To contribute to the debate about whether growth hormone (GH) and insulin-like growth factor 1 (IGF-1) act independently on the growth process. To describe growth in human and animal models of isolated IGF-1 deficiency (IGHD), such as in Laron syndrome (LS; primary IGF-1 deficiency and GH resistance) and IGF-1 gene or GH receptor gene knockout (KO) mice. Since the description of LS in 1966, 51 patients were followed, many since infancy. Newborns with LS are shorter (42-47 cm) than healthy babies (49-52 cm), suggesting that IGF-1 has some influence on intrauterine growth. Newborn mice with IGF-1 gene KO are 30% smaller. The postnatal growth rate of patients with LS is very slow, the distance from the lowest normal centile increasing progressively. If untreated, the final height is 100-136 cm for female and 109-138 cm for male patients. They have acromicia, organomicria including the brain, heart, gonads, genitalia, and retardation of skeletal maturation. The availability of biosynthetic IGF-1 since 1988 has enabled it to be administered to children with LS. It accelerated linear growth rates to 8-9 cm in the first year of treatment, compared with 10-12 cm/year during GH treatment of IGHD. The growth rate in following years was 5-6.5 cm/year. IGF-1 is an important growth hormone, mediating the protein anabolic and linear growth promoting effect of pituitary GH. It has a GH independent growth stimulating effect, which with respect to cartilage cells is possibly optimised by the synergistic action with GH.
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Insulin-like growth factor 1 (IGF-1): a growth
hormone
Z Laron
Abstract
Aim—To contribute to the debate about
whether growth hormone (GH) and
insulin-like growth factor 1 (IGF-1) act
independently on the growth process.
Methods—To describe growth in human
and animal models of isolated IGF-1 defi-
ciency (IGHD), such as in Laron syn-
drome (LS; primary IGF-1 deficiency and
GH resistance) and IGF-1 gene or GH
receptor gene knockout (KO) mice.
Results—Since the description of LS in
1966, 51 patients were followed, many
since infancy. Newborns with LS are
shorter (42–47 cm) than healthy babies
(49–52 cm), suggesting that IGF-1 has
some influence on intrauterine growth.
Newborn mice with IGF-1 gene KO are
30% smaller. The postnatal growth rate of
patients with LS is very slow, the distance
from the lowest normal centile increasing
progressively. If untreated, the final height
is 100–136 cm for female and 109–138 cm
for male patients. They have acromicia,
organomicria including the brain, heart,
gonads, genitalia, and retardation of skel-
etal maturation. The availability of bio-
synthetic IGF-1 since 1988 has enabled it
to be administered to children with LS. It
accelerated linear growth rates to 8–9 cm
in the first year of treatment, compared
with 10–12 cm/year during GH treatment
of IGHD. The growth rate in following
years was 5–6.5 cm/year.
Conclusion—IGF-1 is an important
growth hormone, mediating the protein
anabolic and linear growth promoting
eVect of pituitary GH. It has a GH
independent growth stimulating eVect,
which with respect to cartilage cells is
possibly optimised by the synergistic ac-
tion with GH.
(J Clin Pathol: Mol Pathol 2001;54:311–316)
Keywords: insulin-like growth factor I; growth hor-
mones; Laron syndrome; growth
In recent years, new technologies have enabled
many advances in the so called growth
hormone (GH) axis (fig 1). Thus, it has been
found that GH secretion from the anterior
pituitary is regulated not only by GH releasing
hormone (GHRH) and somatostatin (GH
secretion inhibiting hormone),
1
but also by
other hypothalamic peptides called GH secre-
tagogues,
2
which seem to act in synergism with
GHRH
3
by inhibiting somatostatin.
4
One of
these has been cloned and named Ghrelin.
5
The interplay between GHRH and somatosta-
tin induces a pulsatile GH secretion,
6
which is
highest during puberty. GH induces the
generation of insulin-like growth factor 1
(IGF-1, also called somatomedin 1) in the liver
and regulates the paracrine production of
IGF-1 in many other tissues.
7
IGF-1
IGF-1 and IGF-2 were identified in 1957 by
Salmon and Daughaday
8
and designated “sul-
phation factor” by their ability to stimulate
35
-sulphate incorporation into rat cartilage.
Froesch et al described the non-suppressible
insulin-like activity (NSILA) of two soluble
serum components (NSILA I and II).
9
In
1972, the labels sulphation factor and NSILA
were replaced by the term “somatomedin”,
denoting a substance under control and medi-
ating the eVects of GH.
10
In 1976, Rinderk-
necht and Humbel
11
isolated two active sub-
stances from human serum, which owing to
their structural resemblance to proinsulin were
renamed “insulin-like growth factor 1 and 2”
(IGF-1 and 2). IGF-1 is the mediator of the
anabolic and mitogenic activity of GH.
12
CHEMICAL STRUCTURE
The IGFs are members of a family of insulin
related peptides that include relaxin and
several peptides isolated from lower inverte-
brates.
13
IGF-1 is a small peptide consisting of
70 amino acids with a molecular weight of
7649 Da.
14
Similar to insulin, IGF-1 has an A
and B chain connected by disulphide bonds.
The C peptide region has 12 amino acids. The
structural similarity to insulin explains the
ability of IGF-1 to bind (with low aYnity) to
the insulin receptor.
Figure 1 The cascade of the growth hormone axis. CNS, central nervous system; GH,
growth hormone; GHBP, GH binding protein; GH-S, GH secretagogues; IGF-1,
insulin-like growth factor 1; IGFBPs, IGF binding proteins; +, stimulation; –, inhibition.
