Geriatrics Society. 1985;33(11):800-807. [PubMed: 3902942]

26.

Jorgensen JO, Vahl N, Hansen TB, Thuesen L, Hagen C, Christiansen JS. Growth hormone versus placebo treatment for one year in growth hormone deficient adults: increase in exercise capacity and normalization of body composition. Clinical endocrinology. 1996;45(6):681-688. [PubMed: 9039333]

27.

Williams T, Berelowitz M, Joffe SN, et al. Impaired growth hormone responses to growth hormone-releasing factor in obesity. A pituitary defect reversed with weight reduction. The New England journal of medicine. 1984;311(22):1403-1407. [PubMed: 6436706]

28.

Vahl N, Jorgensen JO, Jurik AG, Christiansen JS. Abdominal adiposity and physical fitness are major determinants of the age associated decline in stimulated GH secretion in healthy adults. The Journal of clinical endocrinology and metabolism. 1996;81(6):2209-2215. [PubMed: 8964853]

29.

Vahl N, Jorgensen JO, Skjaerbaek C, Veldhuis JD, Orskov H, Christiansen JS. Abdominal adiposity rather than age and sex predicts mass and regularity of GH secretion in healthy adults. The American journal of physiology. 1997;272(6 Pt 1):E1108-1116. [PubMed: 9227458]

30.

Papadakis MA, Grady D, Tierney MJ, Black D, Wells L, Grunfeld C. Insulin-like growth factor 1 and functional status in healthy older men. Journal of the American Geriatrics Society. 1995;43(12):1350-1355. [PubMed: 7490385]

31.

Goodman-Gruen D, Barrett-Connor E. Epidemiology of insulin-like growth factor-I in elderly men and women. The Rancho Bernardo Study. American journal of epidemiology. 1997;145(11):970-976. [PubMed: 9169905]

32.

Kiel DP, Puhl J, Rosen CJ, Berg K, Murphy JB, MacLean DB. Lack of an association between insulin-like growth factor-I and body composition, muscle strength, physical performance or self-reported mobility among older persons with functional limitations. Journal of the American Geriatrics Society. 1998;46(7):822-828. [PubMed: 9670867]

33.

Juul A, Bang P, Hertel NT, et al. Serum insulin-like growth factor-I in 1030 healthy children, adolescents, and adults: relation to age, sex, stage of puberty, testicular size, and body mass index. The Journal of clinical endocrinology and metabolism. 1994;78(3):744-752. [PubMed: 8126152]

34.

Rudman D, Feller AG, Nagraj HS, et al. Effects of human growth hormone in men over 60 years old. The New England journal of medicine. 1990;323(1):1-6. [PubMed: 2355952]

35.

Jorgensen JO, Flyvbjerg A, Lauritzen T, Alberti KG, Orskov H, Christiansen JS. Dose-response studies with biosynthetic human growth hormone (GH) in GH-deficient patients. The Journal of clinical endocrinology and metabolism. 1988;67(1):36-40. [PubMed: 3288652]

36.

Moller J, Jorgensen JO, Lauersen T, et al. Growth hormone dose regimens in adult GH deficiency: effects on biochemical growth markers and metabolic parameters. Clinical endocrinology. 1993;39(4):403-408. [PubMed: 7507009]

37.

Toogood AA, Shalet SM. Growth hormone replacement therapy in the elderly with hypothalamic-pituitary disease: a dose-finding study. The Journal of clinical endocrinology and metabolism. 1999;84(1):131-136. [PubMed: 9920073]

38.

Burman P, Johansson AG, Siegbahn A, Vessby B, Karlsson FA. Growth hormone (GH)-deficient men are more responsive to GH replacement therapy than women. The Journal of clinical endocrinology and metabolism. 1997;82(2):550-555. [PubMed: 9024252]

39.

Vahl N, Moller N, Lauritzen T, Christiansen JS, Jorgensen JO. Metabolic effects and pharmacokinetics of a growth hormone pulse in healthy adults: relation to age, sex, and body composition. The Journal of clinical endocrinology and metabolism. 1997;82(11):3612-3618. [PubMed: 9360515]

40.

