Small as Fetus and Short as Child: From Endogenous to Exogenous Growth Hormone1

Francis de Zegher, Inge Francois, monique van helvoirt and greet van den berghe

Departments of Pediatrics and Intensive Care Medicine, University of Leuven, Leuven, Belgium

Address all correspondence and requests for reprints to: Dr. Francis de Zegher, Department of Pediatrics, University Hospital Gasthuisberg, Herestraat 49, 3000 Leuven, Belgium.


    Introduction
 Top
 Introduction
 GH hypersecretion and GH...
 Functional hypersomatotropism in...
 Catch-up growth in infancy
 Endogenous GH in the...
 Exogenous GH to the...
 Conclusion
 References
 
IN THE human species, the fastest enlargement of body size occurs during the last trimester of fetal life, despite the constraints imposed by the maternal environment (1). The first major act in the drama of human growth is played out by term birth, which is partly timed by the fetal pituitary (2). Even so, much growth potential is left at birth, and a great deal of it is used during the first postnatal years (3).

There is a persistent principle in physiology that the faster a growth process is occurring, the more responsive (hence, in the negative sense, vulnerable) it is to forces impinging on it (3). As prenatal growth is more rapid than at any subsequent time, it is also one of the most vulnerable phases. If growth-limiting factors are prenatally exerted in a pronounced or prolonged fashion, they may not only result in substantial growth retardation at birth, but also in a persistent delay or reduction of postnatal growth, as well as in other long term consequences on cogni-tive, endocrine, metabolic, and cardiovascular functions (4, 5, 6).

In approximately one fifth of strikingly short children, postnatal growth failure is thought to be related to intrauterine growth retardation (IUGR) (7, 8). The term IUGR refers to the fetal growth pattern and presumes that at least two intrauterine growth assessments are available: the fetus has a low growth velocity. The term small for gestational age (SGA) does not refer to fetal growth, but to body size: the conceptus has a low weight and/or length for a known gestational age, e.g. below the third percentile or below the -2 SD limit of an appropriate standard. The SGA condition is often, but not necessarily, the consequence of IUGR. Conversely, infants born after a brief episode of IUGR are not necessarily SGA (9).

Here, we review current evidence on prenatal and postnatal secretion and function of endogenous GH in children born SGA, and we present the initial experience with exogenous GH as a therapeutic approach for postnatal growth failure of prenatal origin.


    GH hypersecretion and GH resistance in the small fetus
 Top
 Introduction
 GH hypersecretion and GH...
 Functional hypersomatotropism in...
 Catch-up growth in infancy
 Endogenous GH in the...
 Exogenous GH to the...
 Conclusion
 References
 
Differentiation and proliferation of somatotropes, enabling the anterior pituitary to initiate GH secretion, depend on expression of the transcription factor Pit-1 (10, 11, 12). GH has been detected in the fetal circulation by 10 weeks gestation and appears to originate exclusively from the fetal pituitary, independently of GHRH, pituitary GH or placental GH in the maternal circulation (13, 14, 15, 16). Plasma GH concentrations rise from approximately 50 µg/L at 12 weeks gestation to around 150 µg/L at midpregnancy and decrease subsequently to approach 20 µg/L by term birth (13, 17, 18).

Studies in the mammalian fetus indicate that fetal GH secretion occurs in a pulsatile fashion (19) and is under hypothalamic control, which is presumably exerted primarily through GHRH and somatostatin (20, 21). The intense secretory activity of the fetal somatotropes in vivo is thought to be related to a higher or earlier responsiveness to GH secretagogues, such as GHRH, compared to GH release-inhibiting factors, such as somatostatin (21, 22, 23, 24). Inhibition by circulating insulin-like growth factor I (IGF-I) may be involved in the gradual decrease in fetal GH secretion toward birth, as serum concentrations of endogenous IGF-I rise in late gestation (25, 26) and as exogenous IGF-I is capable of suppressing fetal GH release (27).

The function of GH in the fetus has not been conclusively established. The concentration of circulating GH-binding protein is low in fetal blood, probably reflecting the lower levels of expression of GH receptor in fetal tissues (28, 29). Circulating IGF-I appears to be virtually independent of fetal GH secretion (21, 30). However, the mean birth length of infants with congenital GH deficiency or GH resistance is reduced by about 1 SD or 1 in., indicating that GH action accounts for some linear growth before birth; in contrast, mean birth weight is normal, suggesting that these newborns have a relative excess of weight (31, 32, 33, 34). The clinical impression that this excess consists mainly of fat is in line with experimental evidence attributing lipolytic and insulin-antagonizing properties to GH before birth (35, 36). The presence of GH effects on skeletal growth and fetal metabolism in the absence of documented effects on the IGFs and IGF-binding proteins (IGFBPs) may to some extent be related to the differential distribution of conventional GH receptors in fetal tissues (28, 37, 38). Alternatively, these effects may be mediated by hitherto unidentified receptors that are specific for the fetus and/or placenta (39).

