Ann Nestlé [Engl] 2007;65:97–108
DOI: 10.1159/000112232
Physiology of Growth
Arlan L. Rosenbloom
Division of Endocrinology, Department of Pediatrics, University of Florida College of Medicine, Gainesville, Fla., USA
Key Words
Human growth ⴢ Fetus ⴢ Infancy ⴢ Adolescence ⴢ Nutrition ⴢ
Insulin-like growth factor-I ⴢ Growth hormone ⴢ
Pituitary differentiation ⴢ Growth hormone insensitivity
Abstract
Human growth is a dynamic and complex process that be-
gins with fertilization of the ovum and is completed with the
fusion of epiphyses and metastases of the long bones mark-
ing the completion of adolescence. Growth occurs in phases
with distinctive characteristics in terms of dominant influ-
ences from among genetic, environmental/nutritional, and
hormonal factors and patterns. Prenatal growth is the most
dramatic phase, achieving a velocity that is never again
matched. It is predominantly under the influence of mater-
nal size and nutritional status with little influence of parental
genetic endowment. Insulin-like growth factors (IGFs) and
insulin are critical, but thyroid hormone and growth hor-
mone (GH) are not. Infancy is a period of rapidly changing
growth rate, from 20 cm/year during the first few months to
10–12 cm/year by 1 year of age. This phase is greatly depen-
dent on genetic endowment, with frequent adjustment to
an appropriate percentile; it is also dependent on normal
thyroid hormone and GH secretion and action (i.e. stimula-
tion of IGF-I synthesis from the liver and promotion of chon-
drocyte differentiation and local secretion of IGF-I). Growth
in the second year averages 10–13 cm/year, in the third year
7.5–10 cm/year and thereafter is stable at 5–6 cm/year, with
continued dependency on normal secretion and action of
thyroid hormone and GH. Relaxation of the suppression of
the hypothalamic-gonadotropin axis with a slow increase in
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sex hormone production marks the onset of adolescence
which is associated with a growth spurt resulting from in-
creased insulin, GH, and IGF-I production, in addition to the
sex hormone surge. Environmental influences on growth are
reflected in secular trends over the past 150 years. A myriad
of gene products acting on the growth plate have been de-
scribed. In addition, delineation of pituitary differentiation
factors and their genetic control, as well as identification of
genes controlling multiple steps in key hormonal actions are
increasing the understanding of the complex interplay of
genetics, environment, and hormonal milieu in the growth
process. Copyright © 2008 Nestec Ltd., Vevey/S. Karger AG, Basel
Definition and Natural History of Human Growth
Human growth physiology encompasses the dynamic
period beginning with cleavage of the zygote and ending
with completion of adolescence which is marked by the
end of long bone growth. Linear growth is built upon the
skeletal infrastructure; chondrocytes in the cartilage
growth plate proliferate, enlarge, and ossify, with ulti-
mate fusion of the distal epiphyseal and central metaphy-
seal regions. This complex process is influenced by ge-
netic, nutritional/environmental, and hormonal factors
that vary with the growth phases. These phases of growth
are prenatal, infancy, childhood, and adolescence.
Prenatal Growth
Development of the microscopic zygote into the 51-cm
newborn is the most dramatic period of growth. From
Arlan L. Rosenbloom, MD
Children’s Medical Services Center
1701 Southwest 16th Avenue
Gainesville, FL 32608 (USA)
Tel. +1 352 334 1393, E-Mail Rosenal@peds.ufl.edu
completion of organogenesis in the first trimester, there
is rapid acceleration in the second trimester to a peak ve-
locity of 2.5 cm/week. The most important influence on
fetal growth is maternal size and nutritional status. Ge-
netic factors have little influence on fetal growth, with the
exception of transmitted or new mutations affecting skel-
etal growth, such as achondroplasia, or affecting key hor-
monal mechanisms [1, 2]. The intrauterine endocrine mi-
lieu is a complex interaction of fetal, placental, and ma-
ternal substrates, precursors, and hormones affecting
growth including, in addition to the insulin-like growth
factors (IGFs), fetal insulin production in response to ma-
ternal glycemia, human placental lactogen, and sex ste-
roids. Both IGF-I and IGF-II are essential for fetal growth,
and their production in utero is independent of growth
hormone (GH). While thyroid hormone is absolutely es-
sential for postnatal growth, its absence, as with inborn
errors of thyroidogenesis or thyroid aplasia, does not af-
fect fetal growth. Production of testosterone by the male
fetus, beginning at approximately 10 weeks gestation, is
essential to male genital differentiation. The ‘mini-ado-
lescence’ characterized by elevated testosterone levels
near term promotes penile growth and accounts for the
observation that newborn males have slightly greater
lean mass and less fat mass than females and are on aver-
age 0.9 cm longer and 150 g heavier [3].
Growth in Infancy
Infancy can be considered a period of rapidly chang-
ing growth rate. Following birth, the infant shifts from a
growth velocity primarily determined by maternal fac-
tors to one adjusted for genetic endowment. While the
mid-parental standard deviation score or percentile for
height may estimate what this endowment consists of,
this is only reliable if the parental heights are actually
measured and their own childhoods were devoid of fac-
tors which might have impaired growth. Linear growth
is a stepwise process rather than being continuous, as im-
plied by the smoothed growth charts derived from cross-
sectional data, and this is especially striking in infancy
[4]. Growth velocity in the first year of life declines from
20 cm/year in the first few months to 10–12 cm/year by 1
year of age, by which time length has increased 50% and
weight threefold. The influence of parental genetic en-
dowment on infant growth is reflected in the shift of
growth channels that occurs for about two thirds of nor-
mal infants during the first 6–18 months of life, with
equal numbers shifting upward and downward [5].