Fisker S, Vahl N, Jorgensen JO, Christiansen JS, Orskov H. Abdominal fat determines growth hormone-binding protein levels in healthy nonobese adults. The Journal of clinical endocrinology and metabolism. 1997;82(1):123-128. [PubMed: 8989245]

41.

Aguiar-Oliveira MH, Bartke A. Growth Hormone Deficiency: Health and Longevity. Endocrine reviews. 2019;40(2):575-601. [PMC free article: PMC6416709] [PubMed: 30576428]

42.

Guevara-Aguirre J, Balasubramanian P, Guevara-Aguirre M, et al. Growth hormone receptor deficiency is associated with a major reduction in pro-aging signaling, cancer, and diabetes in humans. Science translational medicine. 2011;3(70):70ra13. [PMC free article: PMC3357623] [PubMed: 21325617]

43.

Chesnokova V, Zonis S, Zhou C, et al. Growth hormone is permissive for neoplastic colon growth. Proceedings of the National Academy of Sciences of the United States of America. 2016;113(23):E3250-3259. [PMC free article: PMC4988562] [PubMed: 27226307]

44.

Kleinberg DL, Wood TL, Furth PA, Lee AV. Growth hormone and insulin-like growth factor-I in the transition from normal mammary development to preneoplastic mammary lesions. Endocrine reviews. 2009;30(1):51-74. [PMC free article: PMC5393153] [PubMed: 19075184]

45.

Slater MD, Murphy CR. Co-expression of interleukin-6 and human growth hormone in apparently normal prostate biopsies that ultimately progress to prostate cancer using low pH, high temperature antigen retrieval. Journal of molecular histology. 2006;37(1-2):37-41. [PubMed: 16807770]

46.

Khan J, Pernicova I, Nisar K, Korbonits M. Mechanisms of ageing: growth hormone, dietary restriction, and metformin. The lancet. Diabetes & endocrinology. 2023;11(4):261-281. [PubMed: 36848915]

47.

Chesnokova V, Zonis S, Apostolou A, et al. Local non-pituitary growth hormone is induced with aging and facilitates epithelial damage. Cell reports. 2021;37(11):110068. [PMC free article: PMC8716125] [PubMed: 34910915]

48.

Bodart G, Farhat K, Charlet-Renard C, Salvatori R, Geenen V, Martens H. The Somatotrope Growth Hormone-Releasing Hormone/Growth Hormone/Insulin-Like Growth Factor-1 Axis in Immunoregulation and Immunosenescence. Frontiers of hormone research. 2017;48:147-159. [PubMed: 28245459]

49.

Villares R, Kakabadse D, Juarranz Y, Gomariz RP, Martinez AC, Mellado M. Growth hormone prevents the development of autoimmune diabetes. Proceedings of the National Academy of Sciences of the United States of America. 2013. [PMC free article: PMC3845149] [PubMed: 24218587]

50.

Lanning NJ, Carter-Su C. Recent advances in growth hormone signaling. Rev Endocr Metab Disord. 2006;7(4):225-235. [PubMed: 17308965]

51.

Dehkhoda F, Lee CMM, Medina J, Brooks AJ. The Growth Hormone Receptor: Mechanism of Receptor Activation, Cell Signaling, and Physiological Aspects. Frontiers in endocrinology. 2018;9:35. [PMC free article: PMC5816795] [PubMed: 29487568]

52.

Kelly PA, Djiane J, Postel-Vinay MC, Edery M. The prolactin/growth hormone receptor family. Endocrine reviews. 1991;12(3):235-251. [PubMed: 1935820]

53.

Brooks AJ, Dai W, O’Mara ML, et al. Mechanism of activation of protein kinase JAK2 by the growth hormone receptor. Science (New York, N.Y.). 2014;344(6185):1249783. [PubMed: 24833397]

54.

Woelfle J, Chia DJ, Rotwein P. Mechanisms of growth hormone (GH) action. Identification of conserved Stat5 binding sites that mediate GH-induced insulin-like growth factor-I gene activation. The Journal of biological chemistry. 2003;278(51):51261-51266. [PubMed: 14532269]

55.

Wormald S, Hilton DJ. Inhibitors of cytokine signal transduction. The Journal of biological chemistry. 2004;279(2):821-824. [PubMed: 14607831]

56.