The association of intrauterine growth retardation with fetal hypersomatotropinemia and GH hyperresponsiveness to GHRH was first established in the ovine species (40, 41). GH hypersecretion may be the direct or indirect result of a reduced negative feedback exerted by IGF-I that circulates in lower concentrations in growth-retarded fetuses (27, 42, 43). The endocrine milieu of the human fetus with growth retardation is not only characterized by low circulating insulin, IGF-I, IGF-II, and IGFBP-3, but also by elevated IGFBP-1 and GH levels (Fig. 1Go) (18, 25, 26). This constellation suggests some degree of amplified GH resistance and is reminiscent of the somatotropic axis in postnatal fasting conditions.



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Figure 1. Serum concentrations of insulin, IGF-I, IGF-II, IGFBP-3, IGFBP-1, and GH in the human fetus at term birth (adapted from Refs. 18 and 26). SGA, AGA, LGA, Small, appropriate, and large for gestational age, respectively.

 

    Functional hypersomatotropism in the small newborn
 Top
 Introduction
 GH hypersecretion and GH...
 Functional hypersomatotropism in...
 Catch-up growth in infancy
 Endogenous GH in the...
 Exogenous GH to the...
 Conclusion
 References
 
The hypersomatotropinemia of the growth-retarded human fetus appears to be maintained during the first postnatal days; moreover, exogenous GHRH was found to elicit a GH hyperresponse in neonates born SGA during the early phase of catch-up growth (44). It is noteworthy that this phenomenon had long been overlooked, probably due to the impact of factors confounding neonatal studies, such as fasting and feeding (45, 46), hypo- and hyperglycemia (47), GH pulsatility (48, 49), and infusion of dopamine (50). Neonatal serum profile studies have now shown that the pulsatile character of GH hypersecretion in SGA newborns may be pronounced (Fig. 2Go).



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Figure 2. Pulsatile hypersecretion of GH in SGA neonates. Profiles were obtained in polycythemic newborns by arterial sampling during a standardized, isovolumetric, partial exchange transfusion (49, 87). Gestational age (weeks), birth weight (grams), and postnatal age of the newborns (hours) are indicated.

 
Three days after birth, hypersomatotropism in SGA newborns was found to be associated with increased levels of circulating IGF-I, suggesting that the somatotropic axis switches to a fully operational status within the first postnatal days (44). Consequently, intense activity of the somatotropic axis is thought to be one of the mechanisms driving the postnatal catch-up growth that occurs in most SGA infants (44).

Exogenous GH had no detectable metabolic or growth-promoting effects in SGA neonates (51, 52). It is currently unknown whether this lack of impact is attributable to the hypersecretion and efficacy of endogenous GH or, rather, to GH resistance in SGA newborns (44, 45).


    Catch-up growth in infancy
 Top
 Introduction
 GH hypersecretion and GH...
 Functional hypersomatotropism in...
 Catch-up growth in infancy
 Endogenous GH in the...
 Exogenous GH to the...
 Conclusion
 References
 
Under favorable environmental circumstances, there is an assortment of relative sizes among infants during the first 12–18 months after birth; on the average, the catch-up growth of SGA infants proceeds a little faster than the slow-down growth of infants born large for gestational age (3). Presently, approximately 85–90% of term newborns with a birth weight and/or length below a -2 SD score display sufficient catch-up growth to attain a height above a -2 SD score by the age of 2 yr (8, 53). Although preterm newborns with a length below a -2 SD score have a longer distance to bridge, the fraction of short premature infants reaching a height above -2 SD score at 2 yr is comparable to that of term infants (54). Advanced perinatal care, including earlier identification of growth-retarded fetuses, elective delivery before term, and neonatal intensive care with emphasis on nutrition, decreases perinatal mortality and accelerates neonatal catch-up growth, but does not alter stature beyond infancy (55). These observations suggest that late gestational and neonatal factors may modulate the timing of catch-up growth in early infancy, but that the amplitude of long term catch-up is essentially determined before the third trimester of gestation. Similarly, the long term risk for growth-retarded newborns to develop obesity has been related to nutritional deprivation in early, not late, gestation (56, 57).

