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 the 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 synergistic (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 several IGF-I binding proteins. The mechanisms underlying the insulin antagonist effect of GH in humans are causally linked to lipolysis and the ensuing elevated levels of circulating free fatty acids. 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 the present 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 a 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 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 the pituitary and blood is the 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 thus 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 the adult pituitary gland (5). The differentiation of somatotroph cell is governed by the pituitary transcription factor 1 (Pit-1). Data in mice suggest that the pituitary holds regenerative competence, the GH-producing cells being regenerated form 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 their 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 the 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 and Figure 4) (8). Integrated 24h GH concentration is significantly greater in women than in men and greater in the young than in older 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 in girls and 1 year later in boys (9).

Figure 1

The secretory pattern of GH in young and old female and male. In young individuals the GH pulses are larger and more frequent and that female 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 amplify hypothalamic GHRH secretion and synergize with its pituitary GH-stimulating effects (Figure 2) (10). Interestingly, recently germline or somatic duplication of GPR101 has been shown to constitutively activate the cAMP pathway in the absence of a ligand, leading to GH release. Although the precise physiology of GPR101 is unclear, it is worth mentioning it since it clearly has an effect on GH pathophysiology (11).

In addition, a multitude of other factors may impact the GH axis, most probably due to interaction with GRHR, 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 mute inhibition by exogenous SST (14). Also, exogenous estrogen potentiates ghrelin’s action (15).

GH release correlates inversely with intraabdominal visceral adiposity via mechanisms that may depend on increased free fatty acids (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 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 up-regulates 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 SST, 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 lead to profound GH deficiency with anterior pituitary hypoplasia. Subsequent 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 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 paraventricular nucleus and arcuate nucleus, produce SST. These neurons secrete SST into the adenohypophyseal portal venous system, via the median eminence, to exert effects on the anterior pituitary. SST has a short half-life of approximately 2 minutes as it is rapidly inactivated by tissue peptidase in humans.

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, the adult pituitary only expresses 4 subtypes (SSTR1, SSTR2, SSTR3, SSTR5). Of these four subtypes, somatotrophs exhibit more sensitivity to SSTR2 and SSTR5 ligands in inhibiting the secretion of GH in a synergistic manner (21). Somatostatin inhibits GH release but not GH synthesis.

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 the stomach and may be involved in the GH response to fasting and food intake.

Clinical Implications

GH levels – influence of body composition, 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 (22,23). It has been hypothesized that many of the senescent changes in body composition and organ function are related to or caused by decreased GH (24), also known as "the somatopause".

Studies carried out 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) (25). It is also known that normal GH levels can be restored in obese subjects following massive weight loss (26), 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 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. life style, 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 performed 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), while 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 (27). In the same population, 24-h spontaneous GH levels also predominantly correlated inversely with intra-abdominal fat mass (Figure 3) (28).

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 (29-31). 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 (32).

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 (33). Whether this reflects an unfavorable balance between effects and side effects in older people or the 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 (34,35), 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 years are highly responsive to even a small dose of GH (36). Interestingly, there is a gender difference response to GH treatment with men being more responsive in terms of IGF-I generation and fat loss during therapy, most probably due to lower estrogen levels that negatively impact the GH effect on IGF-I generation in the liver (37).

The pharmacokinetics and short-term metabolic effects of a near physiological intravenous GH bolus (200μg) were compared in a group of young (30 year) and older (50 year) healthy adults (38). 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 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 proteins correlated strongly and positively with abdominal fat mass (39).

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, leads to increased FFA availability, and induces insulin resistance and hyperinsulinemia; 3. High insulin levels suppress IGF binding protein (IGFBP)-1 resulting in a relative increase in free IGF-I levels; 4. Systemic elevations of FFA, insulin and free IGF-I suppress pituitary GH release, which further increases fat mass; 5. Endogenous GH is cleared more rapidly in subjects with a 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 especially due to concern that the ensuing elevation of IGF-I levels may increase the risk for the development of neoplastic disease (For an extensive discussion of GH in the elderly see the chapter on this topic in the Endocrinology of Aging section of Endotext).

Figure 5.

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

Life-long GH deficiency

A real-life model for GH effects in human physiology is represented by patients 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, and central obesity, and are fertile (40). 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 (41). The decrease of cancer risk in life-long GH deficiency together with reports on the permissive role of GH for neoplastic colon growth (42), pre-neoplastic mammary lesions (43), and progression of prostate cancer (44) demands, at least, a careful tailoring of GH substitution dosage in the GH deficient patients.

GH and the 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 possess immunomodulatory actions. Immune cells, including several lymphocyte subpopulations, express receptors for GH, and respond to its stimulation (45). 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 (46). 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 (46). JAK/STAT signaling, the principal mediator of GHR activation, is well-known to be involved in the modulation of the immune system, so 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 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 (IGFBP) in the circulation.

Following the initial discovery of IGF-I, it was thought that GH governs somatic growth only by IGF-I produced by the liver (69). However, in the 1980s this hypothesis was challenged by the identification of IGF-I production in numerous tissues. 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 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 tetrameric structure, with 2 alpha and 2 beta subunits (70). 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 is more involved 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 IRS-2, which in-turn activates the RAS activating protein SOS. This complex activates the MAPK pathway leading to the stimulation of cell growth (71,72).

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 (73). 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 become 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 (74). 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 (74,75).

METABOLIC EFFECTS OF GROWTH HORMONE

The nutritional status dictates the effects of GH. 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 a state with decreased nutrient intake and during the sleep and exercise, the direct effects of GH are more predominant and this is mainly characterized by stimulation of lipolysis.

Interaction of Glucose and Lipid Metabolism

The effect of FFA on the partitioning of intracellular glucose fluxes was originally described by Randle et al. (96). According to this 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. A. 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. B. 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 the 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.

The Randle hypothesis remains an appealing model to explain the insulin-antagonistic effects of GH when considering its pronounced lipolytic effects. To support this, experiments have shown that co-administration of anti-lipolytic agents and GH reverses GH-induced insulin resistance (97). Moreover it has been shown that GH-induced insulin resistance is associated with suppressed pyruvate dehydrogenase activity in skeletal muscle (98). However, 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), whereas the muscle biopsies from GH deficient adults after GH treatment have revealed increased glucose but low-normal glucose-6-phosphate levels (99).

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 (100). 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 (101), but it is far from physiological.

We know and understand that hypoglycemia is a serious and challenging side effect of insulin therapy as a consequence of inappropriately high insulin levels (during fasting). As a corollary, we must realize that hyperglycemia may result from GH therapy. It is therefore important to carefully monitor glucose metabolism and to use the lowest effective dose when replacing adults with GH.

CONCLUSIONS

The GH/IGF-I axis is specifically regulated and is involved in a multitude of processes during all the aspects of life from intrauterine growth, to childhood and puberty, adulthood and lastly elderly stages of life. GH acts directly or via its principal metabolite, IGF-I, and has a wide range of physiological roles being a metabolic active hormone in adulthood. The nutritional status of an organism dictates the effects of GH, either an impairment of insulin action (fasting state) or promoting protein anabolism (fed state). As our knowledge of 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. Normal aging is associated with a gradual decline in serum IGF-I levels that run in parallel with reductions in muscle mass and function and other senescent changes in organ function. The cause-effect relationship is uncertain, but GH administration to elderly people without pituitary disease has not proven beneficial and sustained supra-physiological IGF levels and actions are likely to be harmful. On the other hand, a stimulation of endogenous GH secretion induced by exercise and calorie restriction may contribute to healthy aging.

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