The effect of the ‘mini-adolescence’ of the male fetus
continues for the first 3–6 months after birth, when males
98 Ann Nestlé [Engl] 2007;65:97–108
grow more rapidly than females. While it was earlier
thought that growth in the first 6 months of life was in-
dependent of GH, it is now recognized that GH deficien-
cy (GHD) and GH receptor deficiency, resulting in severe
IGF-I deficiency, affect postnatal growth from the outset
[6].
Growth in Childhood
In the 2nd year, growth velocity averages 10–13 cm/
year and in the 3rd year, 7.5–10 cm/year. Thereafter, from
age 3 years to puberty, growth is stable at 5–6 cm/year,
although there may be a slowing to as little as 2 cm/year
for a time preceding the adolescent growth spurt. This is
especially noticeable in children with constitutional de-
lay in growth and maturation, and is frequently accom-
panied by reduced GH responses to stimulatory testing,
misdiagnosis of GHD, and inappropriate treatment with
recombinant human GH. Childhood growth is also char-
acterized by a rapid change in body proportions, when
the legs grow faster than the trunk, and both grow much
faster than the head in proportion to overall body length.
The ratio of upper body to lower segment (measured as
the distance from the top of the symphysis pubis to the
floor or measuring board with the legs straight) goes
from 1.7 at birth, to 1.4 at 2 years, to unity by age 10 [3].
Growth in Adolescence
At the appropriate biologic age, as reflected in osseous
maturation, suppression of the hypothalamic-gonado-
tropin axis of childhood begins to be lifted and results in
a slow increase in the levels of sex hormones that result
in adolescence. Although girls start their adolescence,
signaled by breast budding, at an average 6 months ear-
lier than boys, whose signal is testicular enlargement, the
adolescent growth spurt is 2 years earlier in girls. Thus,
the adolescent growth spurt is early in female maturation
and late in male maturation. This timing, giving boys a
longer period of slow growth, accounts for some of the
greater adult height of males, along with the growth ef-
fects of testosterone. The pubertal growth spurt accounts
for more than 20% of adult stature and 50% of adult bone
mass accrual. Growth is completed when, under the in-
fluence of estrogen, either secreted by the ovary or con-
verted by aromatization from testosterone in males, fu-
sion of the epiphyses occurs. In addition to sex hormones,
there are large increases in insulin, GH, and IGF-I that
contribute to adolescent growth which, along with nor-
mal thyroid function, are essential to the adolescent
growth spurt [7].
Rosenbloom
 Environmental Factors in Growth
During the 150 years preceding the mid-20th century,
there was a secular trend in the pace of maturation and
adult size of individuals in the Western countries for
which such data are available. A century and a half ago,
average males did not reach adult height until 23 years of
age as opposed to the current 17 years and the age of men-
arche has declined from 17 to 12.5 years. The most appar-
ent explanation for this phenomenon is the improvement
in nutrition and reduction in childhood disease frequen-
cy and duration with attendant salutary effects on the
GH–IGF-I axis. This secular trend appears to have lev-
eled off in the last 50 years [3]. For much of the world,
undernutrition remains the most common cause of short
stature. Overnutrition with obesity increases the rate of
growth, accelerates skeletal maturation, and may advance
pubertal onset in girls, but in contrast to the permanent
effects of long-term childhood malnutrition or chronic
disease, is not typically associated with an effect on adult
height [7].
It is noteworthy that growth differences in preschool
children are more influenced by socioeconomic factors
than by racial or genetic factors [8]. That size differences
between ethnic or geographic groups result from envi-
ronmental factors, rather than genetics, was demonstrat-
ed by the finding that 7-year-old boys in families in the
upper socioeconomic classes from eight different coun-
tries had very similar heights corresponding to the 50th
percentile in the US [9].
Genetic Control of Growth
It is estimated that 70–90% of adult stature is geneti-
cally determined, nutritional and socioeconomic factors
being equal. In addition to the genetic factors affecting
the production of and response to insulin, thyroid hor-
mone, sex steroids, and the GH–IGF-I axis (discussed
below under Hormonal Control of Growth), extensive
genetic control of growth through the expression of nu-
merous genes acting on the growth plate is being increas-
ingly recognized.
Fibroblast growth factors (FGFs) interact with various
FGF receptors to regulate the growth and development of
enchondral bone and longitudinal growth and fusion of
long bones. The gene for FGF receptor 2 (FGFR2) is ex-
pressed by the earliest chondrocytes and induces the ex-
pression of a transcription factor needed for the differen-
tiation of the chondrocytes, as well as male genital devel-
Physiology of Growth
opment, SOX9. FGFR3 stimulates the proliferation of
immature cells and limits division of proliferating chon-
drocytes. Gain of function mutation of FGFR3 is associ-
ated with achondroplasia [7]. Prehypertrophic chondro-
cytes produce a protein referred to as Indian hedgehog
that coordinates the proliferation and differentiation of
chondrocytes and osteoblasts, and the process of bone
formation; this protein is self-regulated by its control of
parathyroid hormone-related protein, gain of function or
loss of function mutations of which result in specific
chondrodysplasias with stunting.