GH-S
(pituitary)
(CNS)
Neurotransmitters
(hypothalamus)
GHRH Somatostatin
Sex
steroids
(pancreas)
Insulin
IGFBP-1IGFBP-2;IGFBP-3;
(liver)
GHBP
GH
Target tissues
IGF-1
+
–
–
–
–
–
–
–
–
+
+
+
+
+
+
+
+
–
–
+
J Clin Pathol: Mol Pathol 2001;54:311–316 311
Endocrinology and
Diabetes Research
Unit, WHO
Collaborating Center
for the Study of
Diabetes in Youth,
Schneider Children’s
Medical Center, Tel
Aviv University, 14
Kaplan Street, Petah
Tikva 49202, Tel Aviv,
Israel
Z Laron
Correspondence to:
Professor Laron
Accepted 24 April 2001
www.molpath.com
THE IGF-1 GENE
The IGF-1 gene is on the long arm of chromo-
some 12q23–23.
15 16
The human IGF-1 gene
consists of six exons, including two leader
exons, and has two promoters.
17
IGF binding proteins (IGFBPs)
In the plasma, 99% of IGFs are complexed to
a family of binding proteins, which modulate
the availability of free IGF-1 to the tissues.
There are six binding proteins.
18
In humans,
almost 80% of circulating IGF-1 is carried by
IGFBP-3, a ternary complex consisting of one
molecule of IGF-1, one molecule of IGFBP-3,
and one molecule of an 88 kDa protein named
acid labile subunit.
19
IGFBP-1 is regulated by
insulin and IGF-1
20
; IGFBP-3 is regulated
mainly by GH but also to some degree by
IGF-1.
21
The IGF-1 receptor
The human IGF-1 receptor (type 1 receptor) is
the product of a single copy gene spanning over
100 kb of genomic DNA at the end of the long
arm of chromosome 15q25–26.
22
The gene
contains 21 exons (fig 2) and its organisation
resembles that of the structurally related insu-
lin receptor (fig 3).
23
The type 1 IGF receptor
gene is expressed by almost all tissues and cell
types during embryogenesis.
24
In the liver, the
organ with the highest IGF-1 ligand expres-
sion, IGF-1 receptor mRNA is almost undetec-
table, possibly because of the “downregula-
tion” of the receptor by the local production of
IGF-1. The type 1 IGF receptor is a heterote-
tramer composed of two extracellular spanning
á subunits and transmembrane â subunits. The
á subunits have binding sites for IGF-1 and are
linked by disulphide bonds (fig 3). The â subu-
nit has a short extracellular domain, a trans-
membrane domain, and an intracellular do-
main. The intracellular part contains a tyrosine
kinase domain, which constitutes the signal
transduction mechanism. Similar to the insulin
receptor, the IGF-1 receptor undergoes ligand
induced autophosphorylation.
25
The activated
IGF-1 receptor is capable of phosphorylating
other tyrosine containing substrates, such as
insulin receptor substrate 1 (IRS-1), and
continues a cascade of enzyme activations via
phosphatidylinositol-3 kinase (PI3-kinase),
Grb2 (growth factor receptor bound protein
2), Syp (a phophotyrosine phosphatase), Nck
(an oncogenic protein), and Shc (src homology
domain protein), which associated to Grb2,
activates Raf, leading to a cascade of protein
kinases including Raf, mitogen activated pro-
tein (MAP) kinase, 5 G kinase, and others.
26
Physiology
IGF-1 is secreted by many tissues and the
secretory site seems to determine its actions.
Most IGF-1 is secreted by the liver and is
transported to other tissues, acting as an endo-
crine hormone.
27
IGF-1 is also secreted by
other tissues,
28
including cartilagenous cells,
and acts locally as a paracrine hormone (fig
4).
29
It is also assumed that IGF-1 can act in an
autocrine manner as an oncogene.
30
The role of
IGF-1 in the metabolism of many tissues
including growth has been reviewed re-
cently.
31 32
The following is an analysis of whether
IGF-1, the anabolic eVector hormone of pitui-
tary GH, is the “real growth hormone”.
Is IGF-1 “a” or “the” growth hormone?
The discussion on the role of IGF-1 in body
growth will be based on growth in states of
IGF-1 deficiency and the eVects of exogenous
IGF-1 administration. Experiments in nature
(gene deletion or gene mutations) or experi-
mental models in animals, such as gene knock-
outs, help us in this endeavour. In 1966 and
1968,
33 34
we described a new type of dwarfism
indistinguishable from genetic isolated GH
deficiency (IGHD), but characterised by high
serum GH values. Subsequent studies revealed
that these patients cannot generate IGF-1.
35
This syndrome of GH resistance (insensitiv-
ity) was named by Elders et al as Laron dwarf-
ism,
36
a name subsequently changed to Laron
syndrome (LS).
37
Molecular studies revealed
that the causes of GH resistance are deletions
38
or mutations
39
in the GH receptor gene, result-
ing in the failure to generate IGF-1 and a
reduction in the synthesis of several other sub-
stances, including IGFBP-3. This unique
model in humans has enabled the study of the
diVerential eVects of GH and IGF-1.
Growth and development in congenital
(primary) IGF-1 deficiency (LS)
Our group has studied and followed 52
patients (many since birth) throughout child-
hood, puberty, and into adulthood. We found
Figure 2 Type 1 insulin-like growth factor receptor gene and mRNA. Reproduced with
permission from Werner.
22
Gene
mRNA
1 2 3 64 5
α Subunit
Transcription
INR
mRNA
β Subunit
7 8 9 10 11121314151617 18 19 20 21
AUG
Figure 3 Resemblance between the insulin and insulin-like
growth factor 1 (IGF-1) receptors.
Insulin receptor
Cysteine rich
domains
α Subunits
Tyrosine kinase
domains
β Subunits
IGF-1 receptor
312 Laron
www.molpath.com
that newborns with LS are slightly shorter at
birth (42–47 cm) than healthy babies (49–
52 cm), suggesting that IGF-1 has some influ-
ence on intrauterine linear growth.
40
This fact
is enforced by the findings that already at birth,
and throughout childhood, skeletal maturation
is retarded, as is organ growth.
