ArticlePDF AvailableLiterature Review

Abstract and Figures

Pituitary somatotrophs secrete growth hormone (GH) into the bloodstream, to act as a hormone at receptor sites in most, if not all, tissues. These endocrine actions of circulating GH are abolished after pituitary ablation or hypophysectomy, indicating its pituitary source. GH gene expression is, however, not confined to the pituitary gland, as it occurs in neural, immune, reproductive, alimentary, and respiratory tissues and in the integumentary, muscular, skeletal, and cardiovascular systems, in which GH may act locally rather than as an endocrine. These actions are likely to be involved in the proliferation and differentiation of cells and tissues prior to the ontogeny of the pituitary gland. They are also likely to complement the endocrine actions of GH and are likely to maintain them after pituitary senescence and the somatopause. Autocrine or paracrine actions of GH are, however, sometimes mediated through different signaling mechanisms to those mediating its endocrine actions and these may promote oncogenesis. Extrapituitary GH may thus be of physiological and pathophysiological significance.
Content may be subject to copyright.
Extrapituitary growth hormone
S. Harvey
Received: 4 November 2009 / Accepted: 26 August 2010 / Published online: 23 October 2010
ÓSpringer Science+Business Media, LLC 2010
Abstract Pituitary somatotrophs secrete growth hormone
(GH) into the bloodstream, to act as a hormone at receptor
sites in most, if not all, tissues. These endocrine actions of
circulating GH are abolished after pituitary ablation or
hypophysectomy, indicating its pituitary source. GH gene
expression is, however, not confined to the pituitary gland,
as it occurs in neural, immune, reproductive, alimentary,
and respiratory tissues and in the integumentary, muscular,
skeletal, and cardiovascular systems, in which GH may act
locally rather than as an endocrine. These actions are likely
to be involved in the proliferation and differentiation of
cells and tissues prior to the ontogeny of the pituitary
gland. They are also likely to complement the endocrine
actions of GH and are likely to maintain them after pitui-
tary senescence and the somatopause. Autocrine or para-
crine actions of GH are, however, sometimes mediated
through different signaling mechanisms to those mediating
its endocrine actions and these may promote oncogenesis.
Extrapituitary GH may thus be of physiological and path-
ophysiological significance.
Keywords GH Pituitary Extrapituitary
Embryogenesis Cancer Autocrine Paracrine
Although growth hormone (GH) secreted by the pituitary
gland acts as an endocrine to regulate the growth, devel-
opment, and metabolism of many target tissues, a large
body of the literature demonstrates that GH is also present
in many extrapituitary tissues, in which it may act as an
autocrine or paracrine growth factor. This literature, for
neural, immune, and some reproductive tissues, was briefly
reviewed more than 13 years ago [1]. In this review, more
recent literature for these tissues and for other sites of
extrapituitary GH production is considered and the possible
functional significance or pathophysiological relevance of
extrapituitary GH is discussed.
GH in neural tissues
The presence of GH mRNA in the human brain is uncertain
[2], although GH gene transcription occurs in the lateral
hypothalamus of the rat brain, independently of pituitary
GH expression [3]. The abundance of GH mRNA (deter-
mined by the ribonuclease protection assay and 50-rapid
amplification of complimentary DNA ends-polymerase
chain reaction (PCR)) in the hypothalamus is increased by
GH releasing hormone (GHRH) and suppressed by stress,
under conditions that induce minimal changes in pituitary
GH mRNA levels [3]. It is also increased by ginseng [4].
The expression of the GH gene (determined by reverse-
transcription (RT)-PCR and by transcriptional profiling)
was also demonstrated in the rat hippocampus, where GH
mRNA levels were higher in adults than juveniles and
higher in females than males, especially during estrus,
when estrogen levels are elevated [5,6] Hippocampal GH
expression was also increased in ovariectomized females
after treatment with estrogen, which was able to induce GH
mRNA levels in primary neuronal cultures. Hippocampal
GH expression was also increased in both males and
S. Harvey (&)
Department of Physiology, University of Alberta, 7-41 Medical
Sciences Building, Edmonton, AB T6G 2H7, Canada
Endocr (2010) 38:335–359
DOI 10.1007/s12020-010-9403-8
females after acute exposure to electric shock. Hippo-
campal GH expression has also been demonstrated in
normal mice and in Ames mice that have a pituitary GH
deficiency [7,8]. GH mRNA is also present in the brains of
adult trout [9].
In addition to GH mRNA, GH immunoreactivity has
been shown in the rat brain [10] and in cells of the ven-
tricular zone of the mouse brain [11]. Although Ames mice
have a pituitary GH deficiency, hippocampal GH concen-
trations in these mice are higher than in non-dwarf siblings
[7,8]. Neural GH has also been determined in the chicken,
turkey, and dove brains, in which dense GH immunore-
active perikarya and fibers are present in the hippocampus,
in periventricular, paraventricular, inferior, and infundib-
ular hypothalamic nuclei and in medial and septal areas
and in the median eminence [12]. A similar distribution of
GH immunoreactivity was seen in the brains of embryonic
chickens [13,14]. In the chick, the brain develops from the
neural tube at embryonic day (ED) 3 of the 21-day incu-
bation period. At this age the divisions of the brain (the
telencephalon, diencephalon, mesencephalon, metenceph-
alon, and myelencephalon) have intense GH immunore-
activity. GH was also localized in the spinal cord [13,15,
16], and in the otic and optic vesicles [13,14]. It is also
present within the peripheral nervous system of chick
embryos, particularly in the trigeminal and vagal nerves,
the extensor nerve of the limb bud, and the ethmoid nerve
in the head [14,17]. The presence of GH in these neural
tissues occurs in the absence of pituitary GH, since GH
secreting pituitary somatotrophs do not appear until ED
14–15 of chick embryogenesis [18,19]. At ED 14, GH in
the brain was no longer widespread and restricted to spe-
cific tissues and cells. For instance, GH-immunoreactive
cells at ED 14 were present in the molecular and pyramidal
layers of the cerebral cortex, in the gray matter of the
cerebellum, in the choroid plexus and in the walls of the
ventricles [13], and in the pineal gland [16]. At the sub-
cellular level, GH immunoreactivity in neural tissues of the
chick embryo is present in cytosolic compartments and in
nuclear or perinuclear fractions [13,16], as previously
observed in peripheral tissues [15,20]. In the turkey brain
and ring dove brain, GH is present in granules within the
cytoplasm of the cell bodies, whereas these granules are
arranged in a continuous bead-like fashion in fibers or
neurites [12]. The presence of GH in the avian brain
reflects the expression of the pituitary GH gene in hypo-
thalamic and extra-hypothalamic locations, in which 690-
bp cDNA fragments generated by RT-PCR were identical
to pituitary cDNA. This homology extended over a region
spanning nucleotides 65 to 659 of pituitary GH cDNA that
coded for amino acids 4-201 (reviewed in 1). GH has also
been detected in human cerebrospinal fluid (CSF) [21], and
may reflect sequestration through the blood–brain barrier
[22], although as the concentration is lowered in patients
with neural degeneration [23,24], it is likely to reflect
neural GH production.
Within the nervous system, roles for GH in neural
development are now well established and have been
reviewed in recent years [2528]. Accumulating evidence
suggests the involvement of GH in the regulation of brain
growth and development and in neuronal differentiation
and function. Some of these actions may reflect the entry of
systemic GH into the brain and some may be mediated by
the local production of GH or its local induction of IGF-1.
Only a few studies have, however, assessed the possibility
of GH acting as an autocrine/paracrine in the nervous
Scheepens et al.[10,29,30] found increased GH
immunoreactivity in cortical pyramidal neurons after focal
hypoxic–ischemic injury to the brain. The immunoreac-
tivity was seen in myelinated axons and glial cells within
and surrounding the infarcted tissues and within the
ependymal cells of the choroid plexus in the injured
hemisphere. This increase in neural GH content was
thought to be neuroprotective, since exogenous GH mark-
edly reduced the death of neurons after hypoxic–ischemic
injury. The increased hippocampal GH content in Ames
mice [7,8] has also been correlated with their higher rates
of hippocampal neurogenesis. DNA microassay analysis of
hippocampal mRNA extracted following hippocampal-
dependent learning also showed that GH mRNA was the
primary gene to be upregulated [6], suggesting the
involvement of hippocampal GH in learning and memory.
Neural GH may, however, inhibit neuronal differentiation
from neuroprogenitor cells, since somatostatin (SRIF
which inhibits GH release from cultured brain cells [31])
and GH antiserum promoted neuronal development in vitro
[11]. The widespread presence of GH-, GH-receptor
(GHR), and GH-response gene (GHRG)-1 mRNA in the
brain of early chick embryos [3234] also suggests auto-
crine/paracrine roles for GH in neural function, as GHRG-1
is a specific marker of GH action in chickens.
Neural retina
In addition to the brain, the neural retina has been found to
be a neural site of GH expression, particularly within the
retinal ganglion cells (RGCs) of embryonic chicks [35].
Retinal GH mRNA in the chick embryo is identical to
pituitary GH mRNA in nucleotide sequence, but the
translated 24-kDa protein is rapidly converted into a 15-
kDa moiety by proteolysis in retinal tissue [36]. Moreover,
after secretion from the retina, this GH moiety is bound to a
45-kDa proteoglycan, opticin, in vitreous fluid [37]. GH
immunoreactivity within the eye is also found in the cho-
roid layer and in the retinal pigmented epithelium [38,39].
336 Endocr (2010) 38:335–359
A second, severely truncated GH mRNA (small chicken GH,
scGH), lacking residues of the full-length transcript derived
from exons 1, 2, and 3 and having an N-terminal 20 residues
derived from intron C of the full-length mRNA, is also
present in the neural retina of chicks [40]. This protein lacks
critical residues required for binding to the GHR [41]. The
16-kDa protein coded by scGH, detected by a specific anti-
body, is present in extracts derived from the neural retina,
pigmented epithelium, lens, cornea, and choroid of eyes from
early chick embryos, although scGH immunoreactivity is
mainly to a 31-kDa protein that is likely to be a dimerized
form [42]. scGH is, however, not thought to be secreted and
is rarely present in vitreous fluid, consistent with its lack of a
signal sequence and its retention inside transfected HEK
(human embryonic kidney) cells that overexpressed the
protein. Specific scGH immunoreactivity is also detected by
immunocytochemistry in ocular tissues, although it is not in
axons in the optic fiber layer, nor in the optic nerve head,
which are immunoreactive for the 15-kDa protein derived
from the full-length protein [36].
The GH immunoreactivity in the axons emanating from
the RGCs of the neural retina was traced from the fascicles
in the optic fiber layer, through the optic nerve head at the
back of the eye, into the optic nerve, through the optic
chiasm, into the optic tract, and into the stratum opticum
and the retinorecipient layer of the optic tectum of the
brain, where the RGC axons synapse [34]. The GH
immunoreactivity in the tectum is not due to the antero-
grade transport of retinal GH, as it is present prior to
synaptogenesis within RGC axons and reflects the presence
of GH mRNA in the optic tectum. The distribution of GH-
immunoreactivity in the visual system of the early chick
embryo (at embryonic day (ED) 7 of the 21-day incubation
period) also parallels the distribution of the GHR [42,43].
The presence of GHRG-1 in these tissues also suggests that
the visual system is not just a site of GH production, but
also a site of GH action.
The possibility that retinal GH may be involved in the
development of the visual system during early embryo-
genesis [44] is supported by the finding that it is only
present in the RGC axons of ED 4–ED 12 chicks, but not at
ED 14–ED 18 [43,45]. This temporal window corresponds
to the period of RGC axon growth and the completion of
synaptogenesis in the optic tectum. Moreover, the impor-
tance of endogenous RGC GH in axon development is
shown by its siRNA-knockdown in cultured, immuno-
panned RGCs, which reduces axon length by at least 40%.
Axon length is, conversely, increased in response to
exogenous GH treatment in vitro [43].
Within the chick neural retina, retinal GH is neuropro-
tective for RGCs, at a time during embryogenesis when
they undergo a developmental wave of apoptosis (between
ED 6–ED 8 [46]). It was found that exogenous GH
significantly reduces cell death in cultures of retinal
explants or in immunopanned RGCs [46], whereas the
immunoneutralization of endogenous GH augments cell
death [4649]. This neuroprotective action of GH is
mediated by signaling mechanisms that are common to
other established neurotrophins (e.g., brain-derived growth
factor, insulin-like growth factor-1 (IGF-1), transforming
growth factor b-1) [45]. These mechanisms include a
suppression of caspase-3 expression and the expression of
AIF (apoptosis inducing factor), which acts via caspase-
independent death pathways [50]. The induction of apop-
tosis by GH antiserum is accompanied by an increase in
caspase-3 and caspase-9 activation and PARP-1 (poly
ADP-ribose polymerase 1) cleavage [47,48]. Calpain
activation is also a caspase-independent pathway of exog-
enous GH involved in PARP-1 cleavage, and a specific
calpain inhibitor abrogates the apoptotic activity of the GH
antiserum on RGC death [47]. Akt signaling pathways also
participate in GH-induced RGC neuroprotection, since GH
treatment of immunopanned RGCs reduces Akt levels
while concomitantly raising the level of phosphorylated
Akt (Akt-phos) [47]. GH-induced RGC neuroprotection
also involves an activation of cytosolic tyrosine kinases
(Trks) and extracellular-signal-related kinases (ERKs) and
the activation of Akt and Trk pathways [48]. These path-
ways converge in the activation of CREB (cAMP response
element binding protein), which initiates the transcription
of pro- or anti-apoptotic genes [48]. These neuroprotective
actions of GH are likely mediated in large part through the
actions of IGF-1, since the simultaneous immunoneutrali-
zation of GH and IGF-1 does not increase the level of
apoptosis in RGC cultures above that achieved by immu-
noneutralization of GH alone [49].
In addition to the chick embryo, GH and GH mRNA are
similarly found in the ganglion cell layer of the neural
retina in fetal rats [51] and neonatal mice [36]. A neuro-
protective role of retinal GH has also been shown in a cell
line derived from the neural retina of embryonic quail, in
which siRNA-mediated GH gene knockdown induces cell
death [52].