The SHOX gene is found on the pseudo-autosomal re-
gion of the short arms of the X and Y chromosomes and
does not undergo inactivation in normal females; short
stature in those with an absence of the pseudo-autosomal
region of one X chromosome, i.e. Turner syndrome, is at-
tributed to the need for both alleles. Loss of function mu-
tations in one SHOX allele or its isolated deletion has
been described in children with otherwise unexplained
short stature and in Leri-Weill dyschondrosteosis; loss of
both alleles results in another form of osseous malforma-
tion, Langer mesomelic dysplasia. In contrast, overdos-
age of SHOX alleles in girls with triple X syndrome results
in very tall stature and may explain the tall stature of
other multiple X and Y syndromes. Increased stature has
also been associated with variants in the melanocortin-4
receptor, and catecholamine o-methyltransferase affect-
ing estrogen metabolism. The suppressor of cytokine sig-
naling (SOCS2) inhibits GH signaling by competitive
binding to the GH receptor and in mice that have had this
gene knocked out, overgrowth occurs. Overexpression
can also lead to overgrowth, suggesting the kind of dual
effect that is emerging for a variety of gene products [7].
A recently recognized regulator of skeletal growth is
C-type naturetic peptide (CNP). Homozygosity for muta-
tion of the CNP receptor-B resulting in loss of function
causes the skeletal dysplasia referred to as Maroteaux-
Lamy type (acromesomelic dysplasia). Heterozygous car-
riers of the mutation were found to be significantly short-
er than noncarriers, and it was estimated that ⬃3% of
children with idiopathic short stature might be heterozy-
gous for this mutation [10].
Hormonal Control of Growth
As noted above, insulin, thyroid hormone, and sex ste-
roids are important components at various stages of
growth. The absence of insulin in utero results in severe
growth failure in leprechaunism. Thyroid hormone, as
Ann Nestlé [Engl] 2007;65:97–108 99
noted, does not affect intrauterine growth, but is essential
subsequently for the differentiation and proliferation of
chondrocytes and their ability to respond to growth fac-
tors. There are several congenital or genetic defects affect-
ing embryogenesis and migration of the thyroid gland,
thyroid-stimulating hormone (TSH) production, the TSH
receptor, thyroid hormone production and conversion to
active triiodothyronine. In addition, acquired hypothy-
roidism due to autoimmune thyroiditis can completely
stop a child’s growth. Sex steroid effects on bone matura-
tion are via the estrogen receptor; mutations of this recep-
tor or of the aromatase that controls the conversion of tes-
tosterone to estrogen results in prolonged bone growth.
The remainder of this section will focus on the embry-
ology, functional anatomy, genetics, and biochemistry of
the GH–IGF-I pathway. Disorders anywhere along the
GH–IGF-I pathway preceding the IGF-I receptor result in
IGF-I deficiency and may be congenital or acquired. Con-
genital GHD is associated with structural malformations
of the central nervous system, hypothalamus, or pitu-
itary. IGF-I deficiency/resistance may result from genetic
defects involving critical factors in the embryologic de-
velopment of the pituitary or in the cascade from hypo-
thalamic stimulation of GH release to completion of IGF
effects on growth. Acquired abnormalities affecting the
GH/IGF axis range from damage to the hypothalamic
pituitary region from trauma, tumors, infection, autoim-
mune disease, or radiation, to a broad spectrum of chron-
ic conditions characterized by catabolism.
Embryology of the Pituitary Gland
Pituitary differentiation in the embryo is in response
to an orchestration of transcription factors appearing
and disappearing in precise sequence. At 3 weeks gesta-
tion, the ectodermal stomodeum of the embryo develops
an outpouching anterior to the buccopharyngeal mem-
brane. This outpocketing is Rathke’s pouch, which usu-
ally separates from the oral cavity and will give rise to the
adenohypophysis (anterior lobe) of the pituitary gland.
An evagination of the diencephalon then gives rise to the
neurohypophysis of the pituitary gland. Rarely, the prim-
itive oral cavity origin of the pituitary results in a func-
tional pharyngeal adenohypophysis [11]. Secretion of pi-
tuitary hormones can be detected as early as week 12 in
the fetus, and some of these hormones are found within
the pituitary by 8 weeks gestation [12].
Differentiation of the primordial pituitary gland re-
quires a cascade of factors to be expressed in critical tem-
poral and spatial relationships. These include extracellu-
lar signaling factors from the adjacent diencephalon that
100 Ann Nestlé [Engl] 2007;65:97–108
initiate anterior pituitary gland development from the
oral ectoderm, and transcription factors that control pi-
tuitary cell differentiation and specification. Several ho-
meodomain transcription factors directing embryologic
development of the anterior pituitary have been found to
have mutations that result in congenital defects affecting
the synthesis of GH and additional pituitary hormones
[13]. The human mutations that cause isolated GHD or
multiple pituitary hormone deficiency and associated
features are summarized in table 1.
The HESX1 (Homeobox gene Expressed in embryon-
ic Stem cells) gene is important in the development of the
optic nerve as well as the anterior pituitary. HESX1 in-
hibits PROP1-mediated gene effects and mediates fore-
brain development [14]. HESX1 has also been referred to
as the Rpx or Rathke’s pouch homeobox gene. Some mu-
tations that have been described account for a small sub-
set of the cases of septo-optic dysplasia with variable GH
and other pituitary deficiencies [15].
PITX2 is a paired-like homeobox gene expressed in
the fetal pituitary and adult gland, thought to be required
for pituitary development shortly after formation of the
committed Rathke’s pouch. There have been at least eight
mutations in PITX2 resulting in Rieger syndrome which
includes anomalies of the anterior chamber of the eye,
dental hypoplasia, protuberant umbilicus, and mental re-
tardation, but it is uncertain whether pituitary hormone
deficiencies are associated [16].
