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close this bookCauses and Mechanisms of Linear Growth Retardation (International Dietary Energy Consultative Group - IDECG, 1993, 216 pages)
close this folderLinear growth retardation in relation to the three phases of growth
View the document(introductory text...)
View the document1. Introduction
View the document2. The three phases of linear growth
View the document3. Measuring and monitoring linear growth in early life
View the document4. Growth faltering in linear growth
View the document5. Discussion
View the documentReferences
View the documentDiscussion

2. The three phases of linear growth

2.1. Hormonal regulation of linear growth

The growth process is under the control of the endocrine system. However, not only hormones are involved; hormone-binding proteins, growth factors and their binding proteins, as well as the stage of maturity and quantity of the hormone and growth factor receptors on the target cells may play a critical role too (Cianfarani & Holly, 1989; Waters et al., 1990). Furthermore, the secretion of hormones, such as growth hormone (GH), follows a pulsatile pattern with higher peaks during the nights as well as during puberty (Stanhope, Pringle & Brook, 1988). Such growth regulatory mechanisms interact and change in character over the ages (Masse, de Zegter & Vanderschueren-Lodeweyckx, 1992). A further confusing element is that some growth can take place without involvement of central steering mechanisms, as illustrated by an animal study showing that catch-up growth was regulated locally, at the tissue level, and not necessarily by the influence of circulating serum growth factors (Baron et al., 1993). For these reasons, the measurement of a hormone or growth factor in a single serum, urine or tissue sample will shed light on only a small part of this very complicated puzzle.

It is generally agreed that we have at least three distinct endocrine phases of linear growth, as indicated by the solid upper curve in Fig. 1. The pattern of postnatal growth is well documented; a high growth rate is observed from fetal life, with a rapid deceleration up to about 3 years of age. This is followed by a period with lower, slowly decelerating velocity up to puberty. Puberty starts with an increased rate of growth, and after the age of peak height velocity has been reached a deceleration is noted until growth ceases.

Fig. 1. The ICP growth model for height for boys (Karlberg, 1989a). The mean functions are plotted for each of the three components as well as the combined growth. The average at onset of the childhood and puberty components were used. The interrupted curve at 3 years reflects the change in measuring position from lying to standing up (could have been given at 1 or 2 years, as well). The total gains given by each component are given in Table 1. The key hormones involved in the regulation of growth are also given.

How fetal linear growth is regulated is not precisely defined and no key circulating hormone has so far been identified (Gluckman, 1989; Milner & Hill, 1987; Hill, 1989). Uterus size, nutritional support and oxygen level in conjunction with insulin-like growth factors and insulin are believed to be involved in regulating fetal growth (Gluckman, 1989; Milner & Hill, 1987; Hill, 1989).

During fetal life the serum GH level is high, and GH receptors have also been detected (Hill et al., 1988; Werther, Haynes & Waters, 1991). Fetal linear growth, however, is known to be almost independent of GH (Gluckman, 1989; Milner & Hill, 1987). A lack of growth response to GH during fetal life may be due to immature GH-specific receptors in the growth plate, as noted in the rabbit (Barnard et al., 1988). GH-deficient children are on average 1-2 cm, or 2-4% shorter than normal infants at birth (Karlberg & Albertsson-Wikland, 1988; Albertsson-Wikland, Niklasson & Karlberg, 1990; Tse, Hindmarsh & Brook, 1989; Gluckman et al., 1992). Whether this minor deviation is a secondary effect due to the lack of the influential metabolic action of GH or to the lack of a direct effect of GH on the cartilage, is still a matter of debate.

It is more generally accepted that GH is responsible for growth during childhood provided that thyroid hormone secretion is normal. The exact age at which GH begins to control linear growth in humans is still uncertain (vice infra). The majority of children with isolated GH deficiency grow more or less normally during the first 6 months of life, but not thereafter (Karlberg & Albertsson-Wikland, 1988; Albertsson-Wikland, Niklasson & Karlberg, 1990; Tse, Hindmarsh & Brook, 1989; Gluckman et al., 1992).

Growth during adolescence is related both to GH and sex steroids - testosterone in males and oestrogens in females (Copeland, Paunier & Sizonenko; 1977; Keenan et al., 1993). Both GH and sex hormones are needed for normal pubertal growth, although the presence of only one of them is associated with some growth during this period. It is not clear whether GH and sex steroids interact or act independently of each other (Pescovitz, 1990).

It is thus reasonable to conclude that linear growth from birth to maturity is regulated by at least three different growth-promoting systems. Two simultaneously active, superimposed, systems are known to be involved in the adolescent growth spurt. Similarly, a postnatal continuation of the nutritionally driven fetal growth in conjunction with the GH-dependent phase of childhood growth characterizes the growth in the first year of life (Tse, Hindmarsh & Brook, 1989).