41
These growth
abnormalities include a small brain (as ex-
pressed by head circumference),
41
a small heart
(cardiomicria),
42
and acromicria (small chin,
resulting from underdevelopment of the facial
bones, small hands, and small feet).
33 34
IGF-1
deficiency also causes underdevelopment and
weakness of the muscular system,
43
and impairs
and weakens hair
44
and nail growth. These
findings are identical to those described in
IGHD.
45
IGF-1 deficiency throughout child-
hood causes dwarfism (final height if un-
treated, 100–135 cm in female and 110–
142 cm in male patients),
40 41
with an
abnormally high upper to lower body ratio.
41
One patient reported from the UK was found
to have a deletion of exons 4 and 5 of the IGF-1
gene and he too was found to have severe
growth retardation.
46
Impaired growth and skeletal development
in the absence of IGF-1 were confirmed in
mice using knockout (KO) of the IGF-1 gene
or GH receptor gene.
47–49
Knockout of the IGF-1 gene or the IGF-1
receptor gene reduces the size of mice by
40–45%.
49
Lack of the IGF-1 receptor is lethal
at birth in mice owing to respiratory failure
caused by impaired development of the dia-
phragm and intercostal muscles.
49
In another
model, the mice remained alive and their post-
natal growth was reduced.
50
In conclusion, findings in humans and in
animals show that IGF-1 deficiencies causes
pronounced growth retardation in the presence
of increased GH values.
The following is a summary of the results of
the growth stimulating eVects of the adminis-
tration of exogenous IGF-1 to children and
experimental data.
Growth promoting eVects of IGF-1
The first demonstration that exogenous IGF-1
stimulates growth was the administration of
purified hormone to hypophysectomised
rats.
51 52
After the biosynthesis of IGF-1 identi-
cal to the native hormone,
53
trials of its use in
Figure 4 Paracrine insulin-like growth factor 1 (IGF-1) secretion and endocrine IGF-1
targets in the various zones of the epiphyseal cartilage growth zone.
Growth
hormone
IGF-1
mRNA
Differentiation
Receptor
Prechondrocyte
Early
chondrocyte
Clonal expansion
Maturing
chondrocytes
IGF-1
IGF-1
Proximal
zone
Intermediate
zone
Distal
zone
Figure 5 Growth velocity before and during insulin-like growth factor 1 (IGF-1) treatment. Note that in infancy, when
the non-growth hormone/IGF-1 dependent growth velocity is relatively high (but low for age), the change induced by
IGF-1 administration is less than in older children.
12
8
10
6
4
0
2
Growth velocity (cm/year)
8
M
14.6–17.1
9.0–12.7
L.M
7
F
13.8–16.2
11.0 –13..3
T.K
6
F
11.6–13.6
11.0–13.0
D.S
2
M
3.3–5.3
1.5–2.6
Al.B
1
M
3–4
2–2.7
AJ.
No.
sex
CA(y)
BA(y)
Name
Patient
3
F
4.2–5.2
3.3–4.2
A.N
5
M
10.1–11.1
6.5–7.9
A.B
4
M
5.1–7.1
1.8–3.5
Al.G
IGF-1: a growth hormone 313
www.molpath.com
humans were begun; first in adults
54
and then
in children.
55 56
Our group was the first to
introduce long term administration of biosyn-
thetic IGF-1 to children with primary IGF-1
deficiency—primary GH insensitivity or LS.
57
The finding that daily IGF-1 administration
raises serum alkaline phosphatose, which is an
indicator of osteoblastic activity, and serum
procollagen,
57 58
in addition to IGFBP-3,
21
led
to long term treatment. Treatment of patients
with LS was also initiated in other parts of the
world.
59–62
The diVerence between us and the
other groups was that we used a once daily
dose, whereas the others administered IGF-1
twice daily.
60
Table 1 compares the linear
growth response of children with LS treated by
four diVerent groups. It can be seen that before
treatment the mean growth velocity was
3–4.7 cm/year and that this increased after
IGF-1 treatment to 8.2–9.1 cm/year, followed
by a lower velocity of 5.5–6.4 cm/year in the
next two years. (In GH treatment the highest
growth velocity registered is also in the first
year of treatment.) Figure 5 illustrates the
growth response to IGF-1 in eight children
during the first years of treatment.
65
Ranke and
colleagues
60
reported that two of their patients
had reached the third centile (Tanner), as did
the patient of Krzisnik and Battelino
66
;how-
ever, most patients did not reach a normal final
height. The reasons may be late initiation of
treatment, irregular IGF-1 administration,
underdosage, etc. Ranke et al conclude that
long term treatment of patients with LS
promoted growth and, if treatment is started at
an early age, there is a considerable potential
for achieving height normalisation.
60
Because
no patient in our group was treated since early
infancy to final height we cannot confirm this
opinion.
When the growth response to GH treatment
in infants with IGHD was compared with that
of IGF-1 in infants with LS we found that the
infants with IGHD responded faster and better
than those with LS.
67
However, the small
number of patients and the diVerences in
growth retardation between the two groups
makes it diYcult to reach a conclusion.
Both hormones stimulated linear growth,
but GH seemed more eVective than IGF-1.
One cause may be the greater growth deficit of
the infants with LS than those with IGHD, an
insuYcient dose of IGF-1, or that there is a
need for some GH to provide an adequate stem
cell population of prechondrocytes to enable
full expression of the growth promoting action
of IGF-1, as postulated by Green and col-
leagues
68
and Ohlson et al.
69
All the above find-
ings based on a few clinical studies with small
groups of patients and a few experimental
studies remain at present controversial. The
crucial question is whether there are any, and if
so, whether there are suYcient IGF-1 receptors
in the “progenitor cartilage zone” of the
epiphyseal cartilage (fig 4) to respond to endo-
crine and exogenous IGF-1. Using the man-
dibular condyle of 2 day old ICR mice, Maor et
al showed that these condyles, which resemble
the epiphyseal plates of the long bones, contain
IGF-1 and high aYnity IGF-1 receptors also in
the chondroprogenitor cell layers, which ena-
bles them to respond to IGF-1 in vitro.