LHX3 accumulates in Rathke’s pouch and the primor-
dium of the pituitary, and is thought to be involved in the
establishment and maintenance of the differentiated cell
types [17]. Mutations of this transcription factor result in
deficiencies of all pituitary hormones except adrenocor-
ticotropin, and cervical spine rigidity indicating extrapi-
tuitary function for this factor in some families [18].
LHX3 and LHX4 belong to the LIM family of homeobox
genes expressed early in Rathke’s pouch, with expression
persisting into adulthood. This has suggested a mainte-
nance function for anterior pituitary cells. Four patients
in two unrelated families have been identified with LHX3
mutations with a hormonal phenotype similar to PROP1
deficiency, including marked pituitary enlargement in
one patient (see below) [18]. There has been only one re-
port of a mutation within LHX4 [19].
The sonic hedgehog signaling pathway, mediated by
three GLI genes, has been identified in a variety of tissues
and has been implicated in complex disorders of pituitary
development. Mutations of GLI2 are associated with ho-
loprosencephaly [20]. Penetrance is variable, with all af-
fected patients having pituitary gland dysfunction.
Rosenbloom
Table 1. Mutations resulting in isolated growth hormone deficiency (IGHD) or multiple pituitary hormone deficiencies (MPHD)

Gene Hormone deficiency Pituitary anatomy Other abnormalities Inheritance

HESX1 IGHD to MPHD AP hypoplasia, ectopic PP, Septo-optic dysplasia; absent corpus Recessive,
absent infundibulum callosum dominant
LHX3 GH, TSH, LH, FSH, Small, normal, or enlarged AP Short neck and cervical spine with Recessive
PRL limited rotation in some families
LHX4 GH, TSH, ACTH Small AP, ectopic PP Cerebellar abnormalities Dominant
SOX3 IGHD to MPHD AP hypoplasia, ectopic PP, Mental retardation X-linked
absent infundibulum
GLI2 MPHD AP hypoplasia Holoprosencephaly; multiple midline Dominant
defects
PITX2 Unknown in human (Hypoplasia and MPHD in mice) Rieger syndrome (see text) Dominant
PROP1 GH, PRL, TSH, LH, Small, normal, or enlarged AP – Recessive
FSH, 8ACTH
PIT1 (POU1F1) GH, PRL, TSH Normal or hypoplastic AP – Recessive,
dominant
GHRH receptor IGHD Hypoplastic AP Small head size in one population Recessive
GH1 IGHD; some muta- Hypoplastic or normal AP Most IGHD-IA develop antibodies Recessive,
tions with MPHD with GH treatment; agammaglobulin- dominant,
emia in some IGHD III X-linked

AP = Anterior pituitary; PP = posterior pituitary.

X-linked hypopituitarism results from duplications of
Xq26–27, a region that includes the SOX3 gene, for which
a polyalanine expansion has been described in a pedigree
with X-linked mental retardation and GHD [21–23]. Mu-
tations that result in either overdosage or underdosage of
SOX3 are associated with infundibular hypoplasia and
variable hypopituitarism [24].
PROP1 (PROphet of Pit1) represses HESX1 expression
and is required for initial determination of pituitary cell
lineages, including gonadotropes and those of Pit1. At
least 10 recessive mutations have been described in PROP1
that result in GH, prolactin (PRL), thyroid-stimulating
hormone (TSH), gonadotropin and, in some families or
as the patients age, adrenocorticotropic hormone (ACTH)
deficiency [25, 26]. Patients with PROP1 gene mutations
may have pituitary gland enlargement originating from
the intermediate lobe [27, 28]. Eleven recessive and four
dominant mutations have been reported affecting the
Pit1 gene (currently referred to as POU1F1), with resul-
tant GH, PRL, and TSH deficiency [13, 25]. POU1F1 gene
defects are associated with variable pituitary hypoplasia
[29].
Somatotroph development is also dependent on hypo-
thalamic GH-releasing hormone (GHRH). A mutation in
the gene encoding the GHRH receptor results in severe
GHD [30–32].
Functional Anatomy of the Anterior Pituitary Gland
(Adenohypophysis)
The adenohypophysis receives hormonal modulating
signals from the hypothalamus, transmitted from ven-
tromedial and infundibular nuclei axons which termi-
nate in the hypophyseal portal system. These signals re-
sult in production of corticotropin (ACTH) by 8 weeks
gestation, thyrotropin (TSH) by 15 weeks gestation, so-
matotropin (GH) by 10–11 weeks gestation, PRL by 12
weeks, and the gonadotropes luteinizing hormone (LH)
and follicle-stimulating hormone (FSH) by 11 weeks.
There are at least three distinct hormone-producing cell
populations classified by staining characteristics [12].
Fifty percent of the cells are chromophobes, 40% are
characterized as acidophils, and the remainder as baso-
phils. Acidophils secrete GH or PRL. Basophils secrete
TSH, LH, FSH, or ACTH. Some basophils have a positive

Physiology of Growth Ann Nestlé [Engl] 2007;65:97–108 101

periodic acid-Schiff (PAS) base reaction: these are the
cells which secrete the glycoproteins LH, FSH, or TSH.
While chromophobe cells are known to produce ACTH
in the rat pituitary, the role of these cells in the human
pituitary remains unclear.
Anterior pituitary hormones enter the portal venous
system to drain into the cavernous sinus, enter the gen-
eral circulation, and ultimately exert long-distance influ-
ence over their respective target organs. TSH promotes
growth of the thyroid and production of thyroxine. LH
and FSH stimulate gonadal maturation and hormonal cy-
cling. GH exerts indirect growth effects through the elab-
oration of IGF-I in the liver and epiphyses, direct growth
effects on chondrocyte proliferation, and direct metabol-
ic effects primarily in adipose tissue.