Growth hormone is also present in the neural retina of
adult rodents [51,53,54] and is present in the vitreous fluid
of rat eyes, at concentrations in neonates and adults that are
\10% of those in serum [53,54]. The rodent neural retina
is likely to be an autocrine/paracrine site of GH action
since the distribution of GHR immunoreactivity in this
tissue mirrors that of GH [55]. Actions of GH within the
retina are indicated by the increased thickness of its neu-
roblastic, inner plexiform and optic fiber layers in GHR
gene disrupted mice (GHR-/-), in comparison with wild-
type (GHR?/?) littermates [55]. In the absence of GH
signaling, 4 proteins in the retinal proteome of the
GHR-/-mice (identified by 2-D gels and MS) differed in
Endocr (2010) 38:335–359 337
abundance with those in the wild-type mice. Brain abundant
membrane attached signal protein-1 (BASP-1) was down-
regulated, whereas protein kinase C inhibitor-1, cyclophilin
A, KH domain-containing, RNA binding signal transduc-
tion associated protein 3 were upregulated in GHR-/-
mice. These proteins are involved in retinal vasculariza-
tion, neural proliferation, and neurite outgrowth, suggesting
roles for GH in these processes during retinal develop-
ment. The possibility that retinal GH may be neuroprotec-
tive in the rat retina is also suggested by the finding that
the intravitreal administration of SRIF (which blocks
GH release) ameliorated retinal cell death induced by AMPA
(a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid hydro-
bromide) [56]. Other neurophysiological roles of endoge-
nous GH in vision have also been suggested in transgenic
mice overexpressing the bovine GH gene, in which the ERG
response to flashes of light are delayed and reduced in
magnitude [57]. Autocrine or paracrine actions of GH within
the eye are also indicated by the fact that an antisense oli-
gonucleotide targeting the GHR inhibits neovascularization
in a mouse model of diabetic retinopathy [58].
Growth hormone immunoreactivity, identical in size to
pituitary GH, has also been detected in human retinal
extracts and vitreous fluid [59]. This immunoreactivity is
mainly found in the ganglion cell layer of the neural retina
and colocalized with synuclein, an RGC marker [60]. The
presence of GH in the RGCs of elderly patients correlates
with cell survival, as it is not present in apoptotic (TUNEL,
terminal deoxynucleotidyl transferase dUTP nick end
labeling-positive) RGCs, but present in most (67% of)
healthy (TUNEL-negative) RGCs [60]. The loss of RGCs
in diabetics is thus likely to be responsible for the low GH
concentrations in the vitreous of diabetic patients with
ocular dysfunction [61]. Although vitreous GH concentra-
tions in patients with various ocular dysfunctions (epireti-
nal membrane, macular hole, retinal detachment, vitreous
debris, vitreous hemorrhage, subretinal hemorrhage, dis-
located crystalline lens, and central retinal vein occlusion)
are not different from those in cadaver controls with no
history of ocular disease, pituitary GH has been implicated
in the etiology of diabetic retinopathy and in optic nerve
dysfunctions [44]. The possibility that retinal or vitreal GH
might be similarly involved in these disease states has yet
to be determined.
GH in immune tissues
As reviewed previously [1], numerous studies have shown
the presence of GH and GHR and their transcripts in
immune tissues (including the thymus, spleen, tonsils,
lymph nodes, and lymphocytes). Autocrine/paracrine roles
of GH in these tissues have been established. For instance,
it was shown that antisense oligonucleotides for GH
mRNA inhibited lymphocyte proliferation [62], as did the
immunoneutralization of endogenous GH [63]. The
immunoneutralization of lymphocyte GH by GH antibodies
also reduces IGF-1 production and the number of IGF-1
positive lymphocytes [64].
In more recent studies, Recher et al.[65] showed that
GH mRNA, similar in nucleotide sequence to that in the
pituitary, was detectable in the thymus and thymocytes of
the 18-day rat fetus. It was also present in the fetal liver,
but only in circulating lymphocytes and in hematopoietic
cells surrounding the GH mRNA-negative hepatocytes. GH
mRNA was also detected in lymphocytes in the thymus,
spleen, and ileum Peyer’s patches of the adult rat and in the
lymph nodes of dogs [66]. GH mRNA was similarly found
in fetal bovine lymphoid cells (thymocytes and spleno-
cytes) [67] and in human thymocytes and thymic epithelial
cells [68]. Despite having similar or identical GH mRNA,
the GH moieties in human peripheral blood granulocytes
were found to have a higher molecular weight of 37 kDa
and this moiety was retained rather than secreted [69],
suggesting it acts intracellularly. Malarkey et al.[70] found
that the expression of GH mRNA in human lymphocytes
[71,72] was stimulated by Candida (an antibody inducing
antigen) and by interleukin (IL)-12 and suppressed by
cortisol and norepinephrine, at concentrations achievable in
humans during stress. An autocrine or paracrine mecha-
nism of GH action in these lymphocytes was demonstrated
using a pharmaceutical GHR antagonist, B2036, which
blocked endogenous GH-induced IL-12 synthesis and
interferon (IFN) production [70]. The autocrine or para-
crine actions of GH in these immune cells are thought to be
mediated by the PI-3 kinase/Akt pathway (that promotes
cell proliferation) and by the transcription factor NF-kap-
paB (that promotes anti-apoptosis) and by cell cycle
mediators, and by c-Myc and cyclin proteins [73]. GHR
antagonists (B2036 and G120k) similarly demonstrated
that endogenous GH produced in murine immune cells
(Pro-B Ba/F
cells) promoted cell proliferation [73]. These
autocrine or paracrine actins are IGF-1-independent, since
cells do not produce IGF-1 and the actions of GH are
not blocked by IGF-1 antibodies [74].
Growth hormone immunoreactivity is also present in
lymphoid tissues of chickens (spleen, bursa of Fabricius
and thymus), but at concentrations \10% of those in the
pituitary gland [75]. However, because of the much larger
mass of these tissues, the total GH content in these tissues
in 9-week-old birds is 236%, 5.2%, and 32% of that in the
pituitary gland. Moreover, while most of the GH immu-
noreactivity in the pituitary is associated with the 26-kDa
monomer (40%), the glycosylated variant (16%), the 52-
kDa dimer (14%), and the 15-kDa submonomeric isoform
(16%), GH immunoreactivity in chick lymphoid tissues is
338 Endocr (2010) 38:335–359
primarily associated with a 17-kDa moiety, although bands
of 14, 26, 29, 32, 37, 40, and 52 kDa are also present in
these tissues.
The heterogeneous pattern and relative abundance of
bursal GH has been determined during development between
ED 13 and 9 weeks of age. The relative proportion of the
17-kDa moiety is higher (by 45–58%) in post-hatched birds
than in ED 15 and ED 18 embryos (21 and 19%, respec-
tively). The 26-kDa isoform is minimally present in embryos
(\14% of total GH immunoreactivity), but in post-hatched
chicks it increases to 12–20%. Conversely, while the 37-, 40-,
and 45-kDa GH moieties are abundantly present in the
embryonic bursa (approximately 30% at ED 13, 52% at ED
15, and 55% at ED 18), in neonatal and juvenile chicks they
account for \5% of total GH immunoreactivity. These
ontogenic changes are comparable to those previously
reported for similar GH moieties in the chicken testis during
development [76]. These results demonstrate age-related and
tissue-related changes in the content and composition of GH
in the immune tissues of the chicken, in which GH may be an
autocrine or paracrine regulator.
The presence of GH in the bursa of Fabricius reflects the
presence of GH mRNA [77] that is identical in sequence to
that in the pituitary gland [1]. This transcript is mainly
expressed in the cortex of the bursal follicles, comprising
lymphocyte progenitor cells, but is lacking in the medulla,
where lymphocytes mature. In contrast, more GH immu-
noreactivity is present in the medulla than in the cortex of
the follicles. In non-stromal tissues, GH and GH mRNA are
primarily in lymphocytes, and also in macrophage-like
cells and in secretory dendritic cells. In stromal tissues, GH
mRNA, GH, and GHR are expressed in cells near the
connective tissue between follicles and bellow the outer
serosa. In contrast, GH (but not GH mRNA or GHR) is
present in cells of the interfollicular epithelium, the folli-
cle-associated epithelium, and the interstitial corticoepi-
thelium. This mismatch in distribution may reflect dynamic
temporal changes in GH translation. Co-expression of
GHR- and GH-immunoreactivity and GH mRNA and IgG
occurs in immature lymphoid cells near the cortex and in
IgG immunoreactive connective tissue cells, suggesting an
autocrine/paracrine role for bursal GH in B-cell develop-
ment and differentiation. Indeed, while GH is not thought
to be involved in immune system development in mammals
[73], the parallel ontogeny of GH and IgG expressing cells
in the chicken bursa [78] strongly suggests GH involve-
ment in the development of this lymphoid tissue.
GH in reproductive tissues
Growth hormone has well-established roles in male and
female reproduction [7981]. While many of these roles
reflect the actions of pituitary or circulating GH, GH is
produced in many reproductive tissues, in which it may
have autocrine/paracrine actions [82]. Indeed, GH anti-
bodies inhibit the in vitro differentiation of Wolffian ducts
in embryonic rodents [83] and gonadal GH may be
essential for normal reproductive development.
Ovarian tissue
Growth hormone immunoreactivity is not present in the
stromal tissue of bovine ovaries, nor in primordial, pri-
mary, or secondary follicles, but it is present in antral
follicles[2 mm diameter and its abundance increases with
increased follicular size [84]. GH is similarly present in
follicular fluid, in which the concentration is directly
related to oocyte quality (being highest in oocytes that give
rise to embryos with the best morphology and fastest
cleavage rates) [85]. Within the follicles, GH immunore-
activity is present in most granulosa cells and in some, but
not all, thecal cells. GH immunoreactivity is particularly
present in the cumulus cells surrounding the oocyte and
within the oocyte itself [84,86]. As the oocyte and gran-
ulosa cells are avascular, separated from systemic GH by
the basal lamina, GH immunoreactivity in antral follicles is
likely to reflect local GH production. This possibility is
supported by the finding of mRNA for pituitary (hGH-N)
GH in the ovaries of pre- and post-menopausal women
[87]. GH mRNA is similarly expressed in the oocyte and in
the mural granulosa cells surrounding the antral cavity in
bovine follicles, although it is not present in the cumulus
cells of the cumulus oocyte complex (COC) [84].
In birds, GH-immunoreactivity is present in the stromal
tissue of hens before and after the onset of lay and in small
and large follicles, in which it is more intense in granulosa
cells than in thecal cells [88]. This immunoreactivity
reflects the expression of GH mRNA in the follicular epi-
thelium and within granulosa and thecal cells.
The finding of increased GH concentrations in the ovary
during folliculogenesis suggests GH involvement in oocyte
maturation. This possibility is supported by the finding of
GHR protein and GHR mRNA in mural granulosa cells,
cumulus cells, and oocytes [89]. Indeed, it is well estab-
lished that GH accelerates nuclear and cytoplasmic matu-
ration in COCs of cattle [9093], dogs [94], sheep [95], and
mice [96]. This action is IGF-1-dependent in the rat [97],
and rabbit [98] but is IGF-1-independent in the bovine
ovary [89,91,99]. This action is thought to be mediated
through the cumulus cells, since it does not occur in
cumulus-denuded oocytes [97]. GH acts on the cumulus
cells to cause their expansion, as a result of increased
proliferation and reduced apoptosis [99101]. In bovine
COCs [99,102], but not in equine COCs [103], GH
modulates connexin-43 expression and the gap junctions
Endocr (2010) 38:335–359 339
between cumulus cells, through which COC factors regu-
late oocyte maturation. It is also possible that GH acts
directly on the oocyte to induce its maturation, since GHR
mRNA is readily detectable in the oocytes of humans [104,
105], cattle [89,106], horses and pigs [103], and in laying
hens [88] and tilapia [107]. At the cellular level, the GHR
has been localized in the monkey within the oocyte plasma
membrane and in the ooplasm [108].
Uterine tissue
Expression of the GH gene has been demonstrated in
human endometrial tissue [109], in which GH expression is
upregulated in endometriosis and endometrial carcinoma.
Endometrial carcinoma cell lines similarly express the GH
gene [110].
GHR and GHR mRNA are also present in the uterus,
including glandular and stromal cells [111113], the
decidua [114], and myometrium [111]. It is therefore
possible that GH may act in an autocrine or paracrine way
to regulate uterine growth or function. The uterus is a GH
target site since GH promotes uterine growth [115], and the
abundance of uterine GHR is strongly correlated with
estrogen-induced uterine growth [116] and with pregnancy
[117]. GH may thus facilitate implantation, especially as
GHR-KO mice have fewer uterine implantation sites [118].
Mitogenic actions of GH in the uterus have also been
implicated in the etiology of uterine and cervical cancers
[109]. It is therefore of interest that the autocrine produc-
tion of GH in endometrial carcinoma cells stimulates their
in vitro oncogenicity by increasing cell cycle progression,
decreasing apoptotic cell death, and by increasing cell
migration and invasiveness [110].
Mammary tissue
Growth hormone expression has been observed in the
mammary epithelial cells of dogs and cats [119121] and
in both the stromal and epithelial compartments of the
human mammary gland [122]. GH and GH mRNA are
similarly present in the cytoplasm of mouse mammary
epithelial cells, specifically those of the terminal ducts and
terminal end buds (TEBs) [123]. In the mammary glands of
3- and 6-week-old virgin mice, the GH protein is also
localized to the nucleus of epithelial cells. A much weaker
GH signal is also present in some cells of the stromal
compartment, particularly in scattered cells of connective
stroma. In the mouse mammary gland, GH expression is
detectable at 2 weeks of age, is significantly increased at
puberty and is less in adults during pregnancy, lactation,
and involution. The GH protein is not, however, detectable
in the mammary glands of pregnant, lactating, and weaned
females. The mammary expression of GH in the mouse is
thus thought to be of physiological significance in the
morphogenic changes in the mammary gland at puberty
Within mammary epithelial cells, GH has been found
within secretory granules in the dog [119]. GH is secreted
by the mammary epithelial cells and is at concentrations in
milk and colostrum 100- to 1000-fold higher than those in
plasma [124]. Mammary-derived GH is also secreted into
systemic circulation, which is increased in response to
progesterone and may induce an acromegalic-like state
[121]. Mammary-derived GH, acting in an endocrine way,
is also thought to induce endometrial hypertrophy and
cancer in dogs, although this is disputed by Bhatti et al.
The expression of the GH gene in the human mammary
gland has been shown to be Pit-1 dependent [126],
although it is Pit-1-independent in the dog [121]. The
expression of GH in the mammary gland is thought to be
largely dependent upon progesterone [127,128], and
mammary GH production is suppressed by ovariectomy
[129] and by progesterone receptor antagonists [125,130].
It is thus of note that the progesterone receptor is colo-
calized with GH in the mammary gland [130].