Leung KC, Doyle N, Ballesteros M, et al. Estrogen inhibits GH signaling by suppressing GH-induced JAK2 phosphorylation, an effect mediated by SOCS-2. Proceedings of the National Academy of Sciences of the United States of America. 2003;100(3):1016-1021. [PMC free article: PMC298718] [PubMed: 12552091]

57.

Silva CM, Kloth MT, Whatmore AJ, et al. GH and epidermal growth factor signaling in normal and Laron syndrome fibroblasts. Endocrinology. 2002;143(7):2610-2617. [PubMed: 12072393]

58.

Hwa V, Little B, Adiyaman P, et al. Severe growth hormone insensitivity resulting from total absence of signal transducer and activator of transcription 5b. The Journal of clinical endocrinology and metabolism. 2005;90(7):4260-4266. [PubMed: 15827093]

59.

Jorgensen JO, Jessen N, Pedersen SB, et al. GH receptor signaling in skeletal muscle and adipose tissue in human subjects following exposure to an intravenous GH bolus. American journal of physiology. Endocrinology and metabolism. 2006;291(5):E899-905. [PubMed: 16757551]

60.

Dominici FP, Argentino DP, Munoz MC, Miquet JG, Sotelo AI, Turyn D. Influence of the crosstalk between growth hormone and insulin signalling on the modulation of insulin sensitivity. Growth hormone & IGF research : official journal of the Growth Hormone Research Society and the International IGF Research Society. 2005;15(5):324-336. [PubMed: 16112592]

61.

Emanuelli B, Peraldi P, Filloux C, Sawka-Verhelle D, Hilton D, Van Obberghen E. SOCS-3 is an insulin-induced negative regulator of insulin signaling. The Journal of biological chemistry. 2000;275(21):15985-15991. [PubMed: 10821852]

62.

Ridderstrale M, Degerman E, Tornqvist H. Growth hormone stimulates the tyrosine phosphorylation of the insulin receptor substrate-1 and its association with phosphatidylinositol 3-kinase in primary adipocytes. The Journal of biological chemistry. 1995;270(8):3471-3474. [PubMed: 7876077]

63.

Thirone AC, Carvalho CR, Saad MJ. Growth hormone stimulates the tyrosine kinase activity of JAK2 and induces tyrosine phosphorylation of insulin receptor substrates and Shc in rat tissues. Endocrinology. 1999;140(1):55-62. [PubMed: 9886807]

64.

del Rincon JP, Iida K, Gaylinn BD, et al. Growth hormone regulation of p85alpha expression and phosphoinositide 3-kinase activity in adipose tissue: mechanism for growth hormone-mediated insulin resistance. Diabetes. 2007;56(6):1638-1646. [PubMed: 17363744]

65.

Jessen N, Djurhuus CB, Jorgensen JO, et al. Evidence against a role for insulin-signaling proteins PI 3-kinase and Akt in insulin resistance in human skeletal muscle induced by short-term GH infusion. American journal of physiology. Endocrinology and metabolism. 2005;288(1):E194-199. [PubMed: 15339744]

66.

Nielsen C, Gormsen LC, Jessen N, et al. Growth hormone signaling in vivo in human muscle and adipose tissue: impact of insulin, substrate background, and growth hormone receptor blockade. The Journal of clinical endocrinology and metabolism. 2008;93(7):2842-2850. [PubMed: 18460563]

67.

Salmon WD, Jr., Daughaday WH. A hormonally controlled serum factor which stimulates sulfate incorporation by cartilage in vitro. The Journal of laboratory and clinical medicine. 1957;49(6):825-836. [PubMed: 13429201]

68.

Werner H, Weinstein D, Bentov I. Similarities and differences between insulin and IGF-I: structures, receptors, and signalling pathways. Archives of physiology and biochemistry. 2008;114(1):17-22. [PubMed: 18465355]

69.

Denley A, Cosgrove LJ, Booker GW, Wallace JC, Forbes BE. Molecular interactions of the IGF system. Cytokine & growth factor reviews. 2005;16(4-5):421-439. [PubMed: 15936977]

70.

