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.
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Introduction
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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.
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GH hypersecretion and GH resistance in the small fetus
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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. 1
) (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.
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Functional hypersomatotropism in the small newborn
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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. 2
).

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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.
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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).
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Catch-up growth in infancy
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Under favorable environmental circumstances, there is an
assortment of relative sizes among infants during the first 1218
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 8590% 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).
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Endogenous GH in the short SGA child
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Approximately 1015% 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. 3
) 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).
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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).
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Exogenous GH to the short SGA child
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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. 4
). 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, 28 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.
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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.
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Conclusion
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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.
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Acknowledgments
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The authors thank Karin Vanweser and Annika Löfström
(Pharmacia & Upjohn, Stockholm, Sweden) for their contribution in the
preparation of this manuscript.
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Footnotes
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1 The Belgian Endocrine Society Award Lecture (November 23,
1996). 
Received November 22, 1996.
Revised February 5, 1997.
Accepted March 7, 1997.
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References
|
---|
-
Gluckman PD. 1989 Fetal growth: an endocrine
perspective. Acta Paediatr Scand. 349(Suppl):2124.
-
de Zegher F, Kaplan SL, Grumbach MM, et al. 1995 The foetal pituitary, postmaturity and breech presentation. Acta
Paediatr. 83:11001102.
-
Tanner JM. 1994 Growth from birth to two: a
critical review. Acta Med Auxol. 26:745.
-
Fitzhardinge PM, Steven EM. 1972 The
small-for-date infant. II. Neurologic and intellectual sequelae. Pediatrics. 50:5057.[Abstract]
-
Barker DJP, Osmond C, Golding J, Kuh D, Wadsworth
MEJ. 1989 Growth in utero. Blood pressure in childhood and adult
life, and mortality from cardiovascular disease. Br Med J. 298:564567.[Medline]
-
Phillips DIW, Barker DJP, Hales CN, Hirst S, Osmond
C. 1994 Thinness at birth and insulin resistance in adult life. Diabetologia. 37:150154.[CrossRef][Medline]
-
Fitzhardinge PM, Steven EM. 1972 The
small-for-date infant. I. Later growth patterns. Pediatrics. 49:671681.[Abstract]
-
Karlberg J, Albertsson-Wikland K. 1995 Growth in
full-term small-for-gestational-age infants: from birth to final
height. Pediatr Res. 38:733739.[Abstract]
-
Dunn PM. 1985 The search for perinatal definitions
and standards. Acta Paediatr Scand. 319(Suppl):716.
-
Ingraham HA, Albert VR, Chen R, et al. 1990 A
family of POU-domain and Pit-1 tissue-specific transcription factors in
pituitary and neuroendocrine development. Annu Rev Physiol. 52:773782.[CrossRef][Medline]
-
Castrillo JL, Theill LE, Karin M. 1991 Function of
the homeodomain protein GHF1 in pituitary cell proliferation. Science. 253:197199.[Medline]
-
Voss JW, Rosenfeld MG. 1992 Anterior pituitary
development: short tales from dwarf mice. Cell. 70:527529.[Medline]
-
Kaplan SL, Grumbach MM, Shepard TH. 1972 The
ontogenesis of human fetal hormones. I. Growth hormone and insulin. J Clin Invest. 51:30803093.[Medline]
-
Frankenne F, Closset J, Gomez F, Scippo ML, Smal J,
Hennen G. 1988 The physiology of growth hormones (GHs) in pregnant
women and partial characterization of the placental GH variant. J
Clin Endocrinol Metab. 66:11711180.[Abstract]
-
de Zegher F, Vanderschueren-Lodeweyckx M, Spitz B, et
al. 1990 Perinatal growth hormone (GH) physiology: effect of
GH-releasing factor on maternal and fetal secretion of pituitary and
placental GH. J Clin Endocrinol Metab. 77:520522.