70
Sims et al,
71
using mice with GH receptor
KO showed that IGF-1 administration stimu-
lates the growth (width) of the tibial growth
plate and that IGF-1 has a GH independent
eVect on the growth plate. These findings are
similar to those found when treating hypophy-
sectomised rats with IGF-1.
51 52
In conclusion, IGF-1 is an important growth
hormone, mediating the anabolic and linear
growth promoting eVect of pituitary GH
protein. It has a GH independent growth
stimulating eVect, which with respect to
cartilage cells is possibly optimised by the syn-
ergistic action with GH.
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Table 1 Linear growth response of children with Laron syndrome treated by means of insulin-like growth factor 1 (IGF-1)
Authors Year Ref. N
At start Growth velocity (cm/year) Year of treatment
Age range
(years)
BA
(years)
Ht SDS
(m)
IGF-1 dose
(μg/kg/day) 0 1st 2nd 3rd
(n = 26) (n = 18)
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(n=5) (n=5) (n=1)
Backeljauw et al 1996 62 5 2–11 0.3–6.8 −5.6 80–120 b.i.d. 4.0 9.3 6.2 6.2
(n=9) (n=6) (n=5)
Klinger and Laron 1995 63 9 0.5–14 0.2–11 −5.6 150–200 i.d 4.7 (1.3) 8.2 (0.8) 6 (1.3) 4.8 (1.3)*
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314 Laron
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... Beberapa IGF-1 autokrin/parakrin yang disekresikan masuk ke dalam sirkulasi sistemik. 16,17 IGF-1 memiliki keterlibatan dalam mengatur perkembangan saraf termasuk neurogenesis, mielinisasi , sinaptogenesis , dan percabangan dendritik serta perlindungan saraf setelah kerusakan saraf. IGF-1 memediasi banyak aksi GH, merangsang pertumbuhan tulang dan jaringan lain, dan meningkatkan produksi massa otot tanpa lemak. ...
... IGF-1 juga berperan dalam aktivitas non-pertumbuhan, seperti metabolisme glukosa dan lipid , dan terlibat dalam sindrom metabolik. 17 ...
Septi Wulandari Desi Oktariana
Latar Belakang: Platelet Rich Plasma (PRP) merupakan suatu bagian plasma dari darah yang diambil dari pasien itu sendiri (autologous) dengan kandungan konsentrasi platelet atau trombosit yang cukup tinggi yakni 3 sampai 5 kali lebih besar dari konsentrasi trombosit dalam darah. PRP memiliki kandungan Growth Factor (GF) yang melimpah, di antaranya Platelet Derived Growth Factor (PDGF), Transforming Growth Factor (TGF), Vascular Endothelial Growth Factor (VEGF), Epithelial Growth Factor (EGF) dan Insulin-Like Growth Factor (IGF) yang berfungsi mempercepat regenerasi endothelial, epitel, dan epidermal, merangsang angiogenesis, meningkatkan sintesis kolagen, penyembuhan jaringan, mengurangi jaringan parut pada kulit, dan meningkatkan respon hemostatik terhadap cedera. Berbagai studi baik in vitro maupun uji klinis menunjukkan bahwa pemberian PRP berpengaruh signifikan dalam penyembuhan cedera, perbaikan jaringan dan angiogenesis. Terapi PRP telah digunakan dalam dunia kesehatan sebagai pengobatan dalam berbagai penyakit yang berkaitan dengan pertumbuhan sel Kata kunci : Plasma kaya trombosit, faktor pertumbuhan, pengobatan regeneratif
... The regulation of pulsatile GH secretion begins in the hypothalamus, located at the base of the third ventricle in the diencephalon, with the release of growth hormone-releasing hormone (GHRH, a 44amino-acid peptide) from the arcuate nucleus and somatostatin (a 14-amino-acid peptide) from the periventricular nucleus (PeVN) [499,500,501,502]. GH, a glycoprotein composed of 694 amino-acid residues, is secreted by somatotrophs in the anterior pituitary and promotes anabolism and growth in multiple tissues, both directly and indirectly through insulin-like growth factor 1 (IGF-1, a 70-amino-acid polypeptide), which is primarily produced by the liver [499,503,504]. In AT, however, GH exerts catabolic effects by stimulating lipolysis (via activation of hormone-sensitive lipase) and promoting the release of free fatty acids and glycerol to support lipid metabolism [499,505]. ...
Moacir Couto de Andrade Júnior
Several excellent studies use the terms feeding behavior (FB) and eating behavior (EB) interchangeably, although they differ in scope. In the present work, FB refers to neuroendocrine regulation, experimental models, and physiological mechanisms, whereas EB pertains to the clinical, psychological, and social aspects observed in humans. FB is shaped by multiple influences-genetic, psychological, and hormonal-within broader socioeconomic, political, cultural, religious, and nutritional contexts. It can therefore be examined from complementary perspectives, particularly neurobiological, clinical, and therapeutic. Body weight (BW) partially reflects FB and its fluctuations over time. This in-depth narrative review explores alterations in EB and BW associated with various endocrine disorders, including hypothalamic syndrome; pituitary cachexia (Simmonds disease); thyroid dysfunction (hyperthyroidism and hypothyroidism); parathyroid diseases; glycemic disturbances (e.g., diabetes mellitus and insulinoma-induced hypoglycemia); disorders of the hypothalamic-pituitary-ovarian axis (e.g., premenstrual syndrome, contraceptive-related changes, and polycystic ovary syndrome); adrenal disorders (Cushing syndrome and adrenal insufficiency); and growth hormone (GH) imbalances (gigantism, acromegaly, and GH deficiency). Whereas many reviews have focused on hormonal alterations underlying obesity as a distinct nosological entity or on primary eating disorders such as anorexia nervosa, bulimia nervosa, and binge eating disorder, the present review specifically addresses changes in EB and BW as secondary manifestations of endocrine dysfunction. These alterations are discussed primarily as clinical signs and symptoms, along with their underlying pathophysiological mechanisms. Relevant historical and therapeutic aspects are also considered.