Kim JJ, Accili D. Signalling through IGF-I and insulin receptors: where is the specificity? Growth hormone & IGF research : official journal of the Growth Hormone Research Society and the International IGF Research Society. 2002;12(2):84-90. [PubMed: 12175645]

71.

Firth SM, Baxter RC. Cellular actions of the insulin-like growth factor binding proteins. Endocrine reviews. 2002;23(6):824-854. [PubMed: 12466191]

72.

Cabrera-Salcedo C, Mizuno T, Tyzinski L, et al. Pharmacokinetics of IGF-1 in PAPP-A2-Deficient Patients, Growth Response, and Effects on Glucose and Bone Density. The Journal of clinical endocrinology and metabolism. 2017;102(12):4568-4577. [PMC free article: PMC5718699] [PubMed: 29029190]

73.

Fujimoto M, Andrew M, Liao L, et al. Low IGF-I Bioavailability Impairs Growth and Glucose Metabolism in a Mouse Model of Human PAPPA2 p.Ala1033Val Mutation. Endocrinology. 2019;160(6):1363-1376. [PMC free article: PMC6507901] [PubMed: 30977789]

74.

Behringer RR, Lewin TM, Quaife CJ, Palmiter RD, Brinster RL, D’Ercole AJ. Expression of insulin-like growth factor I stimulates normal somatic growth in growth hormone-deficient transgenic mice. Endocrinology. 1990;127(3):1033-1040. [PubMed: 2387246]

75.

Powell-Braxton L, Hollingshead P, Giltinan D, Pitts-Meek S, Stewart T. Inactivation of the IGF-I gene in mice results in perinatal lethality. Annals of the New York Academy of Sciences. 1993;692:300-301. [PubMed: 8215036]

76.

Gluckman PD, Gunn AJ, Wray A, et al. Congenital idiopathic growth hormone deficiency associated with prenatal and early postnatal growth failure. The International Board of the Kabi Pharmacia International Growth Study. The Journal of pediatrics. 1992;121(6):920-923. [PubMed: 1447657]

77.

Savage MO, Blum WF, Ranke MB, et al. Clinical features and endocrine status in patients with growth hormone insensitivity (Laron syndrome). The Journal of clinical endocrinology and metabolism. 1993;77(6):1465-1471. [PubMed: 7505286]

78.

Woods KA, Camacho-Hubner C, Savage MO, Clark AJ. Intrauterine growth retardation and postnatal growth failure associated with deletion of the insulin-like growth factor I gene. The New England journal of medicine. 1996;335(18):1363-1367. [PubMed: 8857020]

79.

Lupu F, Terwilliger JD, Lee K, Segre GV, Efstratiadis A. Roles of growth hormone and insulin-like growth factor 1 in mouse postnatal growth. Developmental biology. 2001;229(1):141-162. [PubMed: 11133160]

80.

Bartke A, Sun LY, Longo V. Somatotropic signaling: trade-offs between growth, reproductive development, and longevity. Physiological reviews. 2013;93(2):571-598. [PMC free article: PMC3768106] [PubMed: 23589828]

81.

Fontana L, Partridge L, Longo VD. Extending healthy life span—from yeast to humans. Science (New York, N.Y.). 2010;328(5976):321-326. [PMC free article: PMC3607354] [PubMed: 20395504]

82.

Moller N, Jorgensen JO. Effects of growth hormone on glucose, lipid, and protein metabolism in human subjects. Endocrine reviews. 2009;30(2):152-177. [PubMed: 19240267]

83.

BA H. The hypophysis and metabolism. The New England journal of medicine. 1936;214:961-985.

84.

Luft R, Ikkos D, Gemzell CA, Olivecrona H. Effect of human growth hormone in hypophysectomised diabetic subjects. Lancet. 1958;1(7023):721-722. [PubMed: 13515335]

85.

Raben MS, Hollenberg CH. Effect of growth hormone on plasma fatty acids. The Journal of clinical investigation. 1959;38(3):484-488. [PMC free article: PMC293181] [PubMed: 13641397]

86.

Henneman DH, Henneman PH. Effects of human growth hormone on levels of blood urinary carbohydrate and fat metabolites in man. The Journal of clinical investigation. 1960;39:1239-1245. [PMC free article: PMC441870] [PubMed: 14401058]

87.