Growth hormone receptors have been found in epi-
thelial and stromal compartments of mammary tissue
[131133]. In the dog, maximum GHR expression occurs
during the proliferation phase of mammary development,
coincident with maximum mammary GH expression
[134]. In the mammary gland, GH increases the prolif-
eration and survival of epithelial cells [123]. The impor-
tance of GH in mammary growth is shown in virgin mice,
in which a GHR antagonist (pegvisomant) reduces ductal
outgrowth, ductal branching, the number of TEBs, and the
complexity of the gland [135]. In addition to mammo-
genesis, GH also has well-established roles in galacto-
poiesis and lactation [136,137]. Autocrine GH is,
however, thought to prevent the lactogenic differentiation
of mouse mammary epithelial cells and to reduce the
expression of b-casein and the expression and epithelial
localization of E-cadherin [138].
Placental tissue
In humans, the pituitary GH gene (hGH-N) is not expressed
in the placenta, in which a placental GH gene (hGH-V) is
transcribed into at least three transcripts that are translated
into several placental GH proteins [139] that have auto-
crine or paracrine roles in placental function [140142].
Similar proteins are also produced in the placenta of other
primates [143145], and related proteins are also expressed
in rodents [146,147]. However, as these proteins differ
from pituitary GH, placental GH and its actions are not
considered in this review.
340 Endocr (2010) 38:335–359
In sheep, a transcript identical to pituitary GH mRNA is
expressed in the placenta after day 27 of the first trimester
of pregnancy [148,149]. The expression of this gene peaks
between days 40 and 45 and declines after day 55. This
transcript codes for a 22-kDa protein, as in the pituitary,
and GH immunoreactivity and GH mRNA are localized in
the syncytium and in the trophectoderm [148,149]. Roles
for GH in the sheep placenta are unknown, although the
presence of GHR mRNA in the trophectoderm suggests the
possibility of autocrine or paracrine actions. It is, however,
possible that the GH gene is polymorphic in sheep and
goats [150], with one haplotype expressed in the pituitary
and another expressed in the placenta [142,151].
Testicular tissue
Growth hormone receptors are widespread in the testicular
tissue of fish [152,153], rodents [154], pigs [155], and
humans [156], and GH has numerous effects on sper-
matogenesis and steroidogenesis [81,82]. Circulating GH,
however, cannot readily access testicular cells within the
blood–testis barrier. It is therefore likely that GH actions
on spermatids and spermatozoa (such as an induction of
spermatozoa motility [157]) reflect the local production of
GH within the testis [158]. This possibility is supported by
the discovery of hGH-N immunoreactivity in the human
testis, although hGH-V is the predominant GH mRNA
normally expressed [159161]. The testis is also an ex-
trapituitary site of GH expression in prejerrey fish [162]
and fathead minnows [163], in which GH mRNA abun-
dance increases during sexual development. GH is also
present in the chick testis, in which GH immunoreactivity
in adults is intense and widespread in the seminiferous
tubules [76]. It is not, however, present in the basal com-
partment of rooster Sertoli cells, nor in spermatogonia or
primary spermatocytes, but it is abundant in secondary
spermatocytes and spermatids and in the interstitial cells
and overlying myocytes. The GH immunoreactivity
detected in the chicken testis is primarily (30–50%) asso-
ciated with a 17-kDa moiety and to proteins of 32 and
45 kDa. The relative abundance of these proteins changes
during ontogeny, in that the abundance of 14- and 40-kDa
moieties is decreased while the abundance of 17- and
45-kDa GH moieties is increased with advancing age. GH
mRNA (99.6% identical to pituitary GH mRNA) is also
expressed in the chicken testis, but it is of low abundance
and not detectable by Northern blotting [164]. In contrast
with GH immunoreactivity, GH mRNA is found in sper-
matogonia and primary spermatocytes and is not present in
secondary spermatocytes, spermatids, or spermatozoa
[164]. This suggests that the expression of the GH tran-
script is stage-specific and does not occur in haploid cells.
Prostate tissue
Expression of the GH gene has been demonstrated in
normal prostate biopsies [165], suggesting it may have
local actions in prostate function.
Gastrointestinal tissues
Growth hormone-like immunoreactivity has been detected
in extracts of normal human colon, small intestine, and
stomach [166,167], although only in trace amounts, which
might have little biological significance. Expression of the
GH gene has also been demonstrated in the liver and
pyloric caeca of adult rainbow trout [9].
Hepatic tissues
In humans, low levels of GH immunoreactivity are present
in extracts of normal fetal and adult liver [166,167].
Intense GH immunoreactivity has also been observed in the
liver of early chick embryos prior to the onset of pituitary
GH secretion [20], although this is not present following
the ontogeny of pituitary somatotrophs. Yang et al.[9]
similarly detected GH mRNA in hepatic extracts of fish
embryos. It is, however, possible that this merely reflects
the presence of GH in lymphoid and hematopoietic cells of
the liver, as Recher et al.[65] found that the GH gene was
not expressed in the non-lymphoid hepatocytes of fetal rats.
Pancreatic tissue
Growth hormone-like immunoreactivity has been demon-
strated in normal pancreatic islet cells of fish, cats, pigs,
dogs, and humans [166168]. GH mRNA has also been
detected in normal canine pancreatic tissue by RT-PCR,
which was of increased abundance in tumorous tissue
[170]. GH receptor mRNA is also widespread in the pan-
creas [171], suggesting autocrine or paracrine actions of
pancreatic GH. This possibility is supported by observa-
tions that exogenous GH can stimulate the growth of
islet cells and the secretion of insulin in vitro and in vivo
Salivary tissue
Growth hormone immunoreactivity has been detected in
human parotids [167] and stimulation of rat parotid tissue
with crude hypothalamic extracts can stimulate GH syn-
thesis [175,176]. GH is also present in the submaxillary
gland of normal adult rats [177], and the GH content is
increased almost 20-fold after implantation of a GHRH
pellet into the gland. After GHRH treatment, GH mRNA is
Endocr (2010) 38:335–359 341
also readily detectable by southern blotting and in situ
hybridization. GH and GH mRNA are also present in the
salivary glands of GHRH-treated and untreated normal and
Ames dwarf mice, independently of the Pit-1 transcription
factor required for pituitary GH expression [178]. Roles for
GH in salivary function are largely unknown although the
absence of granular duct cells in glands of transgenic mice
expressing a GH-antagonist and in GHR knockout mice
[179] suggests GH involvement in the differentiation of
this gland and its production of epidermal growth factor.
Other alimentary tissues
Low levels of GH immunoreactivity have been detected in
the tongue, esophagus, stomach, intestine, duodenum,
colon, and liver of fetal and adult humans [166,167], and
GH mRNA is expressed in the intestines of the salmon
[180] and the pyloric ceca of rainbow trout [9], but the
functional significance of these observations is uncertain.
Skeletal tissue
It is well known that GH is important in the regulation of
longitudinal bone growth and bone remodeling, and GH
receptors have been identified in osteocytes [181183]. The
actions of GH in bone formation and bone resorption may
be direct and/or mediated through the local production of
IGF-1 or other growth factors.
The GH IGF-1 axis regulates longitudinal bone growth
at the growth plate [184] and targeted ablation of the GHR,
IGF-1, or IGF-1R thus impairs bone growth [185,186].
This regulation involves endocrine and autocrine/paracrine
mechanisms [187,188]. Locally, injection of GH into the
tibial growth plate accelerates longitudinal growth in
comparison with the vehicle-injected contralateral growth
plate [189]. This action is largely mediated by the local
production of IGF-1 [190,191], although GH may also
have an effect that is independent of both endocrine and
paracrine IGF-1 [186-188]. Indeed, while some of the
actions of GH on bone cells can be blocked by IGF-1
antibodies, other actions are IGF-1-independent [192].
Similarly, the reduced in vivo femur growth in transgenic
mice with GHR deficiency is not fully restored by trans-
genic IGF-1 overexpression [193].
The possibility that GH may have autocrine actions in
the growth plate is supported by the presence of GH
immunoreactivity in the cartilage [167] and synovial fluid
[194,195] of arthritic patients, at concentrations higher
than those in plasma. The presence of comparable levels of
GH immunoreactivity in the synovial fluid of non-arthritic
patients [195] suggests synovial GH is derived from
articular cartilage rather than from immune cells within
inflammed joints. However, as GH is produced in immune
cells, GH may act within articular joints to regulate carti-
lage growth and/or inflammation [196,197]. This may
explain why intra-articular SRIF treatment is effective in
reducing joint pain and synovial thickness [198200].
Indeed, the overexpression of bovine GH in transgenic
mice results in lesions of the articular cartilage that are
consistent with that described in osteoarthritis [201].
Dental tissue
Growth hormone immunoreactivity has been detected in
odontogenic cells in embryonic rats undergoing histodif-
ferentiation, morphodifferentiation, and dentinogenesis
[202]. It is present in cells of the dental epithelium and
mesenchyme at the primordial bud stage (embryonic day
(E) 17 of the 21-day gestation period), prior to the
expression of pituitary GH. At the cap stage of odonto-
genesis (E18–19) numerous cells in the dental epithelium
and mesenchyme are intensely immunoreactive for GH. In
the early bell stage (E20–21, when most histo-differentia-
tion and morpho-differentiation occurs) most of the mes-
enchymal cells in the dental pulp are mildly positive for
GH, while the dental epithelium and adjacent mesenchy-
mal are more GH immunoreactive. In the late bell stage
(postnatal day 0), GH is localized to the dental epithelium,
differentiating mesenchymal cells, preodontoblasts, and
mature odontoblasts. GH immunoreactivity during tooth
development is also present in the extracellular matrix. It is
also located with immunoreactivity for the GHR during
odontogenesis, suggesting autocrine and paracrine roles for
GH during tooth development. This possibility is supported
by the finding that exogenous GH induces cell proliferation
of both the inner dental epithelium and the dental papilla
[203205]. Molar dentin size and shape are also dependent
upon GH status in transgenic mice overexpressing or un-
derexpressing the GH gene and in transgenics lacking the
GH receptor [206]. Cementum production in molar teeth of
the same mice is similarly GH-dependent [207]. These
actions of GH during tooth morphogenesis may be induced
by IGF-1 or by bone morphometric protein (BMP)-4 [206],
which is upregulated by GH stimulation [208,209].
Integumentary tissue
Growth hormone mRNA is expressed in normal human
skin [210] and in dermal fibroblasts [211]. As GHR protein
and GHR mRNA are also present in human skin [212214],
in which GH actions have been described [213], skin may
be an autocrine or paracrine site for GH action.
342 Endocr (2010) 38:335–359
Muscular tissue
It is well established that GH stimulates muscle growth,
directly or via the local production of IGF-1 [215]. It is also
possible that GH may act as an autocrine/paracrine in
muscle tissue to induce cellular proliferation and differ-
entiation. This possibility is supported by studies using C2
C12 myoblast cells, which are able to differentiate into
myotubules when grown in low serum-containing medium.
These cells express GHRs but are unresponsive to exoge-
nous GH [216]. However, in transfected C2 C12 cells that
overexpress the GHR, sera-induced proliferation is inhib-
ited by anti-GH and anti-IGF-1 antibodies. This suggests
local GH production in muscle tissue, as confirmed by RT-
PCR and radioimmunoassay and autocrine or paracrine GH
actions. This is also suggested by GH overexpression in
these cells which is associated with an inhibition of myo-
tubule differentiation. Taken together, these data suggest
that GH acts as an autocrine factor in myoblasts to enhance
proliferation and to inhibit differentiation. These data also
suggest that autocrine GH has greater affinity for the GHR
than exogenous GH or that the GHR is intracellular and not
accessible to exogenous GH.
Growth hormone mRNA has also been found by in situ
hybridization in endothelial cells and the surrounding
smooth muscle cells of veins and arteries in the liver,
spleen, and thymus of rats [65], embryonic chick lungs
[217], and human immune tissues [72], in which the
autocrine production of GH may be involved in tissue
angiogenesis. GH mRNA has similarly been found in
skeletal muscles of chick embryos [14], with a distribution
similar to that of the GHR [20]. GH immunoreactivity is
similarly present in the skeletal muscle of human fetuses
and adults [166,167].
Cardiovascular tissue
Cardiac tissue
Growth hormone has well-established endocrine roles in
cardiac and cardiovascular function [218,219], but it may
also be produced and act within the cardiovascular system.
In addition to its presence in endothelial cells, GH immu-
noreactivity is present in the hearts of early chick embryos
[20]. The possibility that the heart is an autocrine/paracrine
site of GH action is supported by the widespread expres-
sion of the GHR and GH-response gene (GHRG)-1 in the
heart of embryonic chicks [33]. High levels of GH mRNA
have also been found in the heart of embryonic rainbow
trout [9]. The heart is similarly a site of GH expression in
tilapia [220] and in the human fetus [167].
Respiratory tissue
Lung tissue
The presence of GH, GHR, and GHRG-1 in lungs of chick
embryos [20] suggests it might be an autocrine/paracrine
site of GH action. This possibility is supported by the
discovery of GH mRNA, identical in nucleotide sequence
to pituitary mRNA, in the lungs of embryonic chicks [217].
In situ hybridization localized this transcript to mesen-
chymal and epithelial cells of developing lungs, in which
specific GH immunoreactivity is similarly located. Lung
GH immunoreactivity, as in other extrapituitary embryonic
chick tissues, is primarily associated with a 15-kDa moiety.
This immunoreactivity persists after the onset of pituitary
GH secretion (approximately ED 15–ED 17) although GH
mRNA is barely detectable in the lung at this time. The
widespread presence of GHR in the lung during alveolar-
ization suggests the involvement of autocrine or paracrine
GH in lung development in chick embryos.
The onset of lung development and differentiation in
the rat lung also occurs prior to the ontogenic differen-
tiation of pituitary somatotrophs and it too may be
induced by local actions of extrapituitary GH. GH mRNA
is detected in the lungs of fetal rats in mesenchymal cells,
in the mucosal epithelium, and in smooth muscle cells
[221]. This transcript is expressed in the lungs of neonates
until at least 14 days postnatally and is localized to type I
and type II epithelial cells and to pulmonary tissue
macrophages and alveolar macrophages. GH immunore-
activity is specific and parallels the cellular localization
of GH mRNA throughout this period of alveolarization.
Allen et al.[222] similarly found GH mRNA and immu-
noreactivity in rat lung macrophages, and GH immuno-
reactivity has been detected in extracts of fetal and adult
human lungs [166,167].
