INTRODUCTION

Growth in childhood, one of the most fascinating, complex and dynamic biological processes, is tightly controlled and regulated. Growth evaluation, height and weight determinations, remains one of the most useful of all indices of public health and economic well being, specifically in developing countries and countries in transition. This chapter does not intend to reduce to a brief summary the complex interactions involved in the processes of human growth and great scientific advances of the last decades. Rather, it aims to highlight two key themes. Firstly, the regulation and interaction of the main hormonal axis involved in human growth, the growth hormone (GH)-insulin-like growth factor axis (IGF-I) including the biochemical characteristics of the key members, the ontogeny and main modulators. An updated revision of the "somatomedin" hypothesis is presented. Secondly, current studies revisiting the organization of normal growth from infancy into puberty are briefly discussed. GH is important in promoting somatic growth and in regulating body composition, intermediary muscle and bone metabolism. Some of these GH effects are direct actions whereas others are mediated via IGF-I. IGF-I is the main effector of GH action in linear growth in man; in addition IGF-I and IGF-II are important growth factors involved in diverse cellular actions such as proliferation, differentiation and apoptosis. This chapter should be read in conjunction with chapter 5c dealing with GH in the adult (link)

THE GROWTH HORMONE-INSULIN-LIKE GROWTH FACTOR AXIS

GH is synthesized in the anterior pituitary, where it is store in secretory granules. It is the most abundant hormone in the pituitary accounting for 25% of the gland"s hormones (1). GH is a single polypeptide chain of 191 amino acids with 2 disulphide bridges between amino acids 53-165 and 282-189, respectively. The GH variant 20-kDa accounts for 10-20% of the total content of pituitary GH, results from a different mRNA by alternative splicing of intron B that encodes amino acids in position 32-46. There is another form 17-kDa, which is produced by the same mechanism (2). In man two GH genes are localized on chromosome 17. GH-N gene is expressed in the pituitary and encodes GH. It contains 5 exons and 4 introns. The GH-V gene is expressed in the placenta. There is considerable structural homology between GH, prolactin and hCG (3). In the fetus GH is produced by the pituitary gland from the end of the 1st trimester of gestation and circulating concentrations of GH can reach relatively high levels (4). The biological role of GH during fetal life has been the source of many studies. Early studies with anencephalic fetuses and neonates suggested that GH was not primarily involved in human fetal growth (5). However, the identification of the GH receptor (GHR) and its widespread localization in fetal tissues support a functional role for both GH and its receptor (6-9). There is growing evidence for a role of GH in fetal development although it may contribute only to approximately 20% of fetal size (10). In addition, maternal serum concentrations of placental GH (PGH) and insulin-like growth factor-I (IGF-I) strongly correlate throughout gestation, suggesting that PGH influences fetal growth through IGF-I (11). Chellakooty et al, evaluated the association of maternal serum levels of PGH and IGF-I with fetal growth in a prospective longitudinal study of 89 normal pregnant women (12).PGH levels were detectable in all samples from 5 wk gestation, increasing throughout pregnancy to approximately 37 wk when peak levels of 22 ng/ml (range, 4.6-69.2 ng/ml) were reached. Subsequently, PGH levels decreased until birth. The change in PGH during 24.5-37.5 wk gestation was positively associated with fetal growth rate, birth weight and IGF-I levels (12).

The IGF system

The IGF system is composed of two IGF peptides, two specific receptors, a family of binding proteins and a glycoprotein named the acid-labile subunit (Figure 1). The insulin-like growth factors (IGF-I and IGF-II) are single chain polypeptides with structural similarity to proinsulin. In 1957 Salmon and Daughaday identified the "sulphation factor", later renamed "somatomedin" in the 1970s and referred as IGFs nowadays (49, 50). IGFs are essential regulators of normal fetal and postnatal growth (51-55). IGF-I and IGF-II, as many other growth factors, exert physiologic effects virtually in every organ and tissue during fetal and postnatal life (51-55). The development of IGF knockout models and the identification of four patients with IGF-I gene defects have provided clear evidence on the important role that circulating and locally produced IGF-I play in human and animal fetal and postnatal growth and development (55-60).

Figure 1Schematic representation of the GH-IGF axis.