2.2. The infancy-childhood-puberty (ICP) growth model

The ICP growth model breaks down linear growth mathematically into three additive and partly superimposed components - infancy, childhood and puberty (Karlberg, 1987, 1989a,b; Karlberg et al., 1987a,b). Fig. 1 shows the shape, size and timing of each of the three components, together with their additive effects in boys.

The ICP model represents linear growth during the first three years of life by a combination of a sharply decelerating infancy component and a slowly decelerating childhood component, the latter acting from the second half of the first postnatal year. From about 3 years of age to maturity, linear growth is represented by the sum of the infancy and childhood components and a sigmoid shaped puberty component operating throughout adolescence (Fig. 1).

2.3. Curve fitting procedure

The ICP-model was sequentially fitted to the individual growth curves from birth to adulthood for the children included in the Swedish longitudinal study (Karlberg, 1987; 1989a). In view of the equilibrium of the growth process it seemed rational to represent the period of slowly decelerating growth from 3 years of age to the onset of puberty by a single component, which was called childhood phase. A simple quadratic function was found to fit growth during this period very well. After subtraction of the extrapolated values of the childhood component from the observed values during the periods before and after this phase, two additional components were extracted and modelled. As a result of this modelling process, three separate components could be isolated (Karlberg, 1987; 1989a).

1. Infancy: This constantly decelerating component begins before birth and tails off by 3-4 years of age. It can be represented by an exponential function:


2. Childhood: This phase begins during the first year of life at age tC, decelerates slowly and advances until maturity at age tE A simple second degree polynomial provides a sufficient model for this component:


3. Puberty: This phase depicts the additional growth induced by puberty and accelerates up to age at peak velocity (tV). It then decelerates till growth finishes (tE). It can be modelled using a logistic function:


In these functions, Y denotes attained body size for the relevant component at time t in years from birth and the a's, b's and c's are constants. Age at end of growth (tE) was specified as the middle of the first one-year interval after age at peak velocity, when the overall gain was less than that in the childhood component alone.

2.4. Biological interpretation of the modelled components

Empirical observations have shown that the three components of the ICP model can be observed in isolation, and that they are additive (Karlberg et al., 1987a,b; Karlberg 1989a,b, 1990). Each component of this model is therefore assumed to represent a separate biological phase of the growth process (Karlberg, 1989a). The infancy component, tentatively starting in mid-gestation and continuing, with a rapidly decelerating influence, up to 3-4 years of age, is claimed to represent the postnatal continuation of fetal growth. It is assumed that the childhood component, slowly decelerating during childhood and adolescence, corresponds basically to the effect of GH. The sigmoid shaped puberty component, the size of which is found to be independent of its timing, most likely describes the part of adolescent linear growth stimulated by sex steroids.

In the following presentation we will focus primarily on the age at onset of the childhood phase of growth. In normal infants, the onset occurs between 6 and 12 months of age and is typically abrupt (Karlberg, 1987; 1989b; 1990; Karlberg et al., 1987a), as illustrated, for instance, by the growth of a Pakistani girl plotted out in Figs 2a-f. What mediates the onset of the childhood phase of growth has not been elucidated, because information about the serum level of growth factors, hormones, the serum globulins involvement and the hormone and growth factor receptor activity and their interaction is still lacking during this critical period. However, the most plausible explanation is that it represents the age at which GH begins to influence normal human linear growth significantly. There are two major observations supporting this idea. Firstly, most (84%) of the increased gain in total body length is localised in the lower segment of the body (Karlberg, 1990). It is known that the growth of the long bones, as represented in the legs, is more sensitive to GH than other bone structures, such as the short bones in the vertebra (Frasier, 1983). Secondly, in children with isolated GH deficiency who receive no hormonal therapy, this tempo change of early linear growth is completely absent (Karlberg & Albertson-Wikland, 1988; Tse, Hindmarsh & Brook, 1989). Some other empirical observations point in the same direction (Karlberg, 1990).

Fig. 2. Length and length velocity for a normal Pakistani belonging to an upper middle class family; the monthly recorded values have been used in (a), every second month values in (b), etc. The growth rate has been expressed in mm/month in all graphs.

Figure (2a)

Figure (2b)

Figure (2c)

Figure (2d)

Figure (2e)

Figure (2f)

The final adult height of an individual is the additive result of the three underlying components (Fig. 1). This graph gives the mean path of each component, but there is an individual variation around these mean values, and the SD values for each component are 2-4 cm. It is not only the magnitude of each component that is important for the final height, but also the duration of the childhood phase; a late onset reduces height, and a late end point increases height (Karlberg, 1989a).

Table 1 includes the mean total contribution of each component to height, sitting height and leg length for the two sexes of the Swedish study. The infancy component is contributing more to sitting height than the childhood component, whereas the opposite is true for leg length. Different body tissues are thus unequally influenced by each of the three phases of growth. There is also a sex difference in the influence of the three components; the sex difference in the infancy and puberty components is related to their magnitude, whereas the childhood sex difference is basically due to a disparity in duration (2 years longer in boys than in girls; Karlberg, 1989a).