Autocrine or paracrine actions of GH in the rodent lung
have been shown by GH mRNA knockout, using an aero-
solized antisense oligonucleotide (ODN) directed against
the GH gene [221]. Administration of the GH ODN
decreased lung concentrations of IGF-1 and increased the
concentrations of albumin, calcylin binding protein,
superoxide dismutase, RNA binding protein motif 3 and the
alpha- and beta-subunits of ATP synthase, and electron
transfer flavoprotein. The GH ODN also significantly
altered the abundance of 32 other, unidentified proteins in
the lung. Other proteomic changes in the lungs of
GHR(-/-) mice [223] may similarly reflect a loss of
autocrine or paracrine GH signaling in the lung. Autocrine
or paracrine actions of GH within the lung are also indicated
by proteomic responses to the specific overexpression of
GH within the lung [224]. GH expression increased the lung
concentrations of specific enzymes (nuclear diphosphage
Endocr (2010) 38:335–359 343
kinase B, Cu/Zn superoxide dismutase, glutatinione-S-trans-
ferase, and aldehyde reductase-1) and proteins (beta subunit
G-protein calponin 2, beta 5 tubulin, retinoblastoma binding
protein 4, and fetuin A) while the lung concentrations of
haptoglobin and major acute-phase proteins were reduced.
In addition to the lung, high levels of GH mRNA have been
found in the gills of rainbow trout [9]. The gill may also be
a site of GH gene expression in tilapia [220]. Gills may
also be an autocrine or paracrine site of GH actions since
GHRs are expressed in the gills of salmon [225], flounders
[226], the black porgy [227], and rainbow trout [228], and
actions of GH in osmoregualtion are well established [226].
GH in embryos
Prior to organogenesis and the ontogeny of the pituitary
gland, GH gene expression is widespread in many ex-
trapituitary tissues. For instance, in rodent preimplantation
embryos, GH mRNA and GH immunoreactivity are,
respectively, present at the morula and blastocyst stages of
development [229] after, or coincident with the expression
of the GHR (from day 2). These observations suggest the
involvement of autocrine/paracrine GH in early embryonic
development. The GHR is similarly expressed in bovine
embryos from day 2 and the abundance of the GH tran-
script increases sixfold by day 6 [230]. It is mainly
expressed in the inner cell mass of the blastocyst, where
GHR immunoreactivity is detected from day 3. GH mRNA
is present in bovine embryos from day 8. A functional role
for GH in the blastocyst is shown by the ability of GH
antibodies to inhibit proliferation of the mouse blastocyst
[231]. This autocrine/paracrine action is likely mediated
through the IGF-1 pathway, as the proliferation of the
blastocyst inner cell mass was blocked by an antibody
against the IGF-1 receptor. This antibody did not, however,
block the stimulation of trophectoderm cells induced by
exogenous GH. Markham and Kaye [231] concluded that
(exogenous) GH may selectively regulate the number of
trophoectoderm cells and act in concert with IGF-1 to
stimulate the inner cell mass, and to optimize blastocyst
development. It is, however, possible that the actions of
endogenous GH are mediated through different pathways
to those activated by exogenous GH or that endogenous
GH acts inside the cell, as an intracrine.
As GH is not secreted from chick somatotrophs until ED
15 of the 21-day incubation period, and is not present in
plasma until ED 17 [20], early development of the chick
embryo occurs in the complete absence of pituitary GH but
in the presence of abundant extrapituitary GH [20].
Autocrine or paracrine roles for GH in chick embryonic
development are therefore likely, since mRNA and GHR
mRNA and GH- and GHR immunoreactive proteins are
present in most cells from ED 2 or ED 3 [20]. As organ-
ogenesis proceeds during development, the extrapituitary
distribution of GH becomes more restrictive, presumably
reflecting the extinction of GH expression in specific cells.
GH is, for instance, ubiquitous in the liver in early
embryogenesis but is not present after ED 7 or ED 8 [20].
The involvement of extrapituitary GH in fish develop-
ment is also indicated by the presence of GH transcripts
at very high levels in embryos and larval stages of the
alligator gar Atractosteus spatula [232]. The GH gene is
similarly expressed in extrapituitary tissues prior to (in
zygotes and embryos) and after organogenesis in devel-
oping rainbow trout (Oncorhyncus mykiss [9,233235]),
gilthead seabream (Sparus aurata [236]), silver seabream
(Sparus sarba [237]), Japanese eel (Anguilla japonica
[238]), and orange-spotted grouper (Epinephelus coioides
GH in cancers
Growth hormone and/or GHR expression is correlated with
tumor development in some, but not all, tissues [240], in
which autocrine GH has been implicated in neoplastic
transformation [241].
Human endometrial adenocarcinoma, for instance, is
characterized by an upregulation of GH expression [109],
which is thought to promote cellular proliferation and to
reduce cell-to-cell adhesion, allowing individual cells to
break away from their parent architecture. In endometrial
cancer, autocrine GH may reflect its local production by
endometrial GHRH, as endometrial cancer is regressed by
GHRH antagonists [242], although this may also occur
through GH-independent actions of the antagonist [243].
Autocrine GH is also thought to enhance the in vitro and in
vivo oncogenic potential of endometrial carcinoma cells.
Forced expression of hGH in endometrial carcinoma cell
lines increased their cell number through enhanced cell
cycle progression and decreased apoptotic cell death. In
addition, autocrine hGH expression promoted anchorage-
independent growth and increased cell migration and
invasion in vitro. Autocrine hGH also similarly enhanced
tumor size and progression in a xenograft model of human
endometrial carcinoma [110].
Growth hormone mRNA expression is similarly upreg-
ulated in human primary islet cell adenomas compared
with normal pancreatic tissue, and GH mRNA levels are
highest in metastases [170]. Colorectal cancers have also
been attributed to autocrine/paracrine actions of GH that
may act as a potent mitogen or anti-apoptotic factor in the
344 Endocr (2010) 38:335–359
rapidly renewing epithelial cells of the colon [244]. The
expression of the GH gene in epithelial cells of the thymus
is similarly thought to be causally involved in the induction
of thymoma [245]. GH mRNA and immunoreactivity have
also been detected in canine osteoid-producing tumors
[246]. The finding of GH and GH mRNA in prostate cell
lines [134,247] has similarly suggested the involvement of
autocrine/paracrine GH in prostate tumorigenesis. Indeed,
a disruption of GH signaling has been shown to retard
prostate carcinogenesis in rats [248]. As in the endome-
trium, the production of GH in these cells may be regulated
by GHRH through GHRH receptors, since they express
GHRH mRNA and GHRH receptor mRNA [249] and
GHRH antagonist suppresses prostatic cancer growth
[250]. GH may act locally in prostatic cells since they also
express the GHR gene [247].
Since GH and its receptor are present in immune cells,
immune GH has similarly been implicated in the devel-
opment of leukemia and lymphoma [251]. Indeed, GH may
act in an autocrine fashion in B-cell tumors, as the hGH
gene is expressed in a Burkitt’s lymphoma serum-free
Ramos cell line, in which the proliferation of these cells is
blocked by hGH antiserum [252]. Autocrine or paracrine
actions of GH in lymphoma cells may also reflect the
ability of endogenous GH to induce TGF-b1, which is
similarly blocked by GH antisense oligonucleotides [253].
The induction of TGF-b1 expression by endogenous GH
is not, however, suppressed by GH antibodies. The GH
antibody is thought to immunoneutralize secreted GH and
to block its action on surface GH receptors on these cells,
but it is unlikely to pass the cell membrane and immuno-
neutralize GH within the cell. As most of the GH produced
by lymphocytes remains intracellularly, Farmer and Wei-
gent [253] considered the ability of endogenous GH to
induce TGF-b1 was due to an autocrine or intracrine action
mediated within the cell. Endogenous GH in the same
lymphocyte cells was also found to enhance the production
of nitric oxide (NO), most likely by a mechanism that
involved an increase in the synthesis of nitric oxide syn-
thase and an increase in the transport of arginine, leading to
enhanced cell survival [254]. The overexpression of GH in
these lymphoma cells also results in a decrease in the
production of superoxide (O
) which also protects them
from apoptosis [254]. The antiapoptotic action of GH
overexpression is also due to a decrease in the expression
of bax, BAD, and caspases 3, 8, and 9 and by an increase in
production. These actions are likely mediated through
autocrine or paracrine mechanisms, as DNA fragmentation
is increased when GH expression is prevented by GH
antisense oligonucleotides [255]. The anti-apoptotic action
of GH overexpression is mediated through increased IGF-1
production and IGF-1 receptors, as it is blocked by anti-
bodies to IGF-1 or its receptor [256].
It is well established that the mammary gland is an
extrapituitary site of GH expression and that mammary GH
is an autocrine growth factor that promotes cancer devel-
opment [119,240]. In dogs, progesterone induces the
synthesis of GH in normal and tumorous mammary glands,
in which the GHR is also expressed [134]. Autocrine or
paracrine actions of GH in the canine mammary gland are
thought to be direct or mediated through IGF-1 [120,121].
Mammary GH expression in the human is lowest in
normal tissue, higher in hyperplastic tissues and highest in
metastatic tumors [122]. GH gene expression in normal
glands is restricted to luminal epithelial and myoepi-
thelial cells of ducts and scattered stromal fibroblasts,
whereas GH expression extends to cells of the reactive
stromal (fibroblasts, myofibroblastic cells, and myoepithe-
lial cells) in fibroadenoma, pre-invasive, and metastatic
breast tumors.
Autocrine or paracrine mechanisms of GH action in breast
cancer cells (MCF-7 cells) have largely been determined
by Lobie and coworkers [241]. The induced expression of
hGH in these (MCF-hGH) cells activates intracellular GH
signaling pathways (involving STAT1, STAT3 and STAT5),
which are partially blocked by a GH receptor antagonist
(hGH-G12OR) [257,258]. Expression of the GH gene in
MCF cells also increases their ability to spread in culture
upon a collagen matrix, by increasing the formation of fili-
podia and stress fibers in a JAK2-dependent manner [259].
Enhanced JAK2 tyrosine phosphorylation in MCF-hGH
cells is blocked by B2036, another hGH antagonist, which
also blocks the autocrine GH stimulated increase in total cell
number and DNA synthesis.
Expression of GH in these cells increases cell number by
a mechanism that is also abrogated by a non-receptor-di-
merizing hGH antagonist (hGH-G120R) [259,260]. This
action is direct, since MCF-7 cells do not produce appre-
ciable amounts of IGF-1. Autocrine GH expression also
results in a change in cell morphology, in concert with
increased motility and the acquisition of invasive ability
[123,138]. This metastatic transformation reflects the
disruption of cell contacts, resulting from plakoglobin
downregulation and E-cadherin re-localization from the
periphery to the cytoplasm [261]. The repression of pla-
koglobin gene transcription by autocrine GH results from
increased expression of DNA methyltransferase (DNMT1),
DNMT3A, and DNMT3B, mediated by JAK2 and Src
kinase activity, and direct hypermethylation of the plako-
globin promoter [262].
Increased mitogenesis as a consequence of autocrine GH
production in these cells is prevented by inhibition of either
the p38 MAPK or p42/44 MAPK pathways [259].
Increased activation of the P42/44 kinase pathway is one of
the mechanism by which HOXA1 mediates oncogenic
transformation of human mammary epithelial cells and its
Endocr (2010) 38:335–359 345
downstream activation of EIk-1 mediated transcription
[263]. Other signal transduction pathways also mediate
HOXA1-stimulated oncogenesis, including STAT3, STAT5A,
and STAT5B [264]. Autocrine GH-induced HOXA1 gene
transcription [261,265] also induces oncogenic transfor-
mation in the MCF-7 cell line by upregulating c-Myc, cylin
D1 and Bcl-2 gene transcription [266,267] and by increasing
the activity of PAX (paired box)-5 DNA binding activity, a
nuclear transcription factor [268].
Autocrine GH production in these cells stimulates
transcriptional activation through STAT5, CHOP (p38
MAP kinase specific) or EIk-1 (p44/42 MAP kinase spe-
cific) and this action is similarly blocked by B2036 [260].
This hGHR antagonist also abrogates the potent antiapo-
ptotic action of autocrine GH in protecting MCF-hGH cells
from serum withdrawal [260]. The autocrine actions of
hGH are therefore receptor-mediated. These authors,
Mertani et al. [269] also found that autocrine GH in MCF-
hGH cells upregulates 24 genes and downregulates another
28 genes. CHOP (gadd 153) was one of the upregulated
genes, which results in an increase in the CHOP protein
(a mediator of the antiapoptotic action of autocrine GH),
in a p38 MAPK-dependent manner. The transcriptional
up-regulation of CHOP is therefore one mechanism by
which autocrine hGH increases mammary carcinoma cell
number. Another mechanism involves the transcriptional
repression of the p53-regulated placental transforming
growth factor (PTGH)-bgene, inhibiting its ability to induce
cell cycle arrest and apoptosis [270]. Another mechanism
through which autocrine GH may induce breast carcinoma is
by increasing tumor blood and lymphatic micro-vessel
density [271], by actions blocked by GHR antagonism using
B2036. VEGF (vascular endothelial growth factor) is a
critical regulator of angiogenesis and VEGF-A expression is
greatly increased by autocrine GH in MCF-7 cells [271].
Autocrine production of GH in immortalized human
epithelial cells therefore enhances proliferation and protects
against apoptosis and promotes abnormal mammary acinar
morphogenesis, oncogenic transformation and tumor for-
mation in vivo. The oncogenic and metastatic potential of
forced autocrine GH production is in marked contrast to
exogenous GH, which supports neither tumor formation nor
invasion by human mammary epithelial cells; although it
does promote the proliferation and spreading of mammary
epithelial cells [258,260]. Exogenous GH cannot, however,
mimic the protective effect of autocrine GH against apop-
tosis resulting from serum withdrawal [260]. This selective
effect of endogenous GH may reflect the greater augmenta-
tion of STAT5-mediated gene transcription induced by
autocrine GH compared with exogenous GH [259]. Auto-
crine GH (but not exogenous GH) also inhibits PTGF-bgene
expression [270]. As the GHR is primarily on epithelial cells,
the reduced PTGF must be affecting stromal cell activity in a
paracrine fashion. Higher concentrations of B2036 are also
required to inhibit the action of autocrine GH, suggesting a
difference between endogenous and exogenous GH exists in
GH signaling mechanisms. This possibility is supported
by the fact that microarray analysis of 19,000 human genes
indentified a subset of 305 genes that were differentially
responsive to exogenous and endogenous GH, as well as 167
genes that were regulated in common [272]. Some of the
differentially regulated genes were for trefoil factors (TFFs),
that promote cell survival, anchorage-independent growth,
motility and oncogenic transformation [273,274].
As autocrine GH is more oncogenic than exogenous
(pituitary) GH, selective targeting of autocrine GH may
therefore provide a therapeutic approach to prevent meta-
static extension of human breast carcinoma [273,274].