-
Heinrichs C, de Zegher F, Vansnick F, Vokaer A,
Christophe C, Frankenne F. 1994 Fetal hypopituitarism: perinatal
endocrine and morphological studies in two cases. Acta Paediatr. 83:448451.[Medline]
-
Hindmarsch P. 1987 Hormonal levels in the human
fetus between 14 and 22 weeks gestation. Early Hum Dev. 15:253258.[Medline]
-
de Zegher F, Kimpen J, Raus J, Vanderschueren-Lodeweyckx
M. 1990 Hypersomatotropism in the dysmature infant at term and
preterm birth. Biol Neonate. 58:188191.[Medline]
-
Bassett NS, Gluckman PD. 1986 Pulsatile growth
hormone secretion in the ovine fetus and neonatal lamb. J Endocrinol. 109:307312.[Abstract]
-
Gluckman PD, Parsons Y. 1985 Growth hormone
secretion in the fetal sheep following stereotaxic electrolytic
lesioning of the fetal hypothalamus. J Dev Physiol. 7:2536.[Medline]
-
Grumbach MM, Gluckman PD. 1994 The human fetal
hypothalamus and pituitary gland: the maturation of neuroendocrine
mechanisms controlling the secretion of fetal pituitary growth hormone,
prolactin, gonadotropins, adrenocorticotropin-related peptides and
thyrotropin. In: Tulchinsky D, Little AB, eds. Maternal and fetal
endocrinology, 2nd ed. Philadelphia: Saunders; 193261.
-
Gluckman PD, Mueller PL, Kaplan SL, Rudolph AM, Grumbach
MM. 1979 Hormone ontogeny in the ovine fetus. I. Ovine growth
hormone in mid and late gestation. Endocrinology. 104:162168.[Medline]
-
de Zegher F, Daaboul J, Grumbach MM, Kaplan SL. 1989 Hormone ontogeny in the ovine fetus and neonatal lamb. XXII.
Effect of somatostatin on the growth hormone (GH) response to
GH-releasing factor. Endocrinology. 124:11141117.[Abstract]
-
de Zegher F, Bettendorf M, Grumbach MM, Kaplan SL. 1990 Hormone ontogeny in the ovine fetus. XXV. Somatotrope
desensitization to growth hormone (GH)-releasing factor independent of
short-latency, ultrashortloop GH feedback. Neuroendocrinology. 52:429433.[Medline]
-
Lassare C, Hardouin S, Daffos F, Forestier F, Frankenne
F, Binoux M. 1991 Serum insulin-like growth factors and
insulin-like growth factor binding proteins in the human fetus:
relationships with growth in normal subjects and in subjects with
intrauterine growth retardation. Pediatr Res. 29:219225.[Medline]
-
Giudice LC, de Zegher F, Gargosky SE, et al. 1995 Insulin-like growth factors and their binding proteins in the term and
preterm human fetus and neonate with normal and extremes of
intrauterine growth. J Clin Endocrinol Metab. 80:15481555.[Abstract]
-
de Zegher F, Bettendorf M, Kaplan SL, Grumbach MM. 1988 Hormone ontogeny in the ovine fetus and neonatal lamb. XXI. Effect
of exogenous insulin-like growth factor-1 on plasma growth hormone,
insulin and glucose concentrations. Endocrinology. 123:658660.[Abstract]
-
Hill DJ, Riley SC, Bassett NS, Waters MJ. 1992 Localization of the growth hormone receptor, identified by
immunocytochemistry, in second trimester human fetal tissues and in
placenta throughout gestation. J Clin Endocrinol Metab. 75:646652.[Abstract]
-
Massa G, de Zegher F, Vanderschueren-Lodeweyckx M. 1992 Serum growth hormone-binding protein in the human fetus and
infant. Pediatr Res. 32:6972.[Abstract]
-
de Zegher F, Pernasetti F, Vanhole C, Devlieger H, Van
den Berghe G, Martial JA. 1995 The prenatal role of thyroid
hormone evidenced by fetomaternal pit-1 deficiency. J
Clin Endocrinol Metab. 80:31273130.[Abstract]
-
Gluckman PD, Gunn AJ, Wray A, et al. 1992 Congenital idiopathic growth hormone deficiency is associated with
prenatal and early postnatal growth failure. J Pediatr. 121:920925.[Medline]
-
Wit JM, van Unen H. 1992 Growth of infants with
neonatal growth hormone deficiency. Arch Dis Child. 67:920924.[Abstract]
