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.
Growth Hormone Signaling in Humans
GROWTH RECEPTOR ACTIVATION
GH receptor signaling is a separate and prolific research field by itself (50), so this section will focus on recent data obtained in human models.
GHR have been identified in many tissues including fat, lymphocytes, liver, muscle, heart, kidney, brain, and pancreas (51,52). Activation of receptor-associated Janus kinase (JAK) 2 is the critical step in initiating GH signaling. One GH molecule binds to two GHR molecules that exist as preformed homodimers. Following GH binding, the intracellular domains of the GHR dimer undergo rotation, which brings together the two intracellular domains, each of which bind one JAK2 molecule. This in turn induces cross-phosphorylation of tyrosine residues in the kinase domain of each JAK2 molecule followed by tyrosine phosphorylation of the GHR (51,53). Phosphorylated residues on GHR and JAK2 form docking sites for different signaling molecules including signal transducers and activators of transcription (STAT) 1, 3, 5a and 5b. STATs bound to the activated GHR-JAK2 complex are subsequently phosphorylated on a single tyrosine by JAK2 after which they dimerize and translocate to the nucleus, where they bind to DNA and act as gene transcription factors. A STAT5b binding site has been characterized in the IGF-I gene promoter region, which mediates GH-stimulated IGF-I gene activation (54). Attenuation of JAK2-associated GH signaling is mediated by a family of cytokine-inducible suppressors of cytokine signaling (SOCS) (55). SOCS proteins bind to phosphotyrosine residues on the GHR or JAK2 and suppress GH signaling by inhibiting JAK2 activity and competing with STATs for binding on the GHR. As an example, it has been reported that the inhibitory effect of estrogen on hepatic IGF-I production seems to be mediated via up regulation of SOCS-2 (56).
GH SIGNALING
Data on GHR signaling derive mainly from rodent models and experimental cell lines, although GH-induced activation of the JAK2/STAT5b and the MAPK pathways have been recorded in cultured human fibroblasts from healthy human subjects (57). STAT5b in human subjects is critical for GH-induced IGF-I expression and growth promotion as demonstrated by the identification of mutations in the STAT5b gene of patients presenting with severe GH insensitivity in the presence of normal GHR (58). GHR signaling in human models in vivo has been reported in a study in healthy young male subjects exposed to an intravenous GH bolus vs. saline (59). In muscle and fat biopsies significant tyrosine phosphorylation of STAT5b was recorded after GH exposure at 30-60 minutes. There was no evidence of GH-induced activation of PI 3-kinase, Akt/PKB, or MAPK in either tissue (59).
GH AND INSULIN SIGNALING
There is animal and in vitro evidence to suggest that insulin and GH share post-receptor signaling pathways (60). Convergence has been reported at the levels of STAT5 and SOCS3 (61) as well as on the major insulin signaling pathway: insulin receptor substrates (IRS) 1 and 2, PI 3-kinase, Akt, and extracellular regulated kinases (ERK) 1 and 2 (62,63). Studies in rodent models suggest that the insulin-antagonistic effects of GH in adipose and skeletal muscle involve suppression of insulin-stimulated PI3-kinase activity (60,64). One study assessed the impact of a GH infusion on insulin sensitivity and the activity of PI3-kinase as well as PKB/AKt in skeletal muscle in a controlled design involving healthy young subjects (65). The infusion of GH induced a sustained increase in FFA levels and subsequently insulin resistance as assessed by the euglycemic clamp technique, as expected, but was not associated with any changes in the insulin-stimulated increase in either IRS-1 associated PI3-kinase or PKB/Akt activity. It was subsequently assessed that insulin had no impact on GH-induced STAT5b activation or SOCS3 mRNA expression (66).
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).
Effects of IGF-I
Studies on hypophysectomized animals overexpressing IGF-I demonstrate the independent anabolic effects of IGF-I (74). IGF-I plays a key role in growth, where it acts not only as a determinant of postnatal growth, but also as an intra-uterine growth promoter. Total inactivation of the IGF-I gene in mice produce a perinatal mortality of 80% with the surviving animal showing significant growth retardation compared to controls (75). Human IGF-I deficiency can be either due to GH deficiency, GHR inactivation, or IGF-I gene mutation. Interestingly, infants with congenital GH deficiency and GHR mutations present with only minor growth retardation, whereas the rare patient with IGF-I deficiency, secondary to a homozygous partial deletion of the IGF-I gene, presents with severe pre and postnatal growth failure, mental retardation, sensorineural deafness, and microcephaly (76-78). The differences in the clinical presentation are most likely due to the fact that some degree of IGF-I production is present in patients with GH deficiency, GHR, and GHRH defects. More detailed studies on transgenic mice have clearly demonstrated this fact with selective deletion of IGF-I gene expression only in the liver, showing low serum IGF-I concentrations with only 6-8% postnatal growth retardation. In contrast, animals with total IGF-I deletion or only peripherally produced IGF-I deletion showed marked growth retardation (79).
Both elevated and reduced levels of serum IGF-I are associated with excess mortality in human adults (80). In addition, it is well recognized in many species including worms, flies, rodents, and primates that a reciprocal relationship exists between longevity and activation of the insulin/IGF axis (80). The underlying mechanisms are subject to continued scrutiny and are likely to be complex. In this regard, it is noteworthy that calorie restriction is associated with increased longevity and reduced insulin/IGF activity in many species (81) albeit GH levels are increased by calorie restriction and fasting (82).
In the context of GH and IGF-I physiology it can be concluded that 1) during childhood and adolescence the combined actions of GH and IGF-I in the presence of sufficient nutrition promote longitudinal growth and somatic maturation, 2) continued excess IGF-I activity in adulthood increases the risk for cardiovascular and neoplastic diseases and hence reduces longevity, 3) calorie restriction, which suppresses IGF-I activity and stimulates GH secretion, may promote longevity in human adults (82).
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.
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