Consequently, as autocrine GH production was found to
increase the antioxidant capacity of mammary carcinoma
cells and to protect against oxidative stress-induced apop-
tosis (by increasing both the mRNA and protein levels of
catalase, superoxide dismutase 1, glutathione peroxidase,
and glutamyl synthetase, through a p44/42 MAP kinase-
dependent pathway) antagonism of autocrine GH action
has been proposed as a therapeutic regime for mammary
carcinoma [266,267]. Increasing cellular oxidative stress is
a mechanism through which other chemo-therapeutic
agents are effective. The efficacy of SRIF [275] and GHRH
antagonists [276] as antitumor agents may therefore par-
ticularly reflect the blockade of endogenous GH production
in cancerous tissues.
The differential actions of endogenous and exogenous
GH may reflect differences in concentration and secretion,
since endocrine GH is secreted episodically as a bolus,
whereas endogenous GH is thought to be released contin-
uously at low concentrations [268]. Endogenous GH may,
however, be released in closer proximity to GHRs and at
higher microenvironment concentrations than exogenous
GH. Endogenous GH may also act at intracellular receptors
directly after synthesis, in compartments not readily
accessible to exogenous GH. Indeed, van den Eijnden and
Strous [277] demonstrated that autocrine GH binds the GH
receptor immediately after synthesis in the endoplasmic
reticulum and that this facilitates the maturation of the
GHR. The hormone receptor complex is then inserted into
the plasma membrane, where exogenous GH is unable to
bind these receptors, but signal transduction by endogenous
GH only occurs after exiting the endoplasmic reticulum.
This mechanism also explains why GHR antagonists are
sometimes ineffective in blocking the actions of autocrine
GH [241,278]. The differential actions of endogenous and
exogenous GH could also reflect differences in composi-
tion, since GH variants in extrapituitary tissues differ from
those in the pituitary gland, and are largely sub-monomeric
isoforms [36,40,75,76].
346 Endocr (2010) 38:335–359
Autocrine GH is also thought to act through nuclear
receptors. Indeed, the progression of uterine cervical car-
cinoma in women has also been correlated with the
appearance of the GHR in the nucleus of cancerous cells
[279], and nuclear GHR expression is similarly a marker of
tumorigenesis in other cancerous cells [241,280]. Nuclear
targeting of the GH receptor is thought to induce cell
proliferation, a dysregulated proliferative arrest and an
induction of cell cycle progression, through increased
expression of the proliferation-related proteins Survivin
and Mybbp [280]. Nuclear targeting of the GH receptor by
autocrine GH and dysregulation of cell cycle progression is
also associated with the expression of Dysadherin, which
destabilizes cadherin-based cell contacts, leading to onco-
genic transformation [280,281].
Growth hormone-immunoreactivity, detected by ELISA,
radioimmunoassay, immunocytochemistry, or western
blotting, is present in many extrapituitary tissues. While this
immunoreactivity is often at trace concentrations [166,167],
in many studies it is at concentrations greater than those in
blood plasma [75,76,282]. It is also present in tissues that
are avascular (e.g., in granulosa cells of the ovary [84])
or physically separated from blood by barrier systems
(e.g., in brain tissues [16] and testicular tissues [76,164])
and therefore unlikely to be derived from the circulation.
Extrapituitary GH is also present in early development, prior
to the presence of GH in the pituitary gland or in general
circulation [15,18]. It is also present in adults after pituitary
GH senescence, when circulation GH levels are low or
undetectable [283285]. The presence of GH in extrapitu-
itary tissues is therefore likely to reflect its local production.
The possibility that extrapituitary GH is produced locally
is supported by the demonstration that de novo GH synthesis
has been demonstrated in some extrapituitary tissues, e.g., in
lymphocyte cells [286], in testicular cells [287], and in the
salivary gland [177]. Rat lymphocytes, for instance, produce
a GH cDNA that is identical to pituitary GH cDNA in its
nucleotide sequence and codes for the same protein [288,
289], which is released from lymphocytes in vitro [286].
This possibility is also supported by the demonstration that
GH mRNA, identical to that in the pituitary gland, is, for
instance, present in hypothalamic and extra-hypothalamic
regions of the chicken brain [290], in the chick neural retina
[35], in chicken immune tissues [77,78,291], in the chicken
testis [164], and in the chicken lung [217]. In summary, it is
now well established that authentic GH moieties are present
in many extrapituitary tissues in which they are produced.
Although extrapituitary GH is unlikely to be of biological
importance when present in trace amounts, the local
production of GH in some extrapituitary tissues (e.g., in the
immune and nervous systems) is significant and at contents
and concentrations comparable to those in the pituitary gland
[282]. Extrapituitary GH, in most cases, is not, however,
thought to contribute to the pool of GH in systemic circula-
tion, since it is well established that GH in systemic circu-
lation is largely derived from pituitary somatotrophs, as
serum GH concentrations are undetectable or barely detect-
able following hypophysectomy. Mammary GH expression
may, however, contribute to circulating GH concentrations
and have endocrine actions that may be of physiological and
pathological relevance. Indeed, GH overexpression in the
mammary gland is responsible for elevated plasma GH
concentrations in cycling dogs, since their circulating GH
concentrations are suppressed by mammectomy rather than
by hypophysectomy [292]. This overexpression of mam-
mary GH is also responsible for the induction of an acro-
megalic-like state in bitches [120,121] and may induce
endometrial hypertrophy [125].
Most extrapituitary GH is not, however, thought to
contribute to the systemic GH pool, and it is thus unlikely
to be involved in endocrine function and hence with whole-
body growth during development [18,19]. A deficiency of
extrapituitary GH is thus unlikely to result in a dwarf
phenotype (the hallmark of deficient pituitary GH pro-
duction or deficient pituitary GH signaling). Deficiencies in
the production or action of extrapituitary GH can, however,
result in physiological dysfunctions, demonstrating the
functional importance of extrapituitary GH as an autocrine
or paracrine regulator.
Table 1 Functional autocrine/paracrine actions of endogenous extrapi-
tuitary GH
Blocker of
endogenous GH
Functional response Species References
GH siRNA :cell death Chicken [52]
GH siRNA ;neurite length Chicken [43]
GH antisense ;neovascularization Mouse [58]
GH antisense ;cell proliferation Rat [62]
GH antisense altered proteome Rat [221]
GH antisera :cell death Chicken [4649]
GH antisera ;cell proliferation Mouse [216,231]
GH antisera ;cell proliferation Human [63]
GH antisera :neuronal differentiation Mouse [11]
GH antisera ;Wolffian duct
Mouse [83]
GH antisera ;IGF-1 expression Rat [64]
SRIF :neuronal differentiation Mouse [11]
:cell death Mouse [73]
GHR antagonist ;cytokine production Human [70]
Endocr (2010) 38:335–359 347
Functional roles for extrapituitary GH have been clearly
demonstrated by the abrogated responses that occur when
extrapituitary GH synthesis or secretion is blocked by
siRNA-knockdown, by GH antisense oligonucleotides, or
by SRIF antagonism or when local GH action is blocked by
GHR antagonism (Table 1). Functional roles for GH in
local sites of production and action are also supported by
studies on the transgenic expression of heterologous GH
genes in specific regions of the rodent CNS, especially as
the phenotypes induced after local GH expression differ
from those following the overexpression of GH systemi-
cally (Table 2). For instance, the specific overexpression of
bovine (b) GH in the CNS of mice, using the promoter to
glial acidic fibrillary protein (GFAP), results in hyperpha-
gia-induced obesity [293], whereas mice that systemically
overexpress the bGH gene have unchanged food intake
[293,294] and a reduced percentage of body fat mass
[295]. The increased hyperphagia in mice that trans-
genically express GH in the CNS reflects the autocrine
or paracrine induction of two orexigenic hypothalamic
neuropeptides, agouti-related protein, and neuropeptide Y
[293]. Similarly while the systemic overexpression of bGH,
results in increased body size in transgenic mice [295], the
specific overexpression of human (h) GH in the cerebral
cortex [296], or in hypothalamic GRF neurons [297299]
or in hypothalamic vasopressin neurons [300] results in
dwarfism. This induction of dwarfism results from local
GH actions that increase SRIF tone and decreases GRF,
thereby inhibiting pituitary GH secretion.
Functional autocrine or paracrine actions of extrapitu-
itary GH have also been comprehensively demonstrated by
the blockade of GH production and/or GH action in non-
pituitary cells in vitro (Table 3) and by the forced
expression of heterologous GH genes in carcinoma cell
lines (Table 4). These studies have also shown that some of
the autocrine or paracrine actions of extrapituitary GH are
dissimilar to the endocrine actions of pituitary (exogenous)
GH. This difference is probably because of differences
in GH concentration or patterns of GH secretion, and
differences in GHR proximity and location. The signaling
mechanisms utilized by GH in carcinoma cells may also
differ from those in non-carcinoma cells and promote
oncogenesis [241]. In summary, functional roles for ex-
trapituitary GH have been clearly established both in vivo
and in vitro. GH should therefore be considered, like IGF-1
[301,302] and prolactin [303], as a local growth factor, as
well as an endocrine hormone.
As all cells in an individual have the same genome, all cells
have the potential to express the same genes. The ex-
trapituitary expression of the GH gene is therefore not an
oddity and is consistent with the widespread expression of
other pituitary hormones (e.g., the extrapituitary expression
of prolactin in the placenta, uterus, ovary, testis, mammary
Table 2 Functional autocrine/
paracrine actions of endogenous
extrapituitary GH
Induced GH expression in specific
extra-pituitary sites
Functional response Species References
bGH in CNS hyperphagia-induced obesity
:hypothalamic expression of NPY and
agouti-related protein
Mice [293]
hGH in cerebral cortex :dwarfism
:hypothalamic SRIF mRNA
;hypothalamic GRF mRNA
Mice [296]
hGH in GRF neurons :dwarfism
:hypothalamic SRIF mRNA
;hypothalamic GRF mRNA
Rat [297]
hGH in vasopressin neurons :dwarfism Rat [300]
Table 3 Functional autocrine/paracrine actions of endogenous GH in
Blocker of
endogenous GH
Functional response References
GH antisense ;cytokine production [253]
GH antisense :DNA fragmentation [255]
GH antisera ;cell proliferation [253]
GHR antagonist
;cell proliferation
;cell spreading
;intracellular signaling/
transcriptional activity
;anchorage-independent growth
;cell survival
;cell migration
;cell invasion
;VEGF-A1 expression
GHR antagonist
;cell proliferation [259]
348 Endocr (2010) 38:335–359
gland, prostate, brain, adipose tissue, immune tissue, and
skin [304] and in cancerous tissues [305]). It is also con-
sistent with the occurrence of ectopic hormone syndromes
[306308], leaky gene phenomena [309], and the finding of
proteins in ‘aberrant’ locations [310]. Moreover, although
the pituitary expression of GH was thought to be due to the
pituitary-specific expression of its pit-1 transcription factor,
pit-1 is now known to be similarly expressed in many
extrapituitary tissues [311]. It is therefore not surprising
that GH expression is widespread and in many tissues,
although GH expression is not pit-1-dependent in all tissues
[311]. The expression of GH in pituitary and extrapituitary
tissues may therefore be differentially regulated, as indi-
cated by the expression of GH in the hippocampus and
salivary glands of pituitary GH-deficient dwarf mice [7,8,
178], in which GH deficiency results from a mutation in
prop-1, an upstream transcription factor for Pit-1. GH
expression in immune tissues may similarly be differen-
tially regulated from that in the pituitary gland [312].
The widespread extrapituitary expression of the GH
gene is now an established fact but the mere presence of
GH in extrapituitary tissues does not, by itself, provide
Table 4 Functional autocrine/
paracrine actions of endogenous
GH in oncogenesis
Cancerous cell line Functional response to forced hGH expression References
MCF-7 (human mammary
carcinoma cells)
:cell proliferation
;cell death
:cell spreading
:filipodia stress fibers
:JAK2 activity
:STAT5 activity
:P38 MAP kinase activity
:p44/42 MAP kinase activity
:cytoplasmic phosphotyrosine
MCF-7 :anchorage-independent growth
:oncogenic transformation
:tumor formation in vivo
:HOXA1 expression
:cMyc expression
:cyclin D expression
MCF-7 :antioxidant activity
:catalase activity
:superoxide dismutase activity
:glutathione peroxidase activity
:glutamyl synthetase activity
MCF-7 increased DNA methyltransferase (DNMT-I,
DNMT-3A, DNMT-3B) expression
MCF-7 :PAX 5 DNA binding activity [268]
MCF-7 ;placental transforming growth factor bgene expression [270]
MCF-7 :trefoil factor (TFF3) expression [272]
MCF-7 ;plakoglobin expression
;relocalization of E-cadherin from periphery to cytoplasm
;metastatic transformation of cells
:cell motility
:matrix metalloproteinase activity
HCII mouse (mouse
epithelial cells)
:cell survival
;bcasein expression
;E-cadherin expression and loss of epithelial localization
RL95-2/AN2 (human
carcinoma cells)
:cell migration
:tumor progression in vivo
Endocr (2010) 38:335–359 349
evidence of extrapituitary GH action. Although most tis-
sues and most cells have GHRs [313315], tissue GH
concentrations are largely unknown, as is the GH concen-
tration required to activate local GHRs. Moreover, while
GH immunoreactivity may be detected in a tissue, this may
not correlate with GH bioactivity [316,317] and the
presence of GH mRNA may not correlate with the presence
of GH protein or with identical GH isoforms [164]. The
putative actions of GH in extrapituitary tissues are there-
fore largely speculative and based on the established
actions of exogenous (pituitary) GH in the same tissues. In
the absence of model systems to differentiate between
pituitary and extrapituitary GH actions, functional roles for
extrapituitary GH are indicated by the abrogated in vivo
and in vitro biological responses observed after the
blockade of local GH production or action and by the
induction of physiological and phenotypic responses fol-
lowing locally induced GH expression (Tables 1,2,3,4).
The importance of extrapituitary GH as a local growth
factor is, however, difficult to assess, in view of the
plethora of other autocrines/paracrines involved in growth
and metabolism [19] and the existence of compensatory
pathways that may maintain homeostasis in the absence of
any one factor. Indeed, even the roles for pituitary GH in
growth and development are sometimes difficult to assess,
as some whole-body growth still occurs in the complete
absence of circulating GH and in conditions of GH resis-
tance [318]. Further research on the physiological signifi-
cance of extrapituitary GH is therefore warranted.
Acknowledgments Supported by NSERC of Canada.