Hew FL, Koschmann M, Christopher M, et al. Insulin resistance in growth hormone-deficient adults: defects in glucose utilization and glycogen synthase activity. The Journal of clinical endocrinology and metabolism. 1996;81(2):555-564. [PubMed: 8636267]

88.

Rabinowitz D, Klassen GA, Zierler KL. Effect of human growth hormone on muscle and adipose tissue metabolism in the forearm of man. The Journal of clinical investigation. 1965;44:51-61. [PMC free article: PMC442018] [PubMed: 14254256]

89.

Moller N, Jorgensen JO, Schmitz O, et al. Effects of a growth hormone pulse on total and forearm substrate fluxes in humans. The American journal of physiology. 1990;258(1 Pt 1):E86-91. [PubMed: 2405702]

90.

Arlien-Søborg MC, Madsen MA, Dal J, et al. Ectopic lipid deposition and insulin resistance in patients with GH disorders before and after treatment. European journal of endocrinology / European Federation of Endocrine Societies. 2023;188(1). [PubMed: 36651164]

91.

Bak JF, Moller N, Schmitz O. Effects of growth hormone on fuel utilization and muscle glycogen synthase activity in normal humans. The American journal of physiology. 1991;260(5 Pt 1):E736-742. [PubMed: 1903598]

92.

Orskov L, Schmitz O, Jorgensen JO, et al. Influence of growth hormone on glucose-induced glucose uptake in normal men as assessed by the hyperglycemic clamp technique. The Journal of clinical endocrinology and metabolism. 1989;68(2):276-282. [PubMed: 2563732]

93.

Hjelholt AJ, Charidemou E, Griffin JL, et al. Insulin resistance induced by growth hormone is linked to lipolysis and associated with suppressed pyruvate dehydrogenase activity in skeletal muscle: a 2 × 2 factorial, randomised, crossover study in human individuals. Diabetologia. 2020;63(12):2641-2653. [PubMed: 32945898]

94.

Hjelholt AJ, Lee KY, Arlien-Søborg MC, et al. Temporal patterns of lipolytic regulators in adipose tissue after acute growth hormone exposure in human subjects: A randomized controlled crossover trial. Molecular metabolism. 2019;29:65-75. [PMC free article: PMC6731350] [PubMed: 31668393]

95.

Moller N, Schmitz O, Joorgensen JO, et al. Basal- and insulin-stimulated substrate metabolism in patients with active acromegaly before and after adenomectomy. The Journal of clinical endocrinology and metabolism. 1992;74(5):1012-1019. [PubMed: 1569148]

96.

Sonksen PH, Greenwood FC, Ellis JP, Lowy C, Rutherford A, Nabarro JD. Changes of carbohydrate tolerance in acromegaly with progress of the disease and in response to treatment. The Journal of clinical endocrinology and metabolism. 1967;27(10):1418-1430. [PubMed: 6057823]

97.

Moller N, Moller J, Jorgensen JO, et al. Impact of 2 weeks high dose growth hormone treatment on basal and insulin stimulated substrate metabolism in humans. Clinical endocrinology. 1993;39(5):577-581. [PubMed: 8252748]

98.

Rosenfeld RG, Wilson DM, Dollar LA, Bennett A, Hintz RL. Both human pituitary growth hormone and recombinant DNA-derived human growth hormone cause insulin resistance at a postreceptor site. The Journal of clinical endocrinology and metabolism. 1982;54(5):1033-1038. [PubMed: 7037819]

99.

Randle PJ, Garland PB, Hales CN, Newsholme EA. The glucose fatty-acid cycle. Its role in insulin sensitivity and the metabolic disturbances of diabetes mellitus. Lancet. 1963;1(7285):785-789. [PubMed: 13990765]

100.

Nielsen S, Moller N, Christiansen JS, Jorgensen JO. Pharmacological antilipolysis restores insulin sensitivity during growth hormone exposure. Diabetes. 2001;50(10):2301-2308. [PubMed: 11574412]

101.

Nellemann B, Vendelbo MH, Nielsen TS, et al. Growth hormone-induced insulin resistance in human subjects involves reduced pyruvate dehydrogenase activity. Acta physiologica (Oxford, England). 2014;210(2):392-402. [PubMed: 24148194]

102.