The mechanisms orchestrating neonatal catch-up growth remain among the enigmas of growth physiology. To date, not a single auxological, biochemical, or endocrine marker has been identified to accurately predict the catch-up growth of a neonate born SGA. The appetite of the infant appears to be involved, besides quantity, quality, and partitioning of nutrition, but their precise interrelationships have not been defined. The glucose-induced insulin response in infants with spontaneous catch-up growth is elevated compared to that in infants without significant catch-up (58). However, it is uncertain whether this observation reflects a difference in readily releasable insulin reserve, spontaneous appetite and nutrient intake, body composition, or insulin resistance. In turn, if the latter phenomenon is present, it might be related to the aforementioned increase in GH secretion during early catch-up growth (44). Circulating IGF-I and IGFBP-3 concentrations, measured during catch-up growth of infants born SGA, were normal between 1 month and 2 yr of age (59).


    Endogenous GH in the short SGA child
 Top
 Introduction
 GH hypersecretion and GH...
 Functional hypersomatotropism in...
 Catch-up growth in infancy
 Endogenous GH in the...
 Exogenous GH to the...
 Conclusion
 References
 
Approximately 10–15% of SGA children maintain a height below a -2 SD score throughout childhood (8, 53). An illustrative case of this subgroup would have a midparental height around -1 SD score, birth length and birth weight below a -2 SD score, a height velocity around -1 SD score, a height SD score between -3 and -4 with a low body mass index SD score, a bone age progressing more slowly than chronological age before adrenarche and faster thereafter, a somewhat early onset of puberty, and a final height in the range of -1.5 to -2.0 SD score (7, 8, 53, 55, 60, 61, 62, 63, 64, 65, 66).

GH secretion has only been examined in prepubertal SGA children with short, not normal, stature and thus with incomplete catch-up growth during infancy. Within this subgroup, GH insufficiency is not mandatory, but its prevalence appears to be increased. GH insufficiency may consist of either classical GH deficiency, as diagnosed by stimulation tests, or subtle abnormalities in the GH secretory pattern, as detected by GH profile studies (67, 68, 69, 70, 71). Abnormalities in spontaneous GH release (Fig. 3Go) include high pulse frequency, attenuated pulse amplitude, and relatively elevated interpulse concentrations of serum GH (67, 68, 69, 70, 71). These alterations in the GH secretory pattern are distinctly different from those observed during fasting (increased pulse amplitude), but are similar to those documented in adults during prolonged critical illness (72, 73). Consequently, a novel approach to the abnormal pattern of GH secretion in some short SGA children would be to consider it as a neuroendocrine sequela of prolonged critical illness before birth.



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Figure 3. Neurosecretory GH deficiency in short SGA children: sequential serum GH concentrations obtained overnight in two children with normal GH responsiveness to glucagon testing and with low serum IGF-I levels. Upper panel, A 5-yr-old boy born after a complicated twin pregnancy, with a height SD score of -4.1 and a serum GH response to glucagon of 19.4 µg/L. Lower panel, An 8-yr-old girl born after a pregnancy complicated by maternal ovarian hemorrhage early in the first trimester, with a height SD score of -3.5 and a serum GH response to glucagon of 22.8 µg/L. Both serum GH patterns are characterized by low peak and relatively elevated interpulse concentrations. Deconvolution analysis reveals high frequency, low amplitude pulsatile secretion of GH with elevated approximate entropy scores, indicating pronounced irregularity of GH release (courtesy of Dr. J. D. Veldhuis, University of Virginia, Charlottesville, VA).

 
The pathophysiological mechanisms underlying the abnormal GH patterns in some short SGA children are poorly understood. Somatotrope unresponsiveness to GHRH does not seem to be implied (74). Deficiencies of endogenous GH secretagogues, such as GHRH, galanin, and/or the putative endogenous GH-releasing peptide ligand, remain to be investigated.

Short and slowly growing SGA children without conventional GH deficiency appear to have low normal circulating IGF-I concentrations (70, 75, 76) and normal IGF-II and IGFBP-3 levels (75, 76), suggesting that they are not GH resistant, but may present an altered sensitivity to the growth-promoting actions of some IGFs and/or IGFBPs (39, 77, 78).


    Exogenous GH to the short SGA child
 Top
 Introduction
 GH hypersecretion and GH...
 Functional hypersomatotropism in...
 Catch-up growth in infancy
 Endogenous GH in the...
 Exogenous GH to the...
 Conclusion
 References
 
The potential of exogenous GH to normalize the short stature of SGA children with insufficient spontaneous catch-up growth has been explored for more than a quarter of a century. Three waves of studies can be distinguished.

In the pioneering attempts, GH was administered with low frequency (79, 80) or in substitution doses (81, 82). The observed growth responses were heterogeneous, and it was difficult to draw firm conclusions.

Once recombinant human GH became available, the effects of higher GH doses were explored in short SGA children. High dose GH treatment resulted in a pronounced acceleration of statural growth, whereas placebo injections were documented to exert no consistent growth-promoting effect over 6 months (65). However, therapeutic conclusions beyond 6 months of treatment were again limited by the lack of fully parallel controls (64, 65, 83).

