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Growth Hormone & IGF Research xxx (2016) xxx–xxx

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Growth Hormone & IGF Research

journal homepage: www.elsevier.com/locate/ghir

Growth and growth hormone: An overview

Enrique Teran a, Jaclyn Chesner b, Robert Rapaport b,⁎
a
Colegio de Ciencias de la Salud, Universidad San Francisco de Quito, Quito, Ecuador
b
Division of Pediatric Endocrinology and Diabetes, Icahn School of Medicine at Mount Sina, 1 Gustave L. Levy Place, NY, USA

a r t i c l e i n f o a b s t r a c t

Article history: Growth is a good indicator of a child's health. Growth disturbances, including short stature or growth failure,
Received 22 January 2016 could be indications of illnesses such as chronic disease, nutritional deficits, celiac disease or hormonal abnormal-
Received in revised form 11 February 2016 ities. Therefore, a careful assessment of the various requirements for normal growth needs to be done by history,
Accepted 21 February 2016
physical examination, and screening laboratory tests. More details will be reviewed about the GH-IGF axis, its ab-
Available online xxxx
normalities with special emphasis on GH deficiency, its diagnosis and treatment. GH treatment indications in the
Keywords:
US will be reviewed and a few only will be highlighted. They will include GH deficiency, as well as the treatment
Growth hormone of children born SGA, including the results of a US study using FDA approved dose of 0.48 mg/kg/week. GH defi-
Short stature ciency in adults will also be briefly reviewed. Treatment of patients with SHOX deficiency will also be discussed.
Growth failure Possible side effects of GH treatment and the importance of monitoring safety will be highlighted.
Chronic disease © 2016 Elsevier Ltd. All rights reserved.
Nutritional deficits
Celiac disease

There is a vast range of normal and abnormal growth patterns. So,
evaluation of a child's growth is one of the most important aspects of
the general pediatric visit [1]. There are many approaches to classifying
the numerous causes of short stature. Often, short stature is first desig-
nated as either proportionate, or disproportionate, meaning that either
the limbs or the spine are more affected. Short stature may indicate
skeletal dysplasia, bone and cartilage abnormalities, or rickets, softening
or weakening of bones. Focusing on proportionate short stature, the two
main subtypes defined are those identified prenatally and those identi-
fied postnatally. As endocrinologists, we focus on both categories, pay-
ing particular attention to the GH/IGF axis.
When testing for growth disturbances it is vital to complete a full pa-
tient history and physical examination. Abnormalities of growth are
sensitive indicators of physical well-being during childhood and are
also often harbingers of later adult disease [2]. The patient history
should include the maternal/fetal and perinatal history, birth-weight,
length and head circumference, relation of the segments (ROS), and
family history of stature and puberty. The physical examination mea-
surements should include weight, length/height, head circumference,
body mass index (BMI), upper to lower segment ratio (U/L), and arm
span to test for dysmorphic features, and the thyroid and pubertal status
of the patient.
In 1969, Usher and McLean published fetal growth curves, which are
used to quantitate fetal growth and to provide standards for assessment
of fetal growth retardation and excessive fetal growth [3]. These stan-
dards were obtained from measurements of seven dimensions—crown-
⁎ Corresponding author.
heel length; head, chest, abdominal, and thigh circumferences; foot
length; and double skin thickness—and by birth weight of 300 live-
born Caucasian neonates born between 25 and 44 weeks of gestation
at sea level. Normal smooth curves were drawn of the mean ± 2 SD,
and gestational age was calculated to the nearest week for the last nor-
mal menstrual period.
GH and IGF-1 in growth disorders play a role in the diagnosis and
treatment of growth disturbances in children. The genes involved in an-
terior pituitary development in which mutations have been reported
are PITX1, HESX1, LHX3/LH4, PROP1, and POU1F1 [4]. In particular, de-
fects in the PROP1 gene cause defects in pituitary development, and GH
synthesis and secretion. A primary site of endogenous GH action is the
liver. Hepatocytes express GH receptors. Upon arrival at the liver or
other target tissues, GH dissociates from the GH binding protein
(GHBP) and binds to a pair of GH receptors, referred to as a dimer,
resulting in a change in conformation and activation of the hormone/
receptor complex. This is followed by successive phosphorylation of in-
tracellular proteins, the net result of which is intracellular signal trans-
duction [5].
Based on the hypothesis that GH receptors on circulating B lympho-
cytes contribute to GH-binding proteins, it has been suggested that the
evaluation of GH receptors (GHR) on circulating B lymphocytes is a use-
ful way to evaluate GH-GHR interactions for indications of growth ab-
normalities [6].
Valerio et al. uses the cytofluorimetric method to analyze the expres-
sion of GHR on peripheral blood lymphocytes from normal controls and
short children, and concluded that GH receptor expression on immune
cells appears to be inversely related to the linear growth expression
and BMI of the subjects, contrary to findings with hepatic derived

http://dx.doi.org/10.1016/j.ghir.2016.02.004
1096-6374/© 2016 Elsevier Ltd. All rights reserved.