Jensen RB, Thankamony A, Day F, et al. Genetic markers of insulin sensitivity and insulin secretion are associated with spontaneous postnatal growth and response to growth hormone treatment in short SGA children: the North European SGA Study (NESGAS). The Journal of clinical endocrinology and metabolism. 2015;100(3):E503-507. [PubMed: 25494864]

103.

Christopher M, Hew FL, Oakley M, Rantzau C, Alford F. Defects of insulin action and skeletal muscle glucose metabolism in growth hormone-deficient adults persist after 24 months of recombinant human growth hormone therapy. The Journal of clinical endocrinology and metabolism. 1998;83(5):1668-1681. [PubMed: 9589675]

104.

Shulman GI. Cellular mechanisms of insulin resistance. The Journal of clinical investigation. 2000;106(2):171-176. [PMC free article: PMC314317] [PubMed: 10903330]

105.

Rabinowitz D, Zierler KL. A METABOLIC REGULATING DEVICE BASED ON THE ACTIONS OF HUMAN GROWTH HORMONE AND OF INSULIN, SINGLY AND TOGETHER, ON THE HUMAN FOREARM. Nature. 1963;199:913-915. [PubMed: 14079908]

106.

Jorgensen JO. Human growth hormone replacement therapy: pharmacological and clinical aspects. Endocrine reviews. 1991;12(3):189-207. [PubMed: 1935818]

107.

Takahashi Y, Biller BMK, Fukuoka H, et al. Weekly somapacitan had no adverse effects on glucose metabolism in adults with growth hormone deficiency. Pituitary. 2023;26(1):57-72. [PMC free article: PMC9908671] [PubMed: 36380045]

108.

Ho KK, O’Sullivan AJ, Burt MG. The physiology of growth hormone (GH) in adults: translational journey to GH replacement therapy. The Journal of endocrinology. 2023;257(2). [PubMed: 36524723]

109.

Tanner JM, Hughes PC, Whitehouse RH. Comparative rapidity of response of height, limb muscle and limb fat to treatment with human growth hormone in patients with and without growth hormone deficiency. Acta endocrinologica. 1977;84(4):681-696. [PubMed: 576755]

110.

DB C. Effect of growth hormone on cell and somatic growth. . In: Handbook of physiology (Eds. Knobil and Sawyer)Washington DC. 1974:159-186.

111.

Korner A. Growth hormone control of biosynthesis of protein and ribonucleic acid. Recent progress in hormone research. 1965;21:205-240. [PubMed: 14321059]

112.

Goldberg AL. Protein turnover in skeletal muscle. I. Protein catabolism during work-induced hypertrophy and growth induced with growth hormone. The Journal of biological chemistry. 1969;244(12):3217-3222. [PubMed: 5792657]

113.

Horber FF, Haymond MW. Human growth hormone prevents the protein catabolic side effects of prednisone in humans. The Journal of clinical investigation. 1990;86(1):265-272. [PMC free article: PMC296716] [PubMed: 2195062]

114.

Russell-Jones DL, Weissberger AJ, Bowes SB, et al. The effects of growth hormone on protein metabolism in adult growth hormone deficient patients. Clinical endocrinology. 1993;38(4):427-431. [PubMed: 8319375]

115.

Fryburg DA, Barrett EJ. Growth hormone acutely stimulates skeletal muscle but not whole-body protein synthesis in humans. Metabolism: clinical and experimental. 1993;42(9):1223-1227. [PubMed: 8412780]

116.

Copeland KC, Nair KS. Acute growth hormone effects on amino acid and lipid metabolism. The Journal of clinical endocrinology and metabolism. 1994;78(5):1040-1047. [PubMed: 8175957]

117.

Fryburg DA, Gelfand RA, Barrett EJ. Growth hormone acutely stimulates forearm muscle protein synthesis in normal humans. The American journal of physiology. 1991;260(3 Pt 1):E499-504. [PubMed: 2003602]

118.

Turkalj I, Keller U, Ninnis R, Vosmeer S, Stauffacher W. Effect of increasing doses of recombinant human insulin-like growth factor-I on glucose, lipid, and leucine metabolism in man. The Journal of clinical endocrinology and metabolism. 1992;75(5):1186-1191. [PubMed: 1430077]

119.