... GH is a 191-amino acid pituitary peptide hormone released in a pulsatile, sleep-linked manner under hypothalamic control (18)(19)(20)(21)(22). At the cellular level, GH binding to the GH receptor activates Janus Kinase-2 (JAK2)/STAT signalling and promotes IGF-1 production, while secretion is influenced by factors such as exercise, hypoglycaemia, fasting, obesity, and ageing (23)(24)(25)(26)(27)(28). More broadly, the success of incretin-based therapies for obesity and diabetes has likely increased public familiarity with peptide injectables, potentially lowering barriers to off-label peptide experimentation (29)(30)(31). ...
Aleksander Dominikowski
Zofia Rękoś
Michał Olejarz Marek Ruchała
Performance-enhancing drugs (PEDs) marketed as “research compounds” include unregulated peptides intended to modulate the growth hormone–insulin-like growth factor-1 (GH–IGF-1) axis. The agents most commonly encountered in clinical practice and online self-administration protocols include growth hormone-releasing hormone (GHRH) analogues (e.g., sermorelin, tesamorelin, CJC-1295 with Drug Affinity Complex [DAC], CJC-1295 without DAC), growth hormone secretagogues (GHS; e.g., growth hormone-releasing peptide-2 (GHRP-2), growth hormone-releasing peptide-6 (GHRP-6), hexarelin, ipamorelin), the growth hormone (GH) fragment - AOD9604 (hGH 176–191), and insulin-like growth factor-1 (IGF-1) analogues (e.g., pegylated mechano growth factor (PEG-MGF), IGF-1 Long R3 (IGF-1 LR3)). Reported adverse effects span endocrine and metabolic disturbances (including prolactin and cortisol elevations, appetite changes, and dysglycaemia), fluid retention syndromes, musculoskeletal symptoms (myalgia/arthralgia), and injection-site reactions. Given the absence of regulatory approval for physique- or performance-related indications and the uncertainty surrounding product composition, dose, and stacking practices in unregulated supply chains, clinicians increasingly require a pragmatic framework to interpret symptoms and laboratory abnormalities in patients using these compounds. This narrative review contrasts peer-reviewed pharmacokinetic/pharmacodynamic and clinical evidence with commonly encountered online self-administration protocols, stratifying peptides into evidence tiers from regulatory-grade randomized trial data to a complete absence of human studies, and highlights the resulting uncertainty around putative performance and recomposition benefits. We summarise structural characteristics, pharmacologic effects, and commonly reported dosing patterns, and we synthesise clinically relevant adverse effects with particular attention to hormonal imbalance, endocrine–metabolic risk, and biologically plausible but unproven mitogenic concerns. Finally, we propose a clinically oriented assessment algorithm to support exposure history taking, triage of symptom domains, and risk communication without legitimising off-label peptide regimens.
... IGF-1 is a growth-promoting hormone primarily regulated by growth hormone (GH) and plays a central role in cell proliferation, anabolic processes, and bone formation. Nutritional deficiencies, particularly inadequate energy and protein intake, may reduce IGF-1 levels through increased protein catabolism and GH resistance, thereby contributing to impaired linear growth (38). ...
Novina Novina
Aman B Pulungan
Michael Hermanussen Budi Setiabudiawan
Background Child growth results from the interaction of genetic, endocrine, nutritional, and environmental factors. Short stature is defined as a height-for-age Z-score below −2 standard deviations, according to the WHO Child Growth Standards 2006. Linear bone growth occurs through endochondral ossification, which is influenced by insulin-like growth factor-1 (IGF-1), 25-hydroxyvitamin D [vitamin 25(OH) D], calcium (Ca), phosphorus (Ph), and magnesium (Mg). This study compared these biomarkers across growth phenotypes and examined their associations with short stature in children aged 24–59 months. Methods This cross-sectional analytical study used registry data and stored biological specimens (SBS) from 225 children aged 24–59 months residing in Bandung District, Indonesia (84 underweight children with short stature, 70 normal-weight children with short stature, and 71 children with normal weight and stature), collected between May and August 2021. SBS were preserved at -80 °C. Appropriate statistical tests, post-hoc analyses, and multivariable logistic regression were performed. Results Significant differences in IGF-1, 25(OH)D, calcium, phosphorus, and magnesium were observed across groups (all p < 0.05). Post-hoc analysis indicated that these differences were confined to comparisons between the underweight short stature group and the normal-weight normal stature group, with no significant differences involving the normal-weight short stature group. Multivariable analysis further showed that lower levels of IGF-1, calcium, phosphorus, and magnesium were independently associated with short stature, with these associations largely attributable to the underweight subgroup, while remaining non-significant among children with normal-weight short stature. Conclusion Lower levels of IGF-1, calcium, phosphorus, and magnesium are associated with short stature in children aged 24–59 months, predominantly among those with concurrent undernutrition. In contrast, these associations were not evident in children with normal-weight short stature, underscoring the heterogeneous nature of short stature.
... Щодо ролі факторів росту в загоєнні ран, то слід зазначити, що інсуліноподібний фактор росту опосередковує більшість фізіологічних ефектів гормона росту в периферичних тканинах, стимулює ріст і розвиток тканин, відіграє ключову роль у рості та розвитку організму [21,22]. ...