The rich blood supply of the pituitary gland is subject
to interruption during periods of severe hypotensive
stress and hypoxia, resulting in the Sheehan syndrome of
hypopituitarism, classically described after intrapartum
hypotension, but possible in any hypovolemic crisis or
increased intracranial pressure episode, as in hypopitu-
itarism following recovery from cerebral edema compli-
cating diabetic ketoacidosis [33]. The internal carotid ar-
teries supply the vascular branches which bathe the pitu-
itary. The hypophyseal portal vessels, which originate
from capillary beds in the median eminence and infun-
dibular stem, supply the adenohypophysis [34].
Biochemistry and Physiology of the GH/IGF-I/IGF
Binding Protein Axis
Growth Hormone
Human GH is a single-chain, 191-amino acid, 22-kDa
protein, containing two intramolecular disulfide bonds
[35]. Release of GH from the anterior pituitary somato-
trophs is controlled by the balance between stimulatory
GH-releasing hormone (GHRH) and inhibitory soma-
tostatin from the hypothalamus. This balance is regu-
lated by neurologic, metabolic, and hormonal influences;
numerous neurotransmitters and neuropeptides are in-
volved. These include vasopressin, corticotropin-releas-
ing hormone, thyrotropin-releasing hormone, neuropep-
tide Y, dopamine, serotonin, histamine, norepinephrine,
and acetylcholine, which respond to various circum-
stances that affect GH secretion such as sleep, nutritional
state, stress, and exercise. Other hormones including glu-
cocorticoids, sex steroids, and thyroxin also influence se-
cretion of GH. These various influences are important in
the evaluation of GH secretion, which may be abnormal
despite normal somatotroph function. Stimulation of GH
release by GHRH is via specific GHRH receptors. In ad-
102 Ann Nestlé [Engl] 2007;65:97–108
dition to the GHRH receptor defects noted earlier, four
autosomal recessive disorders, an autosomal dominant
mutation, and an X-linked form of isolated GHD have
been described. Most children with a mutation of the
GH1 gene, resulting in the total absence of GH, treat in-
jected recombinant human GH as a foreign protein and
develop resistance after a few months of treatment due to
the inactivating antibodies they develop.
A number of synthetic hexapeptides, referred to as
GH-releasing peptides (GHRPs), have been developed
that act on other receptors to stimulate GH release [36,
37]. The naturally occurring ligand for the GHRP recep-
tor, ghrelin, has been isolated and cloned [38]. Ghrelin is
unique among mammalian peptides in its requirement of
a posttranslational modification for activation. This in-
volves addition of a straight chain octanyl group confer-
ring a hydrophobic property to the N terminus which
may permit entry of the molecule into the brain. Similar
to synthetic GHRPs, ghrelin binds with high affinity and
specificity to a distinct G protein-coupled receptor [39].
Unlike GHRH, ghrelin is synthesized primarily in the
fundus of the stomach [38], as well as in the hypothala-
mus, heart, lung and adipose tissue, and its receptor is
more widely distributed than that of GHRH [40]. Ghrelin
has widespread metabolic effects in addition to inducing
GHRH release and being synergistic with GHRH in the
stimulation of GH release through the serine 3 residue of
ghrelin. Ghrelin increases prolactin, ACTH, cortisol and
aldosterone release, and increases food intake and weight
gain [41].
Some 75% of the circulating GH is in the 22-kDa form.
Alternative splicing of codon 2 results in a deletion of 11
amino acids and formation of a 20-kDa fragment ac-
counting for 5–10% of secreted GH. Other circulating
forms include deaminated, N-acetylated, and oligomeric
GH. About 50% of GH circulates in the free state, the rest
bound principally to GH-binding protein (GHBP). Be-
cause the binding sites for the radioimmunoassay of GH
are not affected by the GHBP, both bound and unbound
GH are measured [42].
GHBP and the GH Receptor
A high-affinity GHBP was identified in rabbit and hu-
man serum in the mid-1980s [43], and separate reports in
1987 found this binding protein to be absent in the sera
of patients with GH resistance [44, 45], who were identi-
fied by a high circulating GH concentration with a phe-
notype of severe GHD. The recognition that circulating
GHBP in rabbit serum corresponded to liver cytosolic
GHBP was followed by the purification, cloning, and se-
Rosenbloom
quencing of human GHBP [46]. The human GHBP was
found to be structurally identical to the extracellular hor-
mone-binding domain of the membrane-bound GH re-
ceptor (GHR). The entire human GHR gene on chromo-
some 5 was subsequently characterized [47]. The GHR
was the first to be cloned of a family of receptors that in-
cludes the receptor for PRL and numerous cytokine re-
ceptors. Members of this family share ligand and receptor
structure similarities, in particular the requirement that
the ligand bind to two or more receptors or receptor sub-
units and interact with signal transducer proteins to ac-
tivate tyrosine kinases [48].
In humans, GHBP is the proteolytic product of the ex-
tracellular domain of the GHR. This characteristic per-
mits assaying circulating GHBP as a measure of cellular
bound GHR, which usually correlates with GHR func-
tion. The GH molecule binds to cell surface GHR, which
dimerizes with another GHR so that a single GH mole-
cule is enveloped by two GHR molecules [49]. The intact
receptor lacks tyrosine kinase activity, but is closely as-
sociated with JAK2, a member of the Janus kinase family.