Russell-Jones DL, Umpleby AM, Hennessy TR, et al. Use of a leucine clamp to demonstrate that IGF-I actively stimulates protein synthesis in normal humans. The American journal of physiology. 1994;267(4 Pt 1):E591-598. [PubMed: 7943309]

120.

Fryburg DA, Jahn LA, Hill SA, Oliveras DM, Barrett EJ. Insulin and insulin-like growth factor-I enhance human skeletal muscle protein anabolism during hyperaminoacidemia by different mechanisms. The Journal of clinical investigation. 1995;96(4):1722-1729. [PMC free article: PMC185808] [PubMed: 7560063]

121.

Fryburg DA, Louard RJ, Gerow KE, Gelfand RA, Barrett EJ. Growth hormone stimulates skeletal muscle protein synthesis and antagonizes insulin’s antiproteolytic action in humans. Diabetes. 1992;41(4):424-429. [PubMed: 1607069]

122.

Copeland KC, Nair KS. Recombinant human insulin-like growth factor-I increases forearm blood flow. The Journal of clinical endocrinology and metabolism. 1994;79(1):230-232. [PubMed: 8027233]

123.

Fryburg DA. NG-monomethyl-L-arginine inhibits the blood flow but not the insulin-like response of forearm muscle to IGF- I: possible role of nitric oxide in muscle protein synthesis. The Journal of clinical investigation. 1996;97(5):1319-1328. [PMC free article: PMC507186] [PubMed: 8636445]

124.

Boger RH, Skamira C, Bode-Boger SM, Brabant G, von zur Muhlen A, Frolich JC. Nitric oxide may mediate the hemodynamic effects of recombinant growth hormone in patients with acquired growth hormone deficiency. A double-blind, placebo-controlled study. The Journal of clinical investigation. 1996;98(12):2706-2713. [PMC free article: PMC507734] [PubMed: 8981915]

125.

Bartke A, Darcy J. GH and ageing: Pitfalls and new insights. Best practice & research. Clinical endocrinology & metabolism. 2017;31(1):113-125. [PMC free article: PMC5424628] [PubMed: 28477727]

126.

Yarasheski KE, Campbell JA, Smith K, Rennie MJ, Holloszy JO, Bier DM. Effect of growth hormone and resistance exercise on muscle growth in young men. The American journal of physiology. 1992;262(3 Pt 1):E261-267. [PubMed: 1550219]

127.

Yarasheski KE, Zachwieja JJ, Campbell JA, Bier DM. Effect of growth hormone and resistance exercise on muscle growth and strength in older men. The American journal of physiology. 1995;268(2 Pt 1):E268-276. [PubMed: 7864103]

128.

Taaffe DR, Pruitt L, Reim J, et al. Effect of recombinant human growth hormone on the muscle strength response to resistance exercise in elderly men. The Journal of clinical endocrinology and metabolism. 1994;79(5):1361-1366. [PubMed: 7525633]

129.

Papadakis MA, Grady D, Black D, et al. Growth hormone replacement in healthy older men improves body composition but not functional ability. Annals of internal medicine. 1996;124(8):708-716. [PubMed: 8633830]

130.

Hermansen K, Bengtsen M, Kjaer M, Vestergaard P, Jorgensen JOL. Impact of GH administration on athletic performance in healthy young adults: A systematic review and meta-analysis of placebo-controlled trials. Growth hormone & IGF research : official journal of the Growth Hormone Research Society and the International IGF Research Society. 2017;34:38-44. [PubMed: 28514721]

131.

Waters D, Danska J, Hardy K, et al. Recombinant human growth hormone, insulin-like growth factor 1, and combination therapy in AIDS-associated wasting. A randomized, double-blind, placebo-controlled trial. Annals of internal medicine. 1996;125(11):865-872. [PubMed: 8967666]

132.

Schambelan M, Mulligan K, Grunfeld C, et al. Recombinant human growth hormone in patients with HIV-associated wasting. A randomized, placebo-controlled trial. Serostim Study Group. Annals of internal medicine. 1996;125(11):873-882. [PubMed: 8967667]