-
Laron Z, Lilos P, Klinger B. 1993 Growth curves for
Laron syndrome. Arch Dis Child. 68:768772.[Abstract]
-
DeLuca F, Bermasconi S, Blandino A, Cavallo L,
Cistermino M. 1995 Auxological, clinical and neuroradiological
findings in infants with early onset growth hormone deficiency. Acta
Paediatr. 84:561565.[Medline]
-
Parkes MJ, Bassett JM. 1985 Antagonism by growth
hormone of insulin action in fetal sheep. J Endocrinol. 105:379382.[Abstract]
-
Stevens D, Alexander G. 1986 Lipid deposition after
hypophysectomy and growth hormone treatment in the sheep fetus. J Dev
Physiol. 8:139145.[Medline]
-
Werther GA, Haynes KM, Barnard R, Waters MJ. 1990 Visual demonstration of growth hormone receptors on human growth plate
chondrocytes. J Clin Endocrinol Metab. 70:17251730.[Abstract]
-
Werther GA, Haynes K, Waters MJ. 1993 Growth
hormone (GH) receptors are expressed on human mesenchymal tissue:
identification of messenger ribonucleic acid and GH-binding protein. J Clin Endocrinol Metab. 76:16381644.[Abstract]
-
Gluckman PD, Cutfield W, Harding JE, et al. 1996 Metabolic consequences of intrauterine growth retardation. Acta
Paediatr. 417(Suppl):36.
-
de Zegher F, Styne DM, Daaboul J, Bettendorf M, Kaplan
SL, Grumbach MM. 1989 Hormone ontogeny in the ovine fetus and
neonatal lamb. XX. Effect of age, breeding season and twinning on the
growth hormone (GH) response to GH-releasing factor: evidence for a
homeostatic role of fetal GH. Endocrinology. 124:124128.[Abstract]
-
Bauer MK, Breier BH, Harding JE, Veldhuis JD, Gluckman
PD. 1995 The fetal somatotropic axis during long-term maternal
undernutrition in sheep: evidence for nutritional regulation in utero. Endocrinology. 136:12501257.[Abstract]
-
Gluckman PD. 1986 The role of pituitary hormones,
growth factors and insulin in the regulation of fetal growth. In:
Clarke JR, ed. Oxford reviews of reproductive biology, 8th ed. London:
Oxford University Press; 2.
-
Woods KA, Camacho-Hubner C, Savage MO, Clark AJL. 1996 Intrauterine growth retardation and postnatal growth failure
associated with deletion of the igf-1 gene. N Engl J Med. 335:13631367.[Free Full Text]
-
Deiber M, Chatelain P, Naville D, Putet G, Salle B. 1989 Functional hypersomatotropism in small for gestational age (SGA)
newborn infants. J Clin Endocrinol Metab. 68:232234.[Abstract]
-
Cornblath M, Parker ML, Reisner SH, Forbes AE, Daughaday
WH. 1965 Secretion and metabolism of growth hormone in premature
and full term infants. J Clin Endocrinol Metab. 25:209218.[Medline]
-
Adrian TE, Lucas A, Bloom SR, Aynsley-Green A. 1983 Growth hormone response to feeding in term and preterm neonates. Acta
Paediatr Scand. 72:251254.[Medline]
-
Westphal O. 1968 Human growth hormone: a
methodological and clinical study. Acta Paediatr Scand. 57(Suppl
182):181.
-
Miller JD, Esparza A, Wright NM, et al. 1993 Spontaneous growth hormone release in term infants: changes during the
first four days of life. J Clin Endocrinol Metab. 76:10581062.[Abstract]
-
de Zegher F, Devlieger H, Veldhuis JD. 1993 Properties of growth hormone and prolactin hypersecretion by the human
newborn on the day of birth. J Clin Endocrinol Metab. 76:11771181.[Abstract]
-
de Zegher F, Van den Berghe G, Devlieger H, Eggermont E,
Veldhuis JD. 1993 Dopamine inhibits neonatal growth hormone and
prolactin hypersecretion. Pediatr Res. 34:642645.[Abstract]
-
Ducharme JR, Grumbach MM. 1961 Studies on the
effects of human growth hormone in premature infants. J Clin
Invest. 40:243247.[Medline]
-
van Toledo-Eppinga L. 1995 Growth promoting
interventions in preterm infants. PhD Thesis. Amsterdam: Free
University Amsterdam.