JAK2 is activated by binding of GH with the GHR dimer,
which results in self-phosphorylation of the JAK2 and a
cascade of phosphorylation of cellular proteins. Included
in this cascade are signal transducers and activators of
transcription (STATs), which couple ligand binding to
the activation of gene expression, and mitogen-activated
protein kinases. Other effector proteins have also been
examined in various systems. This is a mechanism typi-
cal of the GH/PRL/cytokine receptor family [48, 50]. In
human GH-GHR transduction, STAT5b appears to be
the most important cellular protein activated. Five dis-
tinct homozygous mutations have been described in six
patients from five families, resulting in severe growth
failure and variable immune incompetence, indicating
the importance of STAT5b in cytokine function, as well
as its primary role in GH-GHR transduction [51].
The GHR in humans is also synthesized in a truncated
form (GHRtr) lacking most of the intracellular domain.
Although the quantity of this GHRtr is small relative to
the full-length GHR, release of GHBP from this isoform
is increased [52]. Some of the changes in body composi-
tion that occur with GH treatment in GHD may be re-
lated to changes in the relative expression of GHR and
GHRtr [53].
Over 50 mutations in the GHR have been described in
the approximately 250 known patients with GH insensi-
tivity, which result in a clinical picture identical to that of
severe GHD but with elevated serum GH concentrations
[2, 51]. The report of the characterization of the GHR
Physiology of Growth
gene included the first description of a genetic defect of
the GHR, a deletion of exons 3, 5, and 6 [47]; recognition
that the exon-3 deletion represented an alternatively
spliced variant without functional significance resolved
the dilemma of explaining the deletion of nonconsecu-
tive exons. In contrast to the alternatively spliced variant
lacking exon 3, the first mutation of this exon has been
described in a typical GHR-deficient patient with hetero-
zygosity for a nonsense mutation in exon 4, and family
studies indicate that heterozygosity for the exon 3 mutant
has no effect. This study also raises questions regarding
the origin and function of the exon 3 deleted variant.
More recently this isoform, present in either the homozy-
gous or heterozygous state, was found to be associated
with 1.7–2 times more growth acceleration from GH ad-
ministration during 2 years of treatment of children with
short stature who had been small for gestational age or
had idiopathic short stature. In addition to the original
exon 5, 6 deletion, another deletion of exon 5 has been
described, along with numerous nonsense mutations,
missense mutations, frame shift mutations, splice muta-
tions, and a unique intronic mutation resulting in inser-
tion of a pseudo-exon. A number of other mutations have
been described which are either polymorphisms or have
not occurred in the homozygous or compound heterozy-
gous state [54].
The point mutations, which result in severe GH insen-
sitivity when present in the homozygous state or as a
compound heterozygote, are all associated with the typi-
cal phenotype of severe GHD. All but a few of the defects
result in absent or extremely low levels of GHBP. Note-
worthy is the D152H missense mutation which affects the
dimerization site, thus permitting the production of the
extracellular domain in normal quantities but failure of
dimerization at the cell surface, which is necessary for
signal transduction and IGF-I production. Two defects
that are close to [G223G] or within [R274T], the trans-
membrane domain, result in extremely high levels of
GHBP. These defects interfere with the normal splicing
of exon 8 which encodes the transmembrane domain,
with the mature GHR transcript being translated into a
truncated protein that retains GH-binding activity but
cannot be anchored to the cell surface.
As noted, all these homozygous defects and the com-
pound heterozygotes, whether involving the extracellu-
lar domain or the transmembrane domain and whether
associated with very low or unmeasurable GHBP, result
in a typical phenotype of severe GHD. In contrast, the
intronic mutation present in the heterozygous state in a
mother and daughter with relatively mild growth failure
Ann Nestlé [Engl] 2007;65:97–108 103
(both standard deviation score, SDS, for height –3.6), and
resulting in a dominant negative effect on GHR forma-
tion, is not associated with other phenotypic features of
GHD. This splice mutation preceding exon 9 results in an
extensively attenuated, virtually absent intracellular do-
main. Japanese siblings and their mother have a similar
heterozygous point mutation of the donor splice site in
intron 9, also resulting in mild growth failure compared
to GH receptor deficiency (GHRD), but with definite, al-
though mild, phenotypic features of GHD. GHBP levels
in the Caucasian patients were at the upper limit of nor-
mal with a radiolabeled GH-binding assay, and in the
Japanese patients twice the upper limit of normal, using
a ligand immunofunction assay. These heterozygous
GHR mutants transfected into permanent cell lines have
demonstrated increased affinity for GH compared to the
wild-type full-length GHR, with markedly increased
production of GHBP. When co-transfected with full-
length GHR a dominant negative effect results from over-
expression of the mutant GHR and inhibition of GH-in-
duced tyrosine phosphorylation and transcription acti-
vation. Naturally occurring truncated isoforms have also
shown this dominant negative effect in vitro [54].
A novel intronic point mutation was discovered in a
highly consanguineous family with two pairs of affected
cousins with GHBP-positive GH insensitivity, severe
short stature, but without the facial features of severe
GHD or GH insensitivity. This mutation resulted in a
108-bp insertion of a pseudo-exon between exons 6 and
7, predicting an in-frame, 36-residue amino acid se-
quence. This is a region critically involved in receptor
dimerization.