1. S. Harvey, K.L. Hull, Growth hormone: a paracrine growth
factor? Endocrine 7, 267–279 (1997)
2. J.R. Castro, J.A. Costoya, R. Gallego, A. Prieto, V.M. Arce, R.
Senaris, Expression of growth hormone receptor in the human
brain. Neurosci. Lett. 281, 147–150 (2000)
3. H. Yoshizato, T. Fujikawa, H. Soya, M. Tanaka, K. Nakashima,
The growth hormone (GH) gene is expressed in the lateral hypo-
thalamus: enhancement by GH-releasing hormone and repression
by restraints stress. Endocrinology 139, 2545–2551 (1998)
4. H. Yoshizato, T. Fujikawa, M. Shibata, M. Tanaka, K. Naka-
shima, Stimulation of growth hormone gene expression in the
pituitary and brain by Panax ginseng C. A. MEYER. Endocr. J.
46, S85–S88 (1999)
5. C.P. Donahue, K.S. Kosik, T.J. Shors, Growth hormone is
produced within the hippocampus where it responds to age, sex,
and stress. Proc. Natl Acad. Sci. 103, 6031–6036 (2006)
6. C.P. Donahue, R.V. Jensen, T. Ochiishi, I. Eisenstein, M. Zhao,
T. Shors, K.S. Kosik, Transcriptional profiling reveals regulated
genes in the hippocampus during memory formation. Hippo-
campus 12, 821–833 (2002)
7. L.Y. Sun, M.S. Evans, J. Shieh, J. Panici, A. Bartke, Increased
neurogenesis in dentate gyrus of long-lived Ames dwarf mice.
Endocrinology 146, 1138–1144 (2005)
8. L.Y. Sun, K. Al-Regaiety, M.M. Maternak, J. Wang, A. Bartke,
Local expression of GH and IGF-1 in the hippocampus of GH-
deficient long-lived mice. Neurobiol. Aging 26, 929–937 (2005)
9. B.Y. Yang, M. Green, T.T. Chen, Early embryonic expression of
the growth hormone family protein genes in the developing
rainbow trout, Oncorhynchus mykiss. Mol. Reprod. Dev. 53,
127–134 (1999)
10. A. Scheepens, C.E. Williams, B.H. Breier, J. Guan, P.D.
Gluckman, A role for the somatotropic axis in neural develop-
ment, injury and disease. J. Pediatr. Endocrinol. Metab. 13,
1483–1491 (2000)
11. A.M. Turnley, C.H. Faux, R.L. Rietz, J.R. Coonan, P.F. Bartlett,
Suppressor of cytokine signaling 2 regulates neuronal differen-
tiation by inhibiting growth hormone signaling. Nat. Neurosci.
5, 1155–1162 (2002)
12. R. Ramesh, W.J. Kuenzel, J.D. Buntin, J.A. Proudman, Identi-
fication of growth hormone- and prolactin-containing neurons
within the avian brain. Cell Tissue Res. 299, 371–383 (2000)
13. S. Harvey, C.D. Johnson, E.J. Sanders, Growth hormone in
neural tissues of the chick embryo. J. Endocrinol. 169, 487–498
14. A.E. Murphy, S. Harvey, Extrapituitary beta TSH and GH in early
chick embryos. Mol. Cell. Endocrinol. 185, 161–171 (2001)
15. S. Harvey, C.D. Johnson, P. Sharma, E.J. Sanders, K.L. Hull,
Growth hormone: a paracrine growth factor in embryonic
development? Comp. Biochem. Physiol. C: Pharmacol. Toxicol.
Endocrinol. 119, 305–315 (1998)
16. S. Harvey, K.L. Hull, Neural growth hormone: an update.
J. Mol. Neurosci. 20, 1–14 (2003)
17. A.E. Murphy, H. Peek, M.-L. Baudet, S. Harvey, Extrapituitary
GH in the chicken: underestimation of immunohistochemical
staining by Carnoy’s fixture. J. Endocrinol. 177, 223–234 (2003)
18. E.J. Sanders, S. Harvey, Growth hormone as an early embryonic
growth and differentiation factor. Dev. Dyn. 209, 1–9 (2004)
19. E.J. Sanders, S. Harvey, Peptide hormones as developmental
growth and differentiation factors. Dev. Dyn. 237, 1537–1552
20. S. Harvey, C.D. Johnson, E.J. Sanders, Extra-pituitary growth
hormone in peripheral tissues of early chick embryos. J. Endo-
crinol. 166, 489–502 (2000)
21. M. Coculescu, Blood–brain barrier for human growth hormone
and insulin-like growth factor-I. J. Pediatr. Endocrinol. Metab.
12, 113–124 (1999)
22. W. Pan, Y. Yu, C.M. Cain, F. Nyberg, P.O. Couraud, A.J. Ka-
stin, Permeation of growth hormone across the blood–brain
barrier. Endocrinology 146, 4898–4904 (2005)
23. Z. Poljakovic, N. Zurak, V. Brinar, M. Korsic, S. Basic, S.
Hajnsek, Growth hormone and insulin growth factor-I levels in
plasma and cerebrospinal fluid of patients with multiple scle-
rosis. Clin. Neurol. Neurosurg. 108, 255–258 (2006)
24. E. Bilic, E. Bilic, I. Rudan, V. Kusec, N. Zurak, D. Delimar, M.
Zagar, Comparison of growth hormone, IGF-1 and insulin in
cerebrospinal fluid and serum between patients with motor neuron
disease and healthy controls. Eur. J. Neurol. 13, 1340–1345 (2007)
25. H.J. Schneider, U. Pagotto, G.K. Stalla, Central effects of the
somatotropic system. Eur. J. Endocrinol. 149, 377–392 (2003)
26. A. Scheepens, T.A. Moderscheim, P.D. Gluckman, The role of
growth hormone in neural development. Horm. Res. 64, 66–72
27. N.D. Aberg, K. Gustafson Brywe, J. Isgaard, Aspects of growth
hormone and insulin-like growth factor-I related to neuropro-
tection, regeneration, and functional plasticity in the adult brain.
Sci. World J. 6, 53–80 (2006)
28. J. Isgaard, N.D. Aberg, M. Nilsson, Protective and regenerative
effects of the GH/IGF-I axis on the brain. Min. Endocrinol. 32,
103–113 (2007)
350 Endocr (2010) 38:335–359
29. A. Scheepens, E. Sirimanne, E. Beiharz, B.H. Breier, M.J.
Waters, P.D. Gluckman, C.E. Williams, Alterations in the neural
growth hormone axis following hypoxic–ischemic brain injury.
Brain Res. Mol. Brain Res. 68, 88–100 (1999)
30. A. Scheepens, E. Sirimanne, B.H. Breier, R.G. Clark, P.D.
Gluckman, C.E. Williams, Growth hormone as a neuronal res-
cue factor during recovery from CNS injury. Neuroscience 104,
677–687 (2001)
31. L. Krulich, A.P. Dhariwal, S.M. McCann, Stimulatory and
inhibitory effects of purified hypothalamic extracts on growth
hormone release from rat pituitary in vitro. Endocrinology 83,
783–790 (1968)
32. S. Harvey, I. Lavelin, M. Pines, Growth hormone (GH) action in
the brain: neural expression of a GH-response gene. J. Mol.
Neurosci. 18, 89–95 (2003)
33. S. Harvey, I. Lavelin, M. Pines, Growth hormone (GH) action in
early embryogenesis: expression of a GH-response gene is sites
of GH production and action. Anat. Embryol. 204, 503–510
34. M.-L. Baudet, D. Rattray, S. Harvey, Growth hormone and its
receptor in projection neurons of the chick visual system: ret-
inofugal and tectobulbar tracts. Neuroscience 148, 151–163
35. M.-L. Baudet, E.J. Sanders, S. Harvey, Retinal growth hormone
in the chick embryo. Endocrinology 144, 5459–5468 (2003)
36. S. Harvey, B.T. Martin, M.-L. Baudet, P. Davis, Y. Sauve, E.J.
Sanders, Growth hormone in the visual system: comparative
endocrinology. Gen. Comp. Endocrinol. 153, 124–131 (2007)
37. E.J. Sanders, M.A. Walter, E. Parker, C. Aramburo, S. Harvey,
Opticin binds retinal growth hormone in the embryonic vitreous.
Invest. Ophthalmol. Vis. Sci. 44, 5404–5409 (2003)
38. S. Harvey, M. Kakebeeke, E.J. Sanders, Growth hormone
localization in the neural retina and retinal pigmented epithe-
lium of embryonic chicks. J. Mol. Neurosci. 22, 139–145 (2004)
39. S. Harvey, M. Kakebeeke, A.E. Murphy, E.J. Sanders, Growth
hormone in the nervous system: autocrine or paracrine roles in
retinal function? Can. J. Physiol. Pharmacol. 81, 371–384
40. S. Takeuchi, M. Haneda, K. Teshigawara, S. Takahashi, Iden-
tification of a novel GH isoform: a possible link between GH
and melanocortin systems in the developing chicken eye.
Endocrinology 142, 5158–5166 (2001)
41. M.-L. Baudet, S. Harvey, Small chicken growth hormone
(scGH) variant in the neural retina. J. Mol. Neurosci. 31,
261–271 (2007)
42. M.-L. Baudet, B. Martin, Z. Hassanali, E. Parker, E.J. Sanders, S.
Harvey, Expression, translation, and localization of a novel, small
growth hormone variant. Endocrinology 148, 103–115 (2007)
43. M.-L. Baudet, D. Rattray, B.T. Martin, S. Harvey, Growth
hormone promotes axon growth in the developing nervous
system. Endocrinology 150, 2758–2766 (2009)
44. S. Harvey, M.-L. Baudet, E.J. Sanders, Growth hormone and
developmental ocular function: clinical and basic studies.
Pediatr. Endocrinol. Rev. 5, 510–515 (2007)
45. S. Harvey, M.-L. Baudet, E.J. Sanders, Growth hormone-
induced neuroprotection in the neural retina during chick
embryogenesis. Ann. N. Y. Acad. Sci. 1163, 414–416 (2009)
46. E.J. Sanders, E. Parker, C. Aramburo, S. Harvey, Retinal growth
hormone is an anti-apoptotic factor in embryonic retinal gan-
glion cell differentiation. Exp. Eye Res. 81, 551–560 (2005)
47. E.J. Sanders, E. Parker, S. Harvey, Retinal ganglion cell survival
in development: mechanisms of retinal growth hormone action.
Exp. Eye Res. 83, 1205–1214 (2006)
48. E.J. Sanders, E. Parker, S. Harvey, Growth hormone-mediated
survival of embryonic retinal ganglion cells: signaling mecha-
nisms. Gen. Comp. Endocrinol. 156, 613–621 (2008)
49. E.J. Sanders, M.-L. Baudet, E. Parker, S. Harvey, Signaling
mechanisms mediating local GH action in the neural retina of
the chick embryo. Gen. Comp. Endocrinol. 163, 63–69 (2009)
50. S. Harvey, M.-L. Baudet, E.J. Sanders, Growth hormone and
cell survival in the neural retina: caspase dependence in inde-
pendence. Neuroreport 17, 1715–1718 (2006)
51. S. Harvey, M.-L. Baudet, E.J. Sanders, Retinal growth hormone
in perinatal and adult rats. J. Mol. Neurosci. 28, 257–264 (2006)
52. E.J. Sanders, W.Y. Lin, E. Parker, S. Harvey, Growth hormone
expression and neuroprotective activity in a quail neural retina
cell line. Gen. Comp. Endocrinol. 165, 111-119 (2010)
53. H.D. Modanlou, Z. Gharraee, J. Hasan, J. Waltzman, S. Nage-
otte, K.D. Beharry, Ontogeny of VEGF, IGF-I, and GH in
neonatal rat serum, vitreous fluid, and retina from birth to
weaning. Invest. Ophthalmol. Vis. Sci. 47, 738–744 (2006)
54. K.D. Beharry, H.D. Modanlou, J. Hasan, Z. Gharraee, P. Abad-
Santos, J.H. Sills, A. Jan, S. Nageotte, J.V. Aranda, Comparative
effects of early postnatal ibuprofen and indomethacin on VEGF,
IGF-I, and GH during rat ocular development. Invest. Oph-
thalmol. Vis. Sci. 47, 3036–3043 (2006)
55. M.-L. Baudet, Z. Hassanali, G. Sawicki, E.O. List, J.J. Kopchick,
S. Harvey, Growth hormone action in the developing neural ret-
ina: a proteomic analysis. Proteomics 8, 389–401 (2008)
56. R. Kiagiadaki, K. Thermos, Effect of intravitreal administration
of somatostatin and sst
analogs on AMPA-induced neurotox-
icity in rat retina. Invest. Ophthalmol. Vis. Sci. 49, 3080–3089
57. B.T. Martin, E.O. List, J.J. Kopchick, Y. Sauve, S. Harvey,
Growth hormone overexpression is associated with selective
inner retina dysfunction. Growth Horm. IGF Res. (2010),
58. J.L. Wilkinson-Berka, S. Lofthouse, K. Jaworski, S. Ninkovic,
G. Tachas, C.J. Wraight, An antisense oligonucleotide targeting
the growth hormone receptor inhibits neovascularization in a
mouse model of retinopathy. Mol. Vis. 13, 1529–1538 (2007)
59. S. Harvey, E. Parker, I. MacDonald, E.J. Sanders, Growth hor-
mone is present in the human retina and vitreous fluid. Neurosci.
Lett. 455, 199–202 (2009)
60. E.J. Sanders, E. Parker, S. Harvey, Endogenous growth hormone
in human retinal ganglion cells correlates with cell survival.
Mol. Vis. 15, 920–926 (2009)
61. M. Ziaei, M. Tennant, E.J. Sanders, S. Harvey, Vitreous growth
hormone and visual dysfunction. Neurosci. Lett. 460, 87–91
62. D.A. Weigent, J.E. Blalock, R.D. LeBoeuf, An antisense oli-
godeoxynucleotide to growth hormone messenger ribonucleic
acid inhibits lymphocyte proliferation. Endocrinology 128,
2053–2057 (1991)
63. P. Sabharwal, S. Varma, Growth hormone synthesized and
secreted by human thymocytes acts via insulin-like growth
factor I as an autocrine and paracrine growth factor. J. Clin.
Endocrinol. Metab. 81, 2663–2669 (1996)
64. J.B. Baxter, J.E. Blalock, D.A. Weigent, Characterization of
immunoreactive insulin-like growth factor-I from leukocytes
and its regulation by growth hormone. Endocrinology 129,
1727–1734 (1991)
65. S. Recher, M. Raccurt, A. Lambert, P.E. Lobie, H.C. Mertani,
G. Morel, Prenatal and adult growth hormone gene expression in
rat lymphoid organs. J. Histochem. Cytochem. 49, 347–354
66. I.S. Lantinga van Leeuwen, E. Teske, E. van Garderen, J.A. Mol,
Growth hormone gene expression in normal lymph nodes and
lymphomas of the dog. Anticancer Res. 20, 2371–2376 (2000)
67. H.T. Chen, L.A. Schuler, R.D. Schultz, Growth hormone and
Pit-1 expression in bovine fetal lymphoid cells. Dom. Anim.