N. R. Hrytsevych N. S. Nikitina L.I. Stepanova O. Savchuk
The healing process of minor acute wounds is mainly facilitated by the skin's inherent regenerative capacity, which includes cellular mechanisms, remodeling of the extracellular matrix, and the presence of growth factors. The problem of wound healing is associated with injuries in wars, population aging, and the increase in obesity and diabetes mellitus on a global scale. It is known that the wound healing process is significantly affected by obesity. In this regard, studies of the role of growth factors in wound healing in the development of obesity are relevant. Purpose. To determine the dynamics of wound healing and growth factor concentrations in the skin during the healing of full-thickness excised linear wounds in rats of different sexes with glutamate-induced obesity. Materials and methods. Newborn males and females (n = 64) were randomly divided into 4 groups. Group 1 (males) – control, in rats of this group at the age of 4 months, full-thickness excised linear wounds were simulated, which were not treated with anything. In 4-month-old rats of group 2 (males) with glutamate-induced obesity, full-thickness linear wounds were modeled. Group 3 (females) – control, in rats of this group at the age of 4 months, fullthickness linear wounds were modeled, which were not treated with anything. In 4-month-old rats of group 4 (females) with glutamate-induced obesity, fullthickness linear wounds were modeled. To induce obesity, rats of group 2 and group 4 were subcutaneously injected with a solution of monosodium glutamate at a dose of 4.0 mg/kg on the 2nd, 4th, 6th, 8th and 10th days after birth. The level of growth factors was determined using the appropriate reagent sets by the indirect enzyme-linked immunosorbent assay (ELISA) method according to the standard protocol. Results. It has been shown that in male and female rats, the effect of glutamate-induced obesity on wound length is manifested only on the 12th day of healing. In males, the wound length in obesity during this period is 1.3 times higher (p < 0.05), and in females it is 1.4 times higher (p < 0.05) compared to the control. On the 16th day, males in the control have complete wound healing, and in obesity only on the 20th day. A similar picture is observed on the 16th day in females, in which complete healing also occurs on the 20th day. In male rats with glutamate-induced obesity, the concentration of insulin-like growth factor (IGF) significantly increases by 1.5 times compared to controls without obesity. In females, no difference in IGF concentration was found in the control and in obesity. However, in females, the concentration of IGF in obesity was 1.4 times higher than in obese males (p < 0.05). In obese females, the concentration of EGF was 1.4 times higher, FGF was 1.5 times higher, PDGF was 1.4 times higher, TGF was 1.3 times higher than in obese males. However, no significant difference in the concentrations of NGF and VEGF was found in obesity between males and females. Conclusions. In males and females with glutamate-induced obesity, wound healing occurs 4 days later than in controls without obesity. This process involves the growth factors IGF, EGF, FGF, PDGF and TGF, the concentration of which significantly increases in obesity. N significant difference in the concentrations of NGF and VEGF was found between males and females in both controls and obesity.
... The observed increase in IGF-1 levels in the FGO group was attributed to the acceleration of BA and elevated DPD activity because IGF-1 promotes bone growth and metabolism through its interaction with growth hormone [41,42]. Therefore, the observed increase in IGF-1 levels provides additional evidence supporting the positive impact of FGO on bone growth and metabolic activation [43]. ...
Jongbae Kim Keunwon Kim Minji Park Ae-Son Om
BACKGROUNDS/OBJECTIVES Child growth is affected by genetics, nutrition, physical activity, and environmental factors. Despite the improvements in average height among Korean children due to better socioeconomic and nutritional status, safe and effective growth-promoting interventions are still needed for children with mild short stature. This study evaluated the safety and efficacy of fermented oyster extract (FGO) supplementation in children aged 6 to 9 yrs with heights between the third and 25th percentiles for age and gender. SUBJECTS/METHODS In this randomized, double-blind, placebo-controlled trial, subjects received FGO (n = 40) or placebo (n = 40) once daily (500 mg/day) for 24 weeks. This study evaluated the height growth, bone age (BA), growth hormone (GH), insulin-like growth factor 1 (IGF-1), insulin-like growth factor binding protein 3 (IGFBP-3), and urine deoxypyridinoline (DPD) for the efficacy of FGO and sex hormones, including estradiol, luteinizing hormone, and testosterone, for its safety. Finally, 66 children (33 each in the FGO and placebo group) completed the study. No significant baseline differences existed between the 2 groups. RESULTS After 24 weeks, the FGO group showed significant improvements in height, height SD score, and height velocity (all P < 0.001). BA and BA delay improved significantly in the FGO group (P = 0.024 and P = 0.035). The FGO group showed significantly greater changes in the IGF-1 and urine DPD levels (P = 0.010 and 0.001, respectively). The GH and IGFBP-3 concentrations increased in the FGO group, but the difference between the two groups was not significant. No serious adverse events or increase in sex hormones were observed after FGO supplementation, assuring its safety. CONCLUSION FGO may be a safe and effective health supplement ingredient for height growth in children, irrespective of gender. Future studies will need to evaluate the long-term effects of FGO and its applicability across various populations.
... Patients with growth hormone (GH) resistance caused by defects in the growth hormone receptor (GHR), a condition known as Laron syndrome, have a rare genetic disorder characterized by dwarfism and severe postnatal growth failure (4). These defects in GHR interfere with GH binding to its receptor and/or downstream signaling events (5), resulting in reduced hepatic production of insulin-like growth factor 1 (IGF1), the primary mediator of postnatal growth (6). In addition, GH regulates the cell surface levels of GHR through negative feedback mechanisms involving SOCS family proteins that target GHR for ubiquitindependent degradation (7,8). ...