Of approximately 250 reported cases of typical GHR
deficiency, ethnic origin is predominantly Middle East-
ern, Mediterranean, and South Asian. Nearly 50% are
Oriental Jews as described in the original report, or
known descendants of Iberian Jews who converted to Ca-
tholicism during the Spanish Inquisition. The latter com-
prise the largest cohort (n 170) and the only genetically
homogenous group, all but one subject having the E180
splice site mutation which was also found in one Israeli
patient of Moroccan heritage, and recently in several af-
fected children from four families not previously known
to be related from northeast Brazil [55]. Most of the other
defects appear to be highly family specific, with the R43X
mutation that is seen in a single Ecuadorian patient, two
other nonsense mutations (C38X, R217X), and the intron
4 splice mutation being the only ones thus far described
which appear in disparate populations, on different ge-
netic backgrounds, indicating mutational hotspots [54].
104 Ann Nestlé [Engl] 2007;65:97–108
Insulin-Like Growth Factor-I
Most of the growth effect that gives GH its name is
actually an effect of IGF-I production [56, 57]. IGF-I is a
70-residue single-chain basic peptide, and IGF-II a slight-
ly acidic 67-residue peptide. Their structure is similar to
proinsulin, A and B chains connected by disulfide bonds
and a connecting C-peptide, but unlike the posttransla-
tional processing of insulin, there is no cleavage of C-pep-
tide. The two IGFs share approximately two thirds of
their possible amino acid positions and are 50% homolo-
gous to insulin [58, 59]. The connecting C-peptide is 12
amino acids long in the IGF-I molecule and 8 amino ac-
ids long in IGF-II, and has no homology with the compa-
rable region in the proinsulin molecule. The IGFs also
differ from proinsulin in having carboxy terminal exten-
sions. These similarities and differences from insulin ex-
plain the ability of IGFs to bind to the insulin receptor
and insulin’s ability to bind to the type-1 IGF receptor,
as well as the specificity of IGF binding to the IGF-bind-
ing proteins (IGFBPs).
IGF-Binding Proteins
Hepatic IGF-I circulates almost entirely bound to
IGFBPs, with !1% being free. The IGFBPs are a family of
6 structurally related proteins with a high affinity for
binding IGF. At least 4 other related proteins with lower
affinity for IGF peptides have been identified and are re-
ferred to as IGFBP-related proteins [60]. The principal
binding protein, IGFBP-3, binds about 90% of circulating
IGF-I in a large (150–200 kDa) ternary complex consist-
ing of IGFBP-3, an acid labile subunit (ALS), and the IGF
molecule. ALS and IGFBP-3 are produced in the liver as
a direct effect of GH. The ALS stabilizes the IGF–IGFBP3
complex, reduces the passage of IGF-I to the extravascu-
lar compartment, and extends its half-life [61]. The re-
mainder of bound IGF is in a 50-kDa complex with most-
ly IGFBP-1 and IGFBP-2. IGFBP-1 concentrations are
controlled by nutritional status as reflected in insulin lev-
els, with the highest IGFBP-1 concentrations found in the
fasting, hypoinsulinemic state. The circulating concen-
tration of IGFBP-2 is less fluctuant and is partly under the
control of IGF-I; levels are increased in IGF-I deficiency
due to GH insensitivity, but increase further with IGF-I
therapy of such patients [62].
The IGFBPs modulate IGF action by controlling stor-
age and release of IGF-I in the circulation and influencing
its binding to its receptor, facilitate storage of IGFs in
extracellular matrices, and exert independent actions.
IGFBPs 1, 2, 4, and 6 inhibit IGF action by preventing
binding of IGF-I with its specific receptor. The binding of
Rosenbloom
IGFBP-3 to cell surfaces is thought to decrease its affinity,
effectively delivering the IGF-I to the type-1 IGF receptor.
IGFBP-5 potentiates the effects of IGF-I in a variety of
cells. Its binding to extracellular matrix proteins allows
fixation of IGFs and enhances binding to hydroxyapatite.
IGFs stored in such a manner in soft tissue may enhance
wound healing. IGF independent mechanisms for IGFBP-
1 and IGFBP-3 proliferative effects have been demonstrat-
ed in vitro and nuclear localization of IGFBP-3 has been
reported. In addition to IGFBP phosphorylation and cell
surface association determining the influence of IGFBPs,
specific protease activity, particularly affecting IGFBP-3,
is also important in the modulation of IGF action in target
tissues. The proteolytic activity may alter the affinity of
the binding protein for IGF-I, resulting in the release of
free IGF-I for binding to the IGF-I receptor [63].
IGF Receptors
IGF binding involves 3 types of receptors, the struc-
turally homologous insulin receptor, the type-1 IGF re-
ceptor, and the distinctive type-2 IGF-II/mannose-6-
phosphate receptor. Splice variants and atypical forms
occur but have not been found to have physiologic sig-
nificance, insulin/IGF-I hybrid receptors, however, are
ubiquitous and may be the most important receptors for
IGF-I in some tissues [63].
The type-1 IGF-I receptor and insulin receptor are het-
erotetramers consisting of two ␣ subunits which contain
the binding sites and two ␤ subunits containing a trans-
membrane domain, an adenosine triphosphate-binding
site, and a tyrosine kinase domain comprising the signal
transduction system [63]. The IGF-I receptor is able to
bind IGF-I and IGF-II with high affinity but the affinity
for insulin is approximately 100-fold less. Although the
insulin receptor has a low affinity for IGF-I, IGF-I is pres-
ent in the circulation at molar concentrations that are
1,000 times those of insulin. Thus, even a small insulin-
like effect of IGF-I could be more important than that of
insulin itself, were it not for the IGFBPs that control the
availability and activity of IGF-I. In fact, intravenous in-
fusion of recombinant human IGF-I can induce hypogly-
cemia, especially in the IGFBP-3-deficient state [62]. It is
not known why IGF-II and mannose-6-phosphate share a
receptor. This receptor differs from the type-1 receptor in
binding only IGF-II with high affinity, IGF-I with low af-
finity, and insulin not at all [63].