-
Albertsson-Wikland K, Karlberg J. 1994 Natural
growth in children born small for gestational age with and without
catch-up growth. Acta Paediatr Scand. 399(Suppl):6470.
-
Hokken-Koelega ACS, De Ridder MAJ, Lemmen RJ, et
al. 1995 Children born small for gestational age: do they catch
up? Pediatr Res. 38:267271.[Abstract]
-
Fitzhardinge PM, Inwood S. 1989 Long-term growth in
small-for-date children. Acta Paediatr Scand. 349(Suppl):2733.
-
Ravelli GP, Stein ZA, Susser MW. 1976 Obesity in
young men after famine exposure in utero and early infancy. N Engl
J Med. 295:349353.[Abstract]
-
Dietz WH. 1994 Critical periods in childhood for
the development of obesity. Am J Clin Nutr. 59:955959.[Abstract]
-
Colle E, Schiff D, Andrew G, Bauer CB, Fitzhardinge
P. 1976 Insulin responses during catch-up growth of infants who
were small for gestational age. Pediatrics. 57:6371.
-
Leger J, Noel M, Limal JM, Czernichow P. 1996 Growth factors and intrauterine growth retardation: serum GH, IGF, and
IGFBP-3 levels in children with intrauterine growth retardation as
compared with normal control subjects: prospective study from birth to
2 years of age. Pediatr Res. 40:101107.[Abstract]
-
Francois I, de Zegher F. 1997 Adrenarche and fetal
growth. Pediatr Res. 41:440442.[Abstract]
-
de Zegher F, Albertsson-Wikland K, Wilton P, et al. 1996 Growth hormone treatment of short children born small for
gestational age: a metanalysis of four independent, randomized,
controlled, multicentre studies. Acta Paediatr. 417(Suppl):2731.
-
Tanner JM, Leijarraga H, Cameron N. 1975 The
natural history of the Silver-Russell syndrome: a longitudinal study of
thirty-nine cases. Pediatr Res. 9:611623.[Abstract]
-
Davies PSW, Valley R, Preece MA. 1988 Adolescent
growth and pubertal progression in the Silver-Russell syndrome. Arch
Dis Child. 63:130135.[Abstract]
-
Stanhope R, Preece MA, Hamill G. 1991 Does growth
hormone treatment improve final height attainment of children with
intrauterine growth retardation? Arch Dis Child. 66:11801183.[Abstract]
-
Chatelain P, Job JC, Blanchard J, et al. 1994 Dose-dependent catch-up growth after 2 years of growth hormone
treatment in intrauterine growth-retarded children. J Clin
Endocrinol Metab. 78:14541460.[Abstract]
-
Ranke MB, Lindberg A. 1996 Growth hormone treatment
of short children born small for gestational age or with Silver-Russell
syndrome: results from KIGS, including the first report on final
height. Acta Paediatr Suppl. 417:1826.[Medline]
-
Ackland FM, Stanhope R, Eyre C, Hamill G, Jones J,
Preece MA. 1988 Physiological growth hormone secretion in children
with short stature and intra-uterine growth retardation. Horm Res. 30:241245.[Medline]
-
Rochiccioli P, Tauber M, Moisan V, Pienkowski C. 1989 Investigation of growth hormone secretion in patients with
intrauterine growth retardation. Acta Paediatr Scand.
349(Suppl):4246.
-
Albertsson-Wikland K. 1989 Growth hormone secretion
and growth hormone treatment in children with intrauterine growth
retardation. Acta Paediatr Scand. 349(Suppl):3541.