Joshua K. Tay Kian Chuan Sia Siti Humairah Mohd Rodhi Kok-Onn Lee
Growth hormone (GH) receptor (GHR) mutations give rise to GH-resistance (Laron syndrome). We previously treated GH-resistant Ghr-/- mice (Laron mice) with adeno-associated virus (AAV) delivering mouse (m)Ghr controlled by a constitutively active liver-specific promoter (HLP). A single injection of AAV-HLP-mGHR resulted in a significant but limited increase in body length and weight, consistent with studies of IGF-1 treatment in humans and mice. Here, we performed RNA-seq on male and female mouse livers comprising the following groups: GHR+/+ (wild-type), GHR-/- (Laron), AAV-HLP-mGHR-treated GHR-/- (treatment group), and AAV-HLP-Luc (Luciferase)-treated GHR-/- (control group). Only four genes showed significant differential expression in GHR -/- mouse liver following Luciferase vector treatment, indicating minimal effect of the AAV-HLP vector. AAV-HLP-mGHR stimulated significant expression changes in 448 genes compared to AAV-HLP-Luc control, substantially fewer than the 2781 genes whose expression was altered in GHR-/- compared to GHR+/+. AAV-HLP-mGHR treatment induced the GH-responsive IGF signaling genes Igf1 and Igfals ~16-fold compared to AAV-HLP-Luc control, but only to 40–45% of GHR+/+ liver levels. The treatment also upregulated a small subset of genes beyond GHR+/+ expression levels (p-adj < 0.05), including the proto-oncogenes Ascl1, Tmprss4, and others. Finally, genes dysregulated upon GHR loss and upregulated in livers of AAV-HLP-mGHR-treated mice were significantly enriched for sex-biased genes, consistent with the major role of GH and GHR in regulating liver sex differences. While gene replacement therapy is a potential therapy for Laron syndrome, an unregulated constitutively active promoter may drive unexpected and unbalanced changes in liver gene expression that will require monitoring.
... IGF-1 is an anabolic hormone, primarily produced by the liver in response to GH, that mediates GH effects and plays a crucial role in maintaining muscle mass and strength (11), while also exerting antiapoptotic (12) and antioxidant functions (13). Elevated IGF-1 has been identified as a biomarker predicting Parkinson's disease risk (14), while alterations in the GH/IGF-1 axis have been linked to neurodegenerative and psychiatric disorders such as Alzheimer's disease, depression, and anxiety (15). ...
Cristiano Dani
Livio Tarchi Lorenzo Bonacchi
Giovanni Castellini
Context Anorexia nervosa (AN) is associated with severe metabolic and endocrine alterations, including growth hormone (GH) resistance and reduced insulin-like growth factor 1 (IGF-1). The longitudinal behavior of IGF-1 during treatment remains incompletely characterized. Objective To evaluate IGF-1 levels in current and weight restored AN, determine metabolic correlates, and examine longitudinal changes during clinical treatment. Design Cross-sectional analysis in a population-based cohort and longitudinal analysis in a clinical cohort. Setting UK Biobank (UKB) and a specialist eating disorder clinic. Participants (i) UKB: 129 adult women with current AN, 2,380 weight restored AN, and 2,380 healthy controls (HC) matched for age, sex, and BMI. (ii) Clinical cohort: 189 adult women with AN assessed at baseline and 12-month follow-up. Main outcomes measures Plasma IGF-1 levels; secondary metabolic and reproductive hormones including GH, insulin, glucose, FT3, and gonadal hormones. Results Across the UKB groups, IGF-1 levels showed a graded pattern: lowest in current AN, medium in weight restored AN, and highest in HC. In the clinical cohort, IGF-1 correlated positively with insulin, glucose, and FT3, and negatively with GH, consistent with GH resistance. IGF-1 levels increased significantly over 12 months of treatment (p = 0.003), with higher BMI at baseline predicting greater increases. Higher IGF-1 levels were associated with greater likelihood of menstrual function independent of BMI (p < 0.001). Conclusions IGF-1 appears reduced in current AN and may only partly normalize with weight restoration. IGF-1 may reflect metabolic state and reproductive function, suggesting value as an indicator of severity and treatment response.
... Future studies employing more severe or clinically relevant alcoholic hepatitis models will help clarify whether these pathways persist throughout disease progression. In conclusion, while our study identifies IGFBP3 as a mechanistic candidate in ALD, its therapeutic potential hinges on achieving liver-specific delivery to avoid systemic disruption of the IGF axis and metabolism, and on rigorous safety evaluation (Laron, 2001;Livingstone and Borai, 2014). Systemic modulation of IGFBP3 may have unintended effects on growth, metabolism, and cell survival in other tissues, representing a key limitation for clinical translation. ...
Huimei Cai Chenyu Zhu Xi Zheng Yi Lv
Insulin-like growth factor binding proteins (IGFBPs) are critical regulators of hepatic metabolic homeostasis, and accumulating evidence implicates them in liver disease progression. However, their precise roles and regulatory mechanisms in alcoholic liver disease (ALD) remain elusive. In this study, we performed comprehensive analyses of the expression of IGF system proteins both in vitro and in vivo, and identified a significant downregulation of IGFBP3 in ALD. Subsequently, we overexpressed IGFBP3 or its mutant IGFBP3GGG with an IGF1-binding site mutation in AML12 cells to evaluate its effect on alcohol-induced hepatocyte injury. Our findings revealed that IGFBP3 overexpression exacerbated alcohol-induced lipid accumulation, reactive oxygen species (ROS) generation, and apoptosis in hepatocytes. Compared with the IGFBP3-overexpressing group, the IGFBP3GGG-overexpressing group showed no significant difference in lipid accumulation, whereas the levels of ROS and apoptosis were significantly lower. Furthermore, we generated liver-specific IGFBP3 knockout mice (Alb-cre;Igfbp3f/f), which exhibited significantly attenuated alcoholic liver injury compared to their Igfbp3f/f littermates following chronic ethanol exposure. Mechanistically, IGFBP3 overexpression activates the Akt/GSK3β and TMEM219/Caspase8 signaling pathways, driving hepatic lipid accumulation and hepatocyte apoptosis. Paradoxically, knockout of IGFBP3 also promotes the phosphorylation of Akt/GSK3β in liver. Collectively, these findings suggest a potential cross-talk between the Akt/GSK3β and TMEM219/Caspase8 signaling pathways, and the downregulation of IGFBP3 in chronic liver disease may represent a self-regulatory mechanism of hepatocytes to resist adversity.