Role of the GH/IGF-I Axis in Growth
The growth effect of GH has at least three compo-
nents, their relative contributions being a subject of con-
Physiology of Growth
tinuing investigation. The most familiar of these compo-
nents are IGF-I, IGFBP-3, and ALS, because they are syn-
thesized by the liver and secreted into the circulation,
allowing them to be measured as circulating concentra-
tions. The other GH effects are not directly measurable
but inferred from much animal and some human data;
they are epiphyseal prechondrocyte differentiation and
enhancement of local (autocrine/paracrine) production
of IGF-I, thereby stimulating clonal expansion of the dif-
ferentiating chondrocytes [2, 56, 57].
The importance of IGF-I in normal intrauterine
growth in humans has been demonstrated in a single pa-
tient with a homozygous partial deletion of the IGF-I
gene, a patient with mutation of the IGF-I gene resulting
in high circulating levels of an ineffective IGF-I, and in
two patients with mutations of the IGF-I receptor, all hav-
ing severe intrauterine growth retardation [2]. Cord se-
rum IGF-I and IGF-II concentrations correlate with birth
weight and are significantly increased in large for gesta-
tional age infants compared with appropriate for gesta-
tional age newborns [64]. Intrauterine IGF-I synthesis,
however, does not appear to be GH-dependent, because
most patients with genetically determined severe IGF-I
deficiency, due to GHRH defects, GHRD, or GH gene
mutations, have normal or only minimally reduced intra-
uterine growth. SDS for length declines rapidly after
birth, however, in these conditions, demonstrating the
immediate need for GH-stimulated IGF-I synthesis for
postnatal growth [2]. Growth velocity in the absence of
GH is approximately half normal, but has sometimes
been reported to be normal or supranormal [65]. This ap-
parent growth without GH has been described in patients
after craniopharyngioma resection, in septo-optic dys-
plasia, in obese children with GHD, in GH-deficient in-
fants, and in patients who had undergone resection of a
variety of central nervous system tumors [66]. Normal or
supranormal growth velocity has been attributed to hy-
perinsulinemia, increased leptin levels, or hyperprolac-
tinemia. PRL levels are not consistently increased, how-
ever. Obesity or rapid weight gain is a frequent common
denominator among these patients who demonstrate low
GH levels to provocative stimuli, low IGF-I and IGFBP-1,
and low IGFBP-3 levels.
The metabolic and growth effects of GH and IGF-I are
compared in table 2. In addition to direct protein-sparing
effects and synthesis and release of IGF-I from the liver,
GH stimulates autocrine and paracrine production of
IGF-I in other tissues, primarily bone and muscle. GH
has a direct effect on differentiation of prechondrocytes
into early chondrocytes, which in turn secrete IGF-I. This
Ann Nestlé [Engl] 2007;65:97–108 105
Table 2. Metabolic effects of GH and IGF-I and the stimulation of local production of IGF-I led to
the hypothesis that autocrine/paracrine IGF-I was the
GH IGF-I main determinant of GH-dependent postnatal body
GH secretion – Decreased growth, and that hepatic or endocrine IGF-I served pre-
IGF-I production Increases – dominantly as a negative feedback regulator of GH secre-
IGFBP-1 Decreases Decreases tion [57]. Subsequent studies of mice with selective dele-
IGFBP-2 Decreases Increases tion of the hepatic IGF-I gene described unaffected
IGFBP-3 Increases No effect growth [2]. Deletion of the ALS gene in mice and its mu-
Insulin
Secretion Increases Decreases tation in man results in very low circulating IGF-I and
Sensitivity Decreases Increases IGFBP-3 concentrations, but only a 15% reduction in
Hepatic glucose output Increases Decreases postnatal growth in the mice [61]. It is uncertain if there
Muscle glucose uptake Decreases Increases was any growth effect in the two patients with ALS mu-
Lipolysis Increases No effect1 tations, one of whom reached a stature of –0.9 SDS and
Nitrogen balance Increases Increases
Protein synthesis Increases Increases the other a height that was 0.4 SDS greater than mean
parental height [2].
1 Decreases with high doses.

Conclusion

local IGF-I stimulates clonal expansion and maturation
of the chondrocytes, resulting in growth [57]. It is esti-
mated that 20% of normal growth (i.e. 40% of GH-stimu-
lated growth) is the result of the direct effect of GH
on maturing bone and the autocrine/paracrine produc-
tion of IGF-I in this tissue. Treatment studies of children
with GHRD compared to GHD patients support this hy-
pothesis [2]. IGF-II is considered an important growth
factor in utero, but its role in extrauterine life is unclear;
concentrations of IGF-II in serum parallel those of
IGF-I.
The direct stimulation by GH of mitosis in cartilage
precursor cells of the growth plate, which have GHRs,
The study of the physiology of growth has gone from
auxological observations, description of dysmorphic syn-
dromes and inferred hormonal dysfunction with growth
failure or, far less commonly, excessive growth, to reason-
ably accurate measurement of hormones influencing
growth, identification of many more growth factors, un-
derstanding of the control of bone growth, and definition
of the molecular basis for normal and abnormal growth
states. These developments span only a half century. With
the rapidly accelerating capabilities for hormonal and
molecular study, the complexity of the genetic, hormon-
al, and environmental factors and their interaction in the
growth process will continue to be unraveled.

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