IGF-I is a basic peptide with 70 amino acids and a molecular weight of 7.6-kDa (61). The human IGF-I peptide is the product of a single gene (~ 90-kb), that is located on the long arm of chromosome 12. It contains six exons and two promoters (61). The IGF-I transcribed by exon 1 is ubiquitously expressed, while the IGF-I transcribed by exon 2 is found exclusively in the liver, increasing with the onset of GH dependent linear growth (61). The expression of the IGF-I gene is determined by the activity of its promoters and by transcription factors that stimulate or inhibit their activity. The most potent regulator of IGF-I expression in postnatal life is GH (61). On the other hand IGF-I mediates growth hormone negative feedback (62). Nutritional status and supply of dietary energy and protein are also regulators of IGF-I and possibly the main regulators of IGF-I expression in fetal life (63, 64). IGF-II is a neutral peptide with 67 amino acids and molecular weight of 7.4-kDa (61) and is the product of a single gene (~ 30-kb) located on the short arm of chromosome 11. It contains nine exons (61, 65) with four different promoters (61). The mature IGF-II peptide is encoded by exons 7, 8 and 9. IGF-II is an imprinted gene, with only the paternal allele being expressed while the maternal allele is inactive. IGF-II gene is linked to H-19 gene, a tumor suppressor gene. Overall it is considered that the regulation of IGF-II expression is GH-independent. The IGF-1 Receptor (IGF-1R), located on chromosome 15, is a hetero-tetrameric glycoprotein of two a and β"subunits, product of single gene with 22 exons (65). The a-subunit corresponds to the extracellular cysteine-rich domain necessary for ligand recognition and binding with a transmembrane domain, and an intracellular domain with tyrosine kinase activity. Signaling activation of the IGF-1R is regulated through binding of the IGF ligands. IGF-I binds to the IGF-1R with high affinity, with dissociation constants in the range of 0.2-1.0 nM. The affinity of IGF-II for the IGF-1R is several folds lower, and the affinity of insulin for the IGF-1R is 100-fold lower (65-66). IGF-binding proteins (IGFBP) and acid-labile subunit (ALS): The IGFs are found in association with specific IGFBPs in blood and extracellular fluids. Six IGFBPs have been characterized IGFBP-1 through to IGFBP-6. All six IGFBPs have at least 50% homology among themselves and 80% homology among different species and are product of different genes with different chromosomal location (65). Most of the homology is found in the amino-and carboxy-terminal regions with a distinct mid-region among the six IGFBPs (65). The main functions of this family of proteins are 1) To extend IGFs half-life in the circulation 2) To transport the IGFs to the target cells and to modulate the biological actions of the IGFs (65). Most of the IGFs in circulation are found in a 150-kDa or ternary complex consisting of IGF-I or IGF-II, IGFBP-3 and acid-labile subunit (ALS) (67, 68). The human ALS gene is located on chromosome 16 and encodes a mature protein of 578 amino acids (69). GH is the main regulator of the ternary complex (70-72). In humans, ALS is undetectable in fetal serum at 27 weeks of gestation, but IGFs and IGFBPs can be detected from the first trimester of gestation. Serum IGFs and IGFBPs are present from early fetal life as determined from cord blood and are related to fetal size (70, 71). ALS is present at the end of fetal life, and increases five-fold from birth to puberty with little change during adulthood (73). A number of patients with short stature have been identified carrying homozygous mutations of the ALS gene, with no detectable serum ALS levels, very low IGF-I and IGFBP-3 levels and absence of 150-kDa ternary complex (74-76) The "somatomedin/IGF hypothesis" The original "somatomedin/IGF hypothesis" postulated that somatic growth was controlled by pituitary GH and mediated by circulating IGF-I expressed exclusively by the liver (49). The discovery that most tissues produce IGF-I in the late 1980"s supporting a role of autocrine/paracrine IGF-I led investigators to modify the original hypothesis to what is known today as the "dual effector" theory (77). Recent experiments using gene deletions and transgenic technologies have revealed new information that again has led investigators to revisit both hypotheses (78-85). These experimental studies have shown that the liver is the principal source of IGF-I in the circulation but is not required for postnatal body growth. This finding indicates that autocrine/paracrine IGF-I but not liver-derived IGF-I (endocrine IGF-I) is the major determinant of postnatal body growth (78-80). However, lack of liver-derived IGF-I results in disproportional organ growth. An early study showed that GH increases liver size in proportion to body weight. Thus, increased liver size in the LI-IGF-I -/- mice (inactivation of IGF-I gene in the liver) is a direct result of the increased GH levels. Decrease kidney size in LI-IGF-I -/- mice is also a result of the decreased serum IGF-I levels (80). In the last decade many more models of IGF-I conditional deletion alone or in combination with other mutants (with ALS knockout, GHR KO etc), have been produced to address the question of the contribution of endocrine vs. paracrine/autocrine IGF-I actions as well as the direct contributions of GH vs. IGF-I. Briefly, these models have led to the following conclusions 1. Tissue IGF-I plays an important role in prenatal and early neonatal growth 2. Over-expression of IGF-II cannot rescue the growth phenotype in IGF-I null mice 3. Endocrine or circulating IGF-I contributes approximately 30% of the adult body size but increased concentration of circulating IGF-I levels can compensate to some extent postnatal linear growth (78-83).