Endocrinol. 14, 399–407 (1997)
Endocr (2010) 38:335–359 351
68. V. De Mello-Coelho, M.C. Gagnerault, J.C. Souberbielle, C.J.
Strasburger, W. Savino, M. Dardenne, M.C. Postel-Vinay,
Growth hormone and its receptor are expressed in human thymic
cells. Endocrinology 139, 3837–3842 (1998)
69. R. Kooijman, S. Gerlo, A. Coppens, E.L. Hooghe-Peters,
Growth hormone and prolactin expression in the immune sys-
tem. Ann. N. Y. Acad. Sci. 917, 534–540 (2000)
70. W.B. Malarkey, J. Wang, C. Cheney, R. Glaser, H. Nagaraja,
Human lymphocyte growth hormone stimulates interferon
gamma production and is inhibited by cortisol and norepi-
nephrine. J. Neuroimmunol. 123, 180–187 (2002)
71. H. Wu, J. Wang, J.T. Cacioppo, R. Glaser, J.K. Kiecolt-Glaser,
W.B. Malarkey, Chronic stress associated with spousal care-
giving of patients with Alzheimer’s dementia is associated with
downregulation of B-lymphocyte GH mRNA. J. Gerontol.
A Biol. Sci. Med. Sci. 54, M212–M215 (1999)
72. H. Wu, R. Devi, W.B. Malarkey, Localization of growth hor-
mone messenger ribonucleic acid in the human immune system-
a clinical research center study. J. Clin. Endocrinol. Metab. 81,
1278–1282 (1996)
73. S. Jeay, G.E. Sonenshein, M.C. Postel-Vinay, E. Baixeras,
Growth hormone prevents apoptosis through activation of
nuclear factor-kappa bin interleukin-3-dependent Ba/F3 cell
line. Mol. Endocrinol. 14, 650–661 (2000)
74. E. Baixeras, S. Jeay, P.A. Kelly, M.C. Postel-Vinay, The pro-
liferative and antiapoptotic actions of growth hormone and
insulin-like growth factor-1 are mediated through distinct sig-
naling pathways in the Pro-Ba/F
cell line. Endocrinology 142,
2968–2977 (2001)
75. M. Luna, N. Barraza, L. Berumen, M. Carranza, E. Pedernera, S.
Harvey, C. Aramburo, Heterogeneity of growth hormone
immunoreactivity in lymphoid tissues and changes during
ontogeny in domestic fowl. Gen. Comp. Endocrinol. 144, 28–37
76. M. Luna, L. Huerta, L. Berumen, H. Martinez-Coria, S. Harvey,
C. Aramburo, Growth hormone in the male reproductive tract of
the chicken: heterogeneity and changes during ontogeny and
maturation. Gen. Comp. Endocrinol. 137, 37–49 (2004)
77. M. Luna, A.J. Rodriguez-Mendez, L. Berumen, M. Carranza, J.
Riesgo-Escovar, M.-L. Baudet, S. Harvey, C. Aramburo,
Immune growth hormone (GH): localization of GH and GH
mRNA in the bursa of Fabricius. Dev. Comp. Immunol. 32,
1313–1325 (2008)
78. A.J. Rodriguez-Mendez, J.L. Luna-Acosta, M. Carranza, S.
Harvey, C. Aramburo, Growth hormone expression in stromal
and non-stromal cells in the bursa of Fabricius during brusal
development and involution: causal relationships? Gen. Comp.
Endocrinol. 165, 297-307 (2010)
79. K.L. Hull, S. Harvey, Growth hormone: roles in female repro-
duction. J. Endocrinol. 168, 1–23 (2001)
80. K.L. Hull, S. Harvey, GH as a co-gonadotropin: the relevance of
correlative changes in GH secretion and reproductive state.
J. Endocrinol. 172, 1–19 (2002)
81. K.L. Hull, S. Harvey, Growth hormone: a reproductive endo-
crine-paracrine regulator? Rev. Reprod. 5, 175–182 (2000)
82. K.L. Hull, S. Harvey, Growth hormone: roles in male repro-
duction. Endocrine 13, 243–250 (2000)
83. A.P. Nguyen, A. Chandorkar, C. Gupta, The role of growth
hormone in fetal mouse reproductive tract differentiation.
Endocrinology 137, 3659–3666 (1996)
84. F. Izadyar, J. Zhao, H.T. Van Tol, B. Colenbrander, M.M.
Beavers, Messenger RNA expression and protein localization of
growth hormone in bovine ovarian tissue and in cumulus
oocytes complexes (COCs) during in vitro maturation. Mol.
Reprod. Dev. 53, 398–406 (1999)
85. C. Mendoza, E. Ruiz-Requena, E. Ortega, N. Cremades, F.
Martinez, R. Bernabeu, E. Greco, J. Tesarik, Follicular fluid
markers of oocyte developmental potential. Hum. Reprod. 17,
1017–1022 (2002)
86. S. Modina, V. Borromeo, A.M. Luciano, V. Lodde, F. Francios,
C. Secchi, Relationship between growth hormone concentrations
in bovine oocytes and follicular fluid and oocyte developmental
competence. Eur. J. Histochem. 51, 173–180 (2007)
87. P. Schwartzler, G. Untergasser, M. Hermann, S. Dirnhofer, B.
Abendstein, S. Madersbacher, P. Berger, Selective growth
hormone/placental lactogen gene transcription and hormone
production in pre- and postmenopausal human ovaries. J. Clin.
Endocrinol. Metab. 82, 3337–3341 (1997)
88. A. Hrabia, H.E. Paczoska-Eliasieicz, L.R. Berghman, S. Harvey,
J. Rzasa, Expression and localization of growth hormone and its
receptors in the chicken ovary during sexual maturation. Cell
Tissue Res. 332, 317–328 (2008)
89. F. Izadyar, H.T. Van Tol, B. Colenbrander, M.M. Beavers,
Stimulatory effect of growth hormone in vitro maturation of
bovine oocytes is exerted through cumulus cells and not medi-
ated by IGF-I. Mol. Reprod. Dev. 47, 175–180 (1997)
90. F. Izadyar, B. Colenbrander, M.M. Beavers, In vitro maturation
of bovine oocytes in the presence of growth hormone accelerates
nuclear maturation and promotes subsequent embryonic devel-
opment. Mol. Reprod. Dev. 45, 372–377 (1996)
91. M.M. Beavers, F. Izadyar, Role of growth hormone and growth
hormone receptor in oocyte maturatijon. Mol. Cell. Endocrinol.
197, 173–178 (2002)
92. F. Izadyar, W.G. Hage, B. Colenbrander, M.M. Beavers, The
promontory effect of growth hormone on the development
competence of in vitro matured bovine is due to improved
cytoplasmic maturation. Mol. Reprod. Dev. 49, 444–453 (1998)
93. N.R. Mtango, M.D. Varisanga, Y.J. Dong, R. Rajamahendran,
T. Suzuki, Growth factors and growth hormone enhance in vitro
embryo production and post-thaw survival of vitrified bovine
blastocysts. Theriogenology 59, 1393–1402 (2003)
94. S. Chigioni, C. Secchi, V. Borromeo, S. Modina, M.S. Beretta,
G.C. Luvoni, Effects of growth hormone on oocyte in vitro
maturation and its localization in the canine cumulus-oocyte
complexes. Vet. Res. Commun. 32, S131–S134 (2008)
95. A. Shirazi, N. Shams-Esfandabadi, E. Ahmadi, B. Heidari,
Effects of growth hormone on nuclear maturation of ovine
oocytes and subsequent embryo development. Reprod. Domest.
Anim. 45, 530-536 (2010)
96. E. Kiapekou, D. Loutradis, P. Drakakis, E. Zapanti, G. Masto-
rakos, A. Antsaklis, Effects of GH and IGF-I on the in vitro
maturation of mouse oocytes. Hormones 4, 115–160 (2005)
97. R. Apa, A. Lanzone, F. Miceli, M. Mastrandrea, A. Caruso, S.
Mancuso, R. Canipari, Growth hormone induces in vitro matu-
ration of follicle- and cumulus-enclosed rat oocytes. Mol. Cell.
Endocrinol. 106, 207–212 (1994)
98. Y. Yoshimura, Regulatory system and physiological signifi-
cance of local factors in the ovary during follicular development
and maturation. Nippon Janka Fujinka Gakkai Zasshi 47,
763–774 (1995)
99. S. Kolle, M. Stojkovic, G. Boie, E. Wolf, F. Sinowatz, Growth
hormone-related effects on apoptosis, mitosis, and expression of
connexin 43 on bovine in vitro maturation cumulus–oocyte
complexes. Biol. Reprod. 68, 1584–1589 (2003)
100. N. Songsasen, I. Yu, S.P. Leibo, Nuclear maturation of canine
oocytes cultured in protein-free media. Mol. Reprod. Dev. 62,
407–415 (2002)
101. S. Kolle, M. Stojkovic, G. Boie, E. Wolf, F. Sinowatz, Growth
hormone inhibits apoptosis in in vitro produced bovine embryos.
Mol. Reprod. Dev. 61, 180–186 (2002)
352 Endocr (2010) 38:335–359
102. G.G. Kaiser, S. Kolle, G. Boie, F. Sinowatz, G.A. Palma, R.H.
Alberio, In vivo effect of growth hormone on the expression of
connexin-43 in bovine ovarian follicles. Mol. Reprod. Dev. 73,
600–606 (2006)
103. R. Marchal, M. Caillaud, A. Martoriati, N. Gerard, P. Mermil-
lod, G. Goudet, Effects of growth hormone (GH) on in vitro
nuclear and cytoplasmic oocyte maturation, cumulus expansion,
hyaluronan synthases, and connexons 32 and 43 expression, and
GH receptor messenger RNA expression in equine and porcine
species. Biol. Reprod. 69, 1013–1022 (2003)
104. Y.J. Menezo, S. el Mouatassim, M. Chavrier, E.J. Servy, B.
Nicolet, Human oocytes and preimplantation embryos express
mRNA for growth hormone receptor. Zygote 11, 293–297
105. Y.J. Menezo, B. Nivollet, J. Rollet, A. Hazout, Pregnancy and
delivery after in vitro maturation of naked ICSI-GV oocytes
with GH and transfer of a frozen thawed blastocyst: case report.
J. Assist. Reprod. Genet. 23, 47–49 (2006)
106. F. Izadyar, H.T. Van Tol, W.G. Hage, M.M. Beavers, Preim-
plantation bovine embryos express mRNA of growth hormone
receptor and respond to growth hormone addition during in vitro
development. Mol. Reprod. Dev. 57, 247–255 (2000)
107. S. Kajimura, N. Kawaguchi, T. Kaneko, I. Kawazoe, T. Hirano,
N. Visitacion, E.G. Grau, K. Aida, Identification of the growth
hormone receptor in an advanced teleost, the tilapia (Oreochr-
omis mossambicus) with special reference to its distinct
expression pattern in the ovary. J. Endocrinol. 181, 65–76
108. J.K. dePrada, C.A. VandeVoorte, Growth hormone and in vitro
maturation of rhesus macaque oocytes and subsequent embryo
development. Assist. Reprod. Genet. 25, 145–158 (2008)
109. M. Slater, M. Cooper, C.R. Murphy, Human growth hormone
and interleukin-6 are upregulated in endometriosis and endo-
metrioid adenocarcinoma. Acta Histochem. 108, 13–18 (2006)
110. V. Pandey, J.K. Perry, K.M. Mohankumar, X.J. Kong, S.M. Liu,
Z.S. Wu, M.D. Mitchell, T. Zhu, P.E. Lobie, Autocrine human
growth hormone stimulates oncogenicity of endometrial carci-
noma cells. Endocrinology 149, 3909–3919 (2008)
111. I.F. Sharara, D. Bhartiya, L.K. Nieman, Growth hormone
receptor gene expression in the mouse uterus: modulation by
gonadal steroids. J. Soc. Gynecol. Investig. 1, 285–289 (1994)
112. R.A. Pershing, M.C. Lucy, W.W. Thatcher, L. Badinga, Effects
of BST on oviductal and uterine genes encoding components of
the IGF system in lactating daisy cows. J. Dairy Sci. 85,
3260–3267 (2002)
113. M.L. Rhoads, J.P. Meyer, S.J. Kolath, W.R. Lamberson, M.C.
Lucy, Growth hormone receptor, insulin-like growth factor
(IGF)-1, and IGF-binding protein-2 expression in the repro-
ductive tissues of early postpartum dairy cows. J. Dairy Sci. 91,
1802–1813 (2008)
114. M. Sbracia, F. Scarpillini, R. Poverini, P.L. Alo, G. Rossi, U. Di
Tondo, Immuno-histochemical localization of the growth hor-
mone in human endometrium and decidua. Am. J. Reprod.
Immunol. 51, 112–116 (2004)
115. C.R. Oliveira, R. Salvatori, L.M. Nobrega, E.O. Carvalho, M.
Menezes, C.T. Farias, A.V. Britto, R.M. Pereira, M.H. Aguir-
Oliveira, Sizes of abdominal organs in adults with severe short
stature due to severe, untreated, congenital GH deficiency
caused by a homozygous mutation in the GHRH receptor gene.
Clin. Endocrinol. 69, 153–158 (2008)
116. D. Stygar, N. Muravitskaya, B. Eriksson, H. Eriksson, L. Sahlin,
Effects of SERM (selective estrogen receptor modulator) treat-
ment on growth and proliferation in the rat uterus. Reprod. Biol.
Endocrinol. 7, 1–40 (2003)
117. S. Kolle, F. Sinowatz, G. Boie, D. Lincoln, M.J. Waters, Dif-
ferential expression of the growth hormone receptor and its
transcript in bovine uterus and placenta. Mol. Cell. Endocrinol.
131, 127–136 (2001)
118. D. Zaczek, J. Hammond, L. Suen, S. Wandji, D. Service, A.
Bartke, V. Chandrasheka, K. Coschigano, J. Kopchick, Impact
of growth hormone resistance on female reproductive function:
new insights from growth hormone receptor knockout mice.
Biol. Reprod. 67, 1115–1124 (2002)
119. E. van Garderen, M. de Wit, W.F. Voorhout, G.R. Rutteman,
J.A. Mol, H. Nedergragt, W. Misdorp, Expression of growth
hormone in canine mammary tissue and mammary tumors. Am.