Haim Werner
The biological actions of the insulin-like growth factors (IGFs), as described in this book, are mediated by a family of cell-surface receptors that includes the insulin, the type 1, and the type 2 IGF receptors (1–6). Although there is a certain degree of cross-interaction between the various ligands and their receptors, current evidence supports the view that most of the effects of both IGF-I and IGF-II on growth and differentiation are elicited by the ligand-dependent activation of the type 1 receptor. The type 2 receptor, which is identical to the cation-independent mannose-6-phosphate receptor, is mainly involved in the recycling of lysosomal enzymes containing mannose-6-phosphate residues and its role in the transduction of IGF-mediated biological signals has not yet been elucidated. This chapter focuses on the type 1 IGF receptor and discusses the molecular organization of its gene, mRNA, and protein. Functional aspects of the IGF receptor are examined in light of its specific physical features.
Zvi Laron
Insulin-like growth factor (IGF-1) is a polypeptide of 70 amino acids. The circulatory form of IGF-1 is synthesised in the liver. The metabolic activity of IGF-1 is regulated by 6 IGF-binding proteins (BPs), the most important being IGFBP-3. IGF-1 acts via its own receptor, which resembles that of insulin. It has been demonstrated that the effects of growth hormone (GH) on protein metabolism, including growth and the effect on nerve tissue versus trophic effects, are mediated by IGF-1, whereas these 2 hormones are antagonistic in their effects on insulin and some aspects of lipid metabolism. This paper reviews present knowledge on the physiological role of IGF-1 and clinical effects of recombinant IGF-1 (somatomedin-1). The biosynthesis of somatomedin-1 in 1986 enabled the initiation of clinical trials. Somatomedin-1 has many potential uses in the clinic. The most important is replacement therapy in primary IGF-1 deficiency, such as Laron syndrome (primary GH resistance or insensitivity) and in patients who have developed antibodies to hGH. In Laron syndrome, which is characterised by dwarfism, somatomedin-1 stimulates growth and increases muscle and bone mass, as well as normalising blood chemistry. In types 1 and 2 (insulin-dependent and non-insulin-dependent) diabetes mellitus, somatomedin-1 increases the sensitivity to insulin and improves glucose utilisation. Experimental studies indicate that IGF-1 has a role in nerve tissue metabolism, and in humans may contribute to healing of injured nerve tissue. Other current clinical trials using the anabolic properties of somatomedin-1 are studying its effect on osteoporosis, catabolic states (burns, post-operation, AIDS) and haematopoietic disorders. Adverse effects of somatomedin-1 appear to be related to overdosage. In conclusion, somatomedin-1 is an important hormone which has a promising role as replacement therapy and appears to have many other potential applications in the clinic.
Jaime Guevara-Aguirre
Zvi Laron
In recent years, several biosynthetic hexa- and heptapeptides, as well as non-peptide bezolactam derivatives, have been found to be potent growth hormone (GH) secretagogues. They act synergistically with GH-releasing hormone (GHRH) but via different receptors, and are GHRH dependent. All are active when administered intravenously, orally or subcutaneously. Short and long term experience in adults and children has proven that these drugs evoke the metabolic changes induced by GH and insulin-like growth factor-1 (IGF-1), including ac-celeration of growth velocity in children. With the exception of a partial downregulation phenomenon, no adverse effects have been reported so far. This new class of hormone-like drugs acting as GH secretagogues may have immense clinical potential.
Claes Ohlsson
Michael B Ranke
Martin O Savage
Pierre Chatelain P Wilton
A total of 33 patients (17 female, 16 male) with Laron syndrome (n = 31) or hGH-1 gene (n = 2, type IA deletion) from 22 centres in 12 countries were enrolled in a study conducted by Pharmacia & Upjohn, Stockholm, which was designed to test the efficacy, in terms of growth promotion and safety, of IGF-I (IgefTM). The patients were treated with 40–120 μg/kg IGF-I s.c. twice daily after meals. After the study ended, the patients continued to be treated on an individual basis. The results of 17 patients, who were treated for 48 months or longer were available for the present analysis. Six patients were treated for up to 72 months. When treatment started, the mean age of these patients (8 female, 9 male) was 9.1 (3.7–13.5) years and mean height was –6.5 ± 1.3 SDS. At the end of the observation period, the mean age of the 17 patients was 14.2 (9.1–17.7) years and mean height was –4.9 ± 1.9 SDS. All patients showed a significant increase in growth during the final year on IGF-I, with two of them reaching the age-corresponding 3rd centile. The total gain in height (ΔHT) was 1.7 ± 1.2 SDS. ΔHT SDS correlated negatively with age at onset of treatment (R2 = –0.78, p < 0.02). BMI was 0.6 ± 1.8 SDS at start of treatment and 1.8 ± 1.5 SDS at the end of observation. Total ΔHT SDS correlated positively with total ΔBMI SDS (R2 = 0.59, p < 0.01). Long-term treatment of patients with GHIS thus proved to be effective in promoting growth. If treatment is started at an early age, there is considerable potential for achieving height normalisation. The treatment modalities need to be optimized with respect to the growth-promoting and metabolic effects of IFG-I.
Peter Gluckman
Alistair Gunn
Alison Wray K ALBERTSSONWIKLAND
To assess the role of growth hormone in fetal and infant growth, we analyzed the pretreatment data on 52 patients with a diagnosis of congenital growth hormone deficiency before 2 years of age, obtained from the Kabi Pharmacia international Growth Study. These infants had reduced birth-length standard deviation scores, an excess of birth weight relative to length, and progressive growth failure. We conclude that congenital growth hormone deficiency may cause impaired growth in utero and early infancy, and that growth hormone plays an important role in perinatal and infantile growth.