THE GROWTH PLATE

The most important target organ for linear growth is the epiphyseal growth plate, a layer of cartilage found in growing long bones between the epiphysis and the metaphysis. Longitudinal bone growth occurs at the growth plate by endochondral ossification, in which cartilage is formed and then remodeled into bone tissue (84-88). The cellular distribution is organized according to the stage of cell maturation and differentiation, under a tightly controlled programme, and consists of the following cell layers: germinative, proliferative, hypertrophic and degenerative (85). The germinative cell layer or resting zone consists of the stem cells that enter the proliferative cell layer organized in column following the longitudinal axis of the bone. The proliferative zone is crucial in endochondral bone formation, when the chondrocyte divides; the resulting two cells line up along the bone axis and as this process continues all columns are organized along this axis. Although it is still unclear which factor or factors determine this important spatial orientation. Recent studies using a microdissection technique into individual zones has shown that in the rat proximal tibia growth plate IGF-I mRNA expression is minimal compared to perichondrium, metaphyseal bone, muscle and liver whereas IGF-II mRNA was expressed at higher levels compared to bone and liver (85). IGF-II mRNA expression was significantly higher in the proliferative and resting zones compared to the hypertrophic zone. IGF-I and GH receptors are expressed throughout the growth plate. IGF-I and IGF-II mRNA expression is developmentally regulated; IGF-I mRNA levels increased and IGF-II mRNA levels decreased with increasing with age. These data suggest that in rodents IGF-I is not produced by the chondrocytes in the growth plate but rather by surrounding bone and perichondrium (85). Once cell division ceases these mature cells form part of the hypertrophic cell layer (86) and the final layer, the calcifying zone is where cartilaginous matrix is transformed into bone matrix.

ORGANISATION OF GROWTH

Growth phases

Human growth is a rather regular process characterized by a pattern of changing growth rate or height velocity from infancy to adulthood (Figure 2, 95). In the short-term the height velocity of a healthy individual fluctuates i.e. seasonal or longer periodicity has been shown (96, 97). It appears that some phases of growth are more important in their effect on final height. For example a child who is born short has a greater chance of being a short adult. The timing and duration of puberty are also crucial factors in determining final height.

Figure 2

Growth in height of the Montebeillard"s son from birth to 18 years first described by Scanmon in 1927. Top panel: height attained at each age. Bottom panel: Growth velocity. Reproduced with permission from Tanner JM (95).

The infancy-childhood-puberty growth model divides the human growth process into three phases (95). Thus, the infancy phase begins in the middle of gestation and tails off at around 4 years of age, possibly representing the postnatal continuation of fetal growth. The childhood phase starts during the second half of the first postnatal year slowly decelerating and leading into the final phase at puberty. The puberty phase represents additional growth beyond the childhood phase with significant acceleration until the age of peak height velocity followed by a deceleration until linear growth finally ceases (Figure 3).

Figure 3

Growth velocity, indicating the adolescent height spurt for boys and girls. Reproduced with permission from Tanner JM (95).

OVERVIEW

Elegant studies in the last two decades established that the key hormonal axis, the GH-IGF axis, in which GH and IGF-I are produced from early fetal life play a significant role in human linear growth. More recent in vivo and in vitro studies have demonstrated that this axis is composed of hormones with highly specific binding proteins, which modulate their interactions with specific receptors. The development of the IGF system in the first trimester of gestation appears to be GH independent. However, in postnatal life GH is required for IGF-I synthesis and for the normal functional development of growth plate. It has been shown that endocrine, paracrine and autocrine mode of action both of GH and IGFs play important roles in human growth and development. The "revised somatomedin hypothesis" as described by Le Roith (51) provides the basis for a better understanding of the contribution of systemically secreted and locally acting peptides. However, there are many challenges and interactions at play, with short- and long-term consequences for human growth. Therefore, it is important to appreciate that in addition to the biological and physiological role of our genetic background, of interaction of several hormones and growth factors, other factors such as nutrition and socioeconomic status will have a significant effect in determining the attainment of a normal final height. This phenomenon, known as secular change, has been clearly shown in different populations in the world with a significant difference between current growth pattern and that observed in the early 20th century (103-104).

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