More recently, a third set of studies was launched, including trials with a randomized, fully parallel, untreated control group. Two-year results from a few of these trials are now available (Fig. 4Go). The growth response proved to be dose dependent for all short term variables: height velocity (SD score), increment in height SD score, weight gain, and bone age progression (61). The height SD score for bone age, an index of final height prognosis, increased in all GH-treated groups and was a less sensitive dose-dependent variable (61).



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Figure 4. Meta-analysis of growth and bone maturation results (mean and SD) from three independent, randomized, controlled, multicenter studies in short, prepubertal, non-GH-deficient, SGA children treated with three doses of GH over 2 yr (international units per kg daily, sc). The study population (n = 146) consisted of children from Belgium, Germany, and Scandinavia. The mean birth weight SD score was -2.9, the birth length SD score was -3.6, the mean chronological age at the start of the study was 4.9 yr (range, 2–8 yr), bone age was 3.5 yr, the height SD score was -3.6, and the weight SD score was -6.3 (adapted from Ref. 61). p < 0.05 or p < 0.005, as indicated.

 
A multivariate analysis, including data from a trial in France, indicated that the dose of GH and the age of the SGA child are the dominant factors determining the variation in growth responses (the higher the dose and the younger the child, the greater the increase in height SD score) (61). GH treatment was well tolerated throughout the studied dose range. The growth acceleration induced by GH was accompanied by a rise in circulating insulin, osteocalcin, IGF-I, and IGFBP-3 in the presence of unaltered concentrations of IGF-II (75, 76). Although high dose GH treatment may transiently decrease insulin sensitivity, no significant alterations in fasting blood glucose or hemoglobin A1c were identified after 2 yr (75).

Short SGA children have short linear and normal angular dimensions in the craniofacial complex, resulting in a relatively convex profile of the face. High dose GH treatment for 2 yr leads to a pronounced acceleration of craniofacial growth without inducing a shift toward an acromegalic pattern (84).

The data from the untreated controls confirm that prepubertal children with short stature of prenatal origin have subnormal growth velocity and poor weight gain, thus corroborating the idea that the majority of these children are indeed bound to remain short, at least throughout childhood (8, 53, 55, 62, 85, 86).

It is now clear that exogenous GH is capable of inducing a dose-dependent growth acceleration, apparently without eliciting undue side-effects or compromising long term growth. Thus, GH administration is emerging as a promising therapy to normalize short stature and low weight after insufficient spontaneous catch-up growth in SGA children. Long term strategies incorporating GH treatment remain to be established. At present, the results obtained leave several options open, including continuous or intermittent regimens with, respectively, lower or higher doses of GH.


    Conclusion
 Top
 Introduction
 GH hypersecretion and GH...
 Functional hypersomatotropism in...
 Catch-up growth in infancy
 Endogenous GH in the...
 Exogenous GH to the...
 Conclusion
 References
 
The somatotropic axis has proven to be an interesting pathway to approach the phenomenon of human growth retardation of prenatal origin. During prenatal growth retardation, the somatotropic axis displays characteristics similar to those during postnatal fasting, i.e. GH hypersecretion within a constellation reminiscent of GH resistance. After birth, GH hypersecretion is maintained in the majority of SGA newborns and switches to a functional IGF-generating system, which may be one of mechanisms driving neonatal catch-up growth.

A minority of SGA children present insufficient catch-up growth during infancy and maintain short stature and low body weight at least throughout childhood. The underlying pathophysiology is incompletely understood. Some children present alterations in the somatotropic axis; resistance to GH and/or IGF-IGFBPs remains to be firmly established, but GH deficiency has been repeatedly demonstrated either in the conventional form or as so-called neurosecretory dysfunction.

In short SGA children without conventional GH deficiency, the results of GH treatment over 2 yr are promising; GH elicits dose-dependent accelerations of statural growth, weight gain, and, to a lesser extent, bone maturation. The next step is to explore long term strategies incorporating GH treatment.


    Acknowledgments
 
The authors thank Karin Vanweser and Annika Löfström (Pharmacia & Upjohn, Stockholm, Sweden) for their contribution in the preparation of this manuscript.


    Footnotes
 
1 The Belgian Endocrine Society Award Lecture (November 23, 1996). Back

Received November 22, 1996.

Revised February 5, 1997.

Accepted March 7, 1997.


    References
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 Introduction
 GH hypersecretion and GH...
 Functional hypersomatotropism in...
 Catch-up growth in infancy
 Endogenous GH in the...
 Exogenous GH to the...
 Conclusion
 References
 

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