-
de Waal WJ, Hokken-Koelega ACS, Stijnen T, de Muinck
Keizer-Schrama SMPF, Drop SLS. 1994 Endogenous and stimulated GH
secretion, urinary GH excretion and plasma IGF-I and IGF-II levels in
prepubertal children with short stature after intrauterine growth
retardation. Clin Endocrinol (Oxf). 41:621630.[Medline]
-
Boguszewski M, Rosberg S, Albertsson-Wikland K. 1995 Spontaneous 24-hour growth hormone profiles in prepubertal small
for gestational age children. J Clin Endocrinol Metab. 80:25992606.[Abstract]
-
Van den Berghe G, de Zegher F, Lauwers P, Veldhuis
JD. 1994 Growth hormone secretion in critical illness: effect of
dopamine. J Clin Endocrinol Metab. 79:11411146.[Abstract]
-
Van den Berghe G, de Zegher F. 1996 Anterior
pituitary function during critical illness and dopamine treatment. Crit
Care Med. 24:15801590.[Medline]
-
Job JC, Chatelain P, Rochiccioli P, Ponte C, Olivier M,
Sagnard L. 1990 Growth hormone response to a bolus injection of
144 growth hormone-releasing hormone in very short children with
intrauterine onset of growth failure. Horm Res. 33:161165.[Medline]
-
de Zegher F, Maes M, Gargosky SE, et al. 1996 High-dose growth hormone treatment of short children born small for
gestational age. J Clin Endocrinol Metab. 81:18871892.[Abstract]
-
Boguszewski M, Jansson C, Rosberg S, Albertsson-Wikland
K. 1996 Changes in serum IGF-1 and IGFBP-3 levels during growth
hormone treatment in prepubertal short children born small for
gestational age. J Clin Endocrinol Metab. 81:39023908.[Abstract]
-
Balsamo A, Tassoni P, Cassio A, et al. 1995 Response to growth hormone therapy in patients with growth hormone
deficiency who at birth were small or appropriate in size for
gestational age. J Pediatr. 126:474477.[Medline]
-
Chatelain PG, Cauderay MC, de Zegher F, et al. 1996 Growth hormone secretion and sensitivity in children born small for
gestational age. Acta Paediatr. 417(Suppl):1516.
-
Tanner JM, Whitehouse RH, Hughes PCR, Vince FP. 1971 Effect of human growth hormone for one to seven years on growth of
100 children, with growth hormone deficiency, low birth weight,
inherited smallness, Turners syndrome and other complaints. Arch Dis
Child. 46:745782.[Medline]
-
Grunt JA, Enriquez AR, Daughaday WH, Budd S. 1972 Acute and long-term responses to hGH in children with idiopathic
small-for-dates dwarfism. J Clin Endocrinol Metab. 35:157168.[Medline]
-
Foley Jr TP, Thompson RG, Shaw M, Baghdassavian A,
Nissley SP, Blizzard RM. 1974 Growth responses to human growth
hormone in patients with intra-uterine growth retardation. J
Pediatr. 84:635641.[Medline]
-
Lanes R, Plotnick LP, Lee PA. 1979 Sustained effect
of human growth hormone therapy on children with intra-uterine growth
retardation. Pediatrics. 63:731735.[Abstract]
-
Job JC, Chaussain JL, Job B, et al. 1996 Follow-up
of three years of treatment with growth hormone and of one
post-treatment year in children with severe growth retardation of
intrauterine onset. Pediatr Res. 39:354359.[Abstract]
-
Van Erum R, Mulier M, Carels C, Verbeke G, de Zegher
F. Craniofacial growth in short children born small for
gestational age: effect of growth hormone treatment. J Dent Res. In
press.
-
Job JC, Rolland A. 1986 Histoire naturelle des
retards de croissance debut intra-uterin. Arch Fr Pediatr. 43:301306.[Medline]
-
Westwood M, Kramer MS, Nunz D, Lovett JM, Watters
GV. 1983 Growth and development of full term nonasphyxiated
small-for-gestational age newborns: follow-up through adolescence. Pediatrics. 71:376382.[Abstract]
-
de Zegher F, Devlieger H, Veldhuis JD. 1992 Pulsatile and sexually dimorphic secretion of luteinizing hormone in
the human infant on the day of birth. Pediatr Res. 32:605607.[Abstract]