Please cite this article as: E. Teran, et al., Growth and growth hormone: An overview, Growth Horm. IGF Res. (2016), http://dx.doi.org/10.1016/
j.ghir.2016.02.004
2 E. Teran et al. / Growth Hormone & IGF Research xxx (2016) xxx–xxx
serum GHBP. This finding may reflect alternate exon usage in lymphoid
cells, and indicates that GH has a distinctive role in the immune system
[7].
The diagnosis of GH deficiency can include low growth rate, low IGF-
1 and IGFBP-3, and low GH secretion, characterized by spontaneous
(12/24) or stimulated. GH stimulation tests have been with us for de-
cades, but as time has gone by, we have had more and more questions
about their validity in management of pediatric growth disorders. The
threshold for diagnosis of GH deficiency has moved with time, from 5
to 7 to 10 ng/mL and while the extremes are obvious—the patient
who does not respond at all to stimulation, or the patient who produces
a peak of 50 or 100 ng/mL—the threshold that defines “true” GH defi-
ciency in childhood is unclear. Additional investigations, such as an
MRI scan, may be ordered to assist in the diagnostic process [8].
In Turner syndrome, a condition in which a female is partly or
completely missing an X chromosome causes major growth defects,
one of the symptoms, a web neck, is formed by redundant skin that ini-
tially stretched over the cystic hygroma [9]. During late gestation, when
the truncal lymphatics finally communicate with the venous system,
the lymph collection comprising the nuchal hygroma resolves, leaving
loose, redundant skin. Peripheral lymphedema, present dorsally on
the hands and feet, may be the initial presenting sign in Turner syn-
drome and is found in approximately one third of affected infants.
Lymphedema tends to improve with age. In contrast to the distribution
of edema in congestive heart failure or in venous insufficiency, there is
usually a crease across the ankle joint and less edema distal to the
metatarsophalangeal joint line.
Human GH treatment started in 1921 when Evans and Long admin-
istered beef pituitary extracted to rats, producing gigantism [10]. GH
first was isolated from the human pituitary gland in 1956, by both Li
and Papkoff, in California, and Raben, in Massachusetts, but its biochem-
ical structure was not elucidated until 1972. In 1958, Raben reported the
results of the first trial to show the effects of human GH on growth. By
1960 it was clear that GH deficient children would benefit from pitui-
tary GH [11].
The first recombinant human GH (rhGH) was developed in 1981 by
a biosynthetic process (Genentech, South San Francisco, CA). Later, an
improved process to develop rhGH was developed called protein secre-
tion technology [11]. Then and in a few years, Eli Lilly launched a com-
peting natural sequence GH. Many companies, including Pfizer, Novo
Nordisk, Merck Serono, Ferring Pharmaceuticals, Sandoz, and Teva
supply.
In more than 12,000 children in the United Sates, who received re-
combinant GH daily for up to 7 years, as part of the National Cooperative
Growth Study [12], the average age at which GH therapy was initiated
was 9.2 ± 4.1 years, and it was found that the growth velocity increased
from 4.4 ± 2.8 cm per year to 10.0 ± 3.1 cm per year after 1 year of
treatment. The standard deviation (SD) score for height changed from
−2.6 ± 1.1 to −0.5 ± 1.1 after 7 years of therapy.
Rapaport et.al [13] researched the predictors of first-year growth re-
sponse to GH treatment in children born small for gestational age. With-
in the scope of the US SGA study to assess pretreatment predictors of the
response to GH in the SGA child, their aim was to evaluate the effects of
GH (Genotropin) therapy at a dose of 0.48 mg/kg/week on carbohydrate
metabolism and, specifically, to investigate whether GH might influence
glucose tolerance in short children born SGA. They enrolled 139 patients
meeting the inclusion criteria. An assessment of fasting oral glucose tol-
erance, using an OGTT, and HbA1c was made for each patient at baseline
and at the end of the 12-month study. Insulin resistance was deter-
mined using HOMA and QUICKI calculations and the American Diabetes
Association criteria were used to estimate glucose tolerance. Results
showed that GH at 0.48 mg/kg/wk. was well tolerated and improved
growth in children born SGA. The Δ IGF-I was not predictive of the
12 month height SDS gain, while the Δ height SDS at 3 and 6 months
were predictive. Finally, underweight children grew as well as normal
weight children, and both groups showed improved body composition
Please cite this article as: E. Teran, et al., Growth and growth hormone: An overview, Growth Horm. IGF Res. (2016), http://dx.doi.org/10.1016/
j.ghir.2016.02.004
following GH treatment. HOMA and HgbA1c increased at 1 year, but
not in a clinically concerning manner.
One transcription factor known to be involved in cellular events
within the growth plate is the Short Stature Homeobox (SHOX) contain-
ing gene. The SHOX gene is located at the distal tip of the X and Y chro-
mosomes. It is not a classical X-linked gene since, being located in the
pseudoautosomal region, it does not undergo X-inactivation; 2 active
copies of the gene are required for normal linear growth [14]. Treatment
of patients with SHOX deficiency was reviewed recently [15] and it was
found that GH and IGF-1 characteristics of children with short stature
were not different between children with SHOX+ variants and children
with no variants.
Some GH therapy uses that are not FDA approved include syn-
dromes: Down, neurofibromatosis [16], and 18q deletion [17]; gastroin-
testinal problems: adult Crohn disease [18] and liver transplantation
[19]; and bone dysplasias: hypochondroplasia, anchondroplasia,
hypophosphatemia, and rickets [20,21]. However, more research must
be conducted in order to create a definitive treatment protocol for chil-
dren with HCH. Subtle skeletal dysplasias, such as HCH, may be difficult
to identify and it is therefore “important to establish treatment regi-
mens as well as manage expectations for short-term growth and adult
height” for affected children [22].
Additionally, GH therapy has not been FDA approved for pulmonary
problems such as cystic fibrosis [23], hematologic problems such as
thalassemia major [24] and hemato-immune reconstitution [25], endo-
crine problems such as precocious puberty [26] and congenital adrenal
hyperplasia [27], and healing wounds and burns [28].
In conclusion, GH therapy is beneficial in children primarily as re-
placement therapy. Other uses of growth hormone are under investiga-
tion, and the results of these studies will probably show additional
benefits.
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