J. Pathol. 150, 1037–1047 (1997)
120. J.A. Mol, I.S. Lantinga-van Leeuwen, E. van Garderen, P.J.
Selman, M.A. Oosterlaken-Dijksterhuis, J.A. Schalken, A. Ri-
jnberk, Mammary growth hormone and tumorigenesis-lessons
from the dog. Vet. Q. 21, 111–115 (1999)
121. J.A. Mol, I. Lantinga-van Leeuwen, E. van Garderen, A. Rijn-
berk, Progestin-induced mammary growth hormone (GH) pro-
duction. Adv. Exp. Med. Biol. 480, 71–76 (2000)
122. M. Raccurt, P.E. Lobie, E. Moudilou, T. Garcia-Caballero, L.
Frappart, G. Morel, H.C. Mertani, High stromal and epithelial
human GH gene expression is associated with proliferative dis-
orders of the mammary gland. J. Endocrinol. 175, 307–318 (2002)
123. S. Mukhina, D. Liu, K. Guo, M. Raccurt, S. Borges-Bendris,
H.C. Mertani, P.E. Lobie, Autocrine growth hormone prevents
lactogenic differentiation of mouse mammary epithelial cells.
Endocrinology 147, 1819–1829 (2006)
124. I. Schoenmakers, H.S. Kooistra, A.C. Okkens, H.A. Hazewin-
kel, M.M. Bevers, J.A. Mol, Growth hormone concentrations in
mammary secretions and plasma of the peripaturient bitch and in
plasma of the neonate. J. Reprod. Fertil. Suppl. 51, 363–367
125. S.F. Bhatti, L. Duchateu, A.C. Okkens, L.M. Van Ham, J.A.
Mol, H.S. Kooistra, Treatment of growth hormone excess in
dogs with the progesterone receptor antagonist alglepristone.
Theriogenology 66, 797–803 (2007)
126. C. Gil-Puig, S. Seoane, M. Blanco, M. Macia, T. Garcia-
Caballero, C. Segura, R. Perez-Fernandez, Pit-1 is expressed in
normal and tumorous human breast and regulates GH secretion
and cell proliferation. Eur. J. Endocrinol. 153, 335–344 (2005)
127. H.S. Kooistra, G. Voorhout, P.J. Selman, A. Rijnberk, Progestin-
induced growth hormone (GH) production in the treatment of
dogs with congenital GH deficiency. Domest. Anim. Endocrinol.
15, 93–102 (1998)
128. E.L. Gregoraszczuk, T. Milewicz, J. Kolodziejczyk, J. Krzysiek,
A. Basta, K. Sztefko, S. Kurek, J. Stachura, Progesterone-
induced secretion of growth hormone, insulin-like growth factor
I and prolactin by human breast cancer explants. Gynecol.
Endocrinol. 15, 251–258 (2001)
129. W.M. Lee, H.S. Kooistra, J.A. Mol, S.J. Dieleman, A.C.
Schaefers-Okkens, Ovariectomy during the luteal phase influ-
ences secretion of prolactin, growth hormone, and insulin-like
growth factor-I in the bitch. Theriogenology 66, 484–490 (2006)
130. I.S. Lantinga van Leeuwen, E. van Garderen, G.R. Rutteman,
J.A. Mol, Cloning and cellular localization if the canine pro-
gesterone receptor: co-localization with growth hormone in the
mammary gland. J. Steroid Biochem. Mol. Biol. 75, 219–228
131. E. van Garderen, H.J. van der Poel, J.F. Swennenhuis, E.H.
Wissink, G.R. Rutteman, E. Hellmen, J.A. Mol, J.A. Schalken,
Expression and molecular characterization of the growth hor-
mone receptor in canine mammary tissue and mammary tumors.
Endocrinology 140, 5907–5914 (1999)
132. F. Sinowatz, D. Schams, S. Kolle, A. Plath, D. Lincoln, M.J.
Waters, Cellular localization of GH receptors in the bovine
mammary gland during mammogenesis, lactation and involu-
tion. J. Endocrinol. 166, 503–510 (2000)
Endocr (2010) 38:335–359 353
133. A. Plath-Gabler, C. Gabler, F. Sinowatz, B. Berisha, D. Schams,
The expression of the IGF family and GH receptor in the bovine
mammary gland. J. Endocrinol. 168, 39–48 (2001)
134. E. van Garderen, J.A. Schalken, Morphogenic and tumorigenic
potentials of the mammary growth hormone/growth hormone
receptor system. Mol. Cell. Endocrinol. 197, 153–165 (2002)
135. J. Divisova, I. Kuiatse, Z. Lazard, H. Weiss, F. Vreeland, D.L.
Hadsell, R. Schiff, C.K. Osborne, A.V. Lee, The growth hor-
mone receptor antagonist pegvisomant blocks both mammary
gland development and MCF-7 breast cancer xenograft growth.
Breast Cancer Res. Treat. 98, 315–327 (2006)
136. P.A. Kelly, A. Bachelot, C. Kedzia, L. Hennighausen, C.J.
Ormandy, J.J. Kopchick, N. Binart, The role of prolactin and
growth hormone in mammary gland development. Mol. Cell.
Endocrinol. 197, 127–131 (2002)
137. J.F. Trott, B.K. Vonderhaar, R.C. Hovey, Historical perspectives
of prolactin and growth hormone as mammogens, lactogens and
galactogogues-agog for the future!. J. Mammary Gland Biol.
Neoplasia 13, 3–11 (2008)
138. S. Mukhina, H.C. Mertani, K. Guo, K.O. Lee, P.D. Gluckman,
P.E. Lobie, Phenotypic conversion of human mammary carci-
noma cells by autocrine human growth hormone. Proc. Natl
Acad. Sci. 101, 15166–15171 (2004)
139. C.L. Boguszewski, P.A. Svensson, T. Jansson, R. Clark, L.M.
Carlsson, B. Carlsson, Cloning of two novel growth hormone
transcripts expressed in human placenta. J. Clin. Endocrinol.
Metab. 83, 2878–2885 (1998)
140. M.C. Lacroix, J. Guibourdenche, J.L. Frendo, G. Pidoux, D.
Evain-Brion, Placental growth hormones. Endocrine 19, 73–79
141. J. Fuglsang, P. Ovesen, Aspects of placental growth hormone
physiology. Growth Horm. IGF Res. 16, 67–85 (2006)
142. D. Haig, Placental growth hormone-related proteins and pro-
lactin-related proteins. Placenta 22, S36–S41 (2008)
143. T.G. Golos, M. Durning, J.M. Fisher, P.D. Fowler, Cloning of
four growth hormone/chorionic somatomammotropin-related
complementary deoxyribonucleic acids differentially expressed
during pregnancy in the rhesus monkey placenta. Endocrinology
133, 1744–1752 (1993)
144. C. Ye, Y. Li, P. Shi, Y.P. Zhang, Molecular evolution of growth
hormone gene family in old world monkeys and hominoids.
Gene 350, 183–192 (2005)
145. O.C. Wallis, M. Wallis, Evolution of growth hormone in pri-
mates: the GH gene clusters of the New World monkeys mar-
moset (Callithrix jacchus) and while-fronted capuchin (Cebus
albifrons). J. Mol. Evol. 63, 591–601 (2006)
146. J. Lin, J. Poole, D.I. Liner, Two novel members of the prolactin/
growth hormone family are expressed in the mouse placenta.
Endocrinology 138, 5535–5540 (1997)
147. K. Ishibashi, M. Imai, Identification of four new members of the
rat prolactin/growth hormone gene family. Biochem. Biophys.
Res. Commun. 262, 575–578 (1999)
148. M.C. Lacroix, E. Devinoy, J.L. Servely, C. Puissant, G. Kann,
Expression of the growth hormone gene in ovine placenta:
detection and cellular localization of the protein. Endocrinology
137, 4886–4892 (1996)
149. M.C. Lacroix, E. Devinoy, S. Cassy, J.L. Servely, M. Vidaud, G.
Kann, Expression of growth hormone and its receptor in the
placental and feto-maternal environment during early pregnancy
in sheep. Endocrinology 140, 5587–5597 (1999)
150. M. Wallis, A. Lioupis, O.C. Wallis, Duplicate growth hormone
genes in sheep and goat. J. Mol. Endocrinol. 21, 1–5 (1998)
151. E. Gootwine, Placental hormones and fetal-placental develop-
ment. Anim. Reprod. Sci. 82–83, 551–566 (2004)
152. X. Ma, X. Liu, Y. Zhang, P. Zhu, W. Ye, H. Lin, Two growth
hormone receptors in Nile tilapia (Oreochromis niloticus):
molecular characterization, tissue distribution and expression
profiles in the gonad during the reproductive cycle. Comp.
Biochem. Physiol. B: Biochem. Mol. Biol. 147, 325–339 (2007)
153. L.K. Davis, A.L. Peirce, N. Hiramatsu, C.V. Sullivan, T. Hirano,
E.G. Grau, Gender-specific expression of multiple estrogen
receptors, growth hormone receptors, insulin-like growth factors
and vitellogenins, and effects of 17 beta-estradiol in the male
tilapia (Oreochromis mossambicus). Gen. Comp. Endocrinol.
156, 544–551 (2008)
154. P.E. Lobie, W. Breipohl, J.G. Aragon, M.J. Waters, Cellular
localization of the growth hormone receptor/binding protein in
the male and female reproductive systems. Endocrinology 126,
2214–2221 (1990)
155. M.R. N’Diaye, S.S. Sun, S.P. Fanua, K.J. Loseth, E.F. Shaw
Wilgis, B.G. Crabo, Growth hormone receptors in the porcine
testis during prepuberty. Reprod. Domest. Anim. 37, 305–309
156. E.B. Berensztein, M.S. Baquedano, C.M. Pepe, M. Costanzo,
N.I. Saraco, R. Ponzio, M.A. Rivarola, A. Blgorosky, Role of
IGFs and insulin in the human testis during postnatal activation:
differentiation of steroidogenic cells. Pediatr. Res. 63, 662–666
157. Z.J. Champion, M.H. Vickers, C.G. Gravance, B.H. Breier, P.J.
Casey, Growth hormone or insulin-like growth factor-I extends
longevity of equine spermatozoa in vitro. Theriogenology 57,
1793–1800 (2002)
158. J.F. Roser, Regulation of testicular function in the stallion: an
intricate network of endocrine, paracrine and autocrine systems.
Anim. Reprod. Sci. 107, 179–196 (2008)
159. G. Untergasser, W. Kranewitter, F. Walser, S. Madersbacher, S.
Dirnhofer, P. Berger, The testis as eutopic production site of
human growth hormone, placental lactogen and prolactin: pos-
sible autocrine/paracrine effects on testicular function. Wien.
Klin. Wochenschr. 108, 541–546 (1996)
160. G. Untergasser, W. Kranewitter, P. Schwarzler, S. Madersb-
acher, S. Dirnhofer, P. Berger, Organ-specific expression pattern
of the human growth hormone/placental lactogen gene-cluster in
the testis. Mol. Cell. Endocrinol. 130, 53–60 (1997)
161. P. Berger, G. Untergasser, M. Hermann, A. Hittmair, S. Mad-
ersbacher, S. Dinhofer, The testis-speicific expression pattern of
the growth hormone/placental (GH/PL) gene cluster changes
with malignancy. Hum. Pathol. 30, 1201–1206 (1999)
162. A.A. Sciara, J.A. Rubiolo, G.M. Somozoa, S.E. Arranz,
Molecular cloning, expression and immunological character-
ization of prejerrey (Odontesthes bonariensis) growth hor-
mone. Comp. Biochem. Physiol. C: Toxicol. Pharamacol. 142,
284–292 (2006)
163. A.L. Filby, C.R. Tyler, Cloning and characterization of cDNAs
for hormones and/or receptors of growth hormone, insulin-like
growth factor-I, thyroid hormone, and corticosteroid and the
gender-, tissue-, and developmental-specific expression of their
mRNA transcripts in fathead minnow (Pimephales promelas).
Gen. Comp. Endocrinol. 150, 151–163 (2007)
164. S. Harvey, M.-L. Baudet, A.E. Murphy, M. Luna, K.L. Hull, C.
Aramburo, Testicular growth hormone (GH): GH expression in
spermatogonia and primary spermatocytes. Gen. Comp. Endo-
crinol. 139, 158–167 (2004)
165. M.D. Slater, C.R. Murphy, Co-expression of interleukin-6 and
human growth hormone in apparently normal prostate biopsies
that ultimately progress to prostate cancer using low pH, high
temperature antigen retrieval. J. Mol. Hist. 37, 37–41 (2006)
166. C.V. Kyle, M.C. Evans, W.D. Odell, Growth hormone-like
material in normal human tissues. J. Clin. Endocrinol. Metab.
53, 1138–1144 (1981)
167. A. Costa, G. Zoppetti, C. Benedetto, E. Bertino, L. Marozio, C.
Fabris, R. Arisio, G.F. Giraudi, O. Testori, M. Ariano, V. Maula,
354 Endocr (2010) 38:335–359
E. Bertini, Immunolike growth hormone substance in tissues
from human embryos/fetuses and adults. J. Endocrinol. Invest.
16, 625–633 (1993)
168. R. Sundler, J. Alumets, R. Hakanson, Growth hormone-like
immunoreactivity in gastrin cells and gastrinomas. Histochem-
istry 59, 343–356 (1979)
169. Q.S. Pan, Z.P. Fang, F.J. Huang, Identification, localization and
morphology of APUD cells in gastroenteropancreatic system of
stomach containing teleosts. World J. Gastroenterol. 6, 842–847
170. J.H. Robben, E. van Garderen, J.A. Mol, J. Wolfswinkel, A.
Rijnberk, Locally produced growth hormone in canine insuli-
nomas. Mol. Cell. Endocrinol. 197, 187–195 (2002)
171. N.M. Very, J.D. Kittilson, L.A. Norbeck, M.A. Heridan, Isola-
tion, characterization, and distribution of two cDNAs encoding
for growth hormone receptor in rainbow trout (Oncorhynchus
mykiss). Comp. Biochem. Physiol. B: Biochem. Mol. Biol. 140,
615–628 (2005)
172. T.C. Brelje, L.E. Stout, N.V. Bhagroo, R.L. Sorenson, Distinc-
tive roles for prolactin and growth hormone in the activation of
signal transducer and activator of transcription 5 in pancreatic
islets of Langerhans. Endocrinology 145, 4162–4175 (2004)
173. Q. Zhang, M. Kohler, S.N. Yang, F. Zhang, O. Larsson, P.O.
Berggren, Growth hormone promotes Ca(2?)-induced Ca
release in insulin-secreting cells by ryanodine receptor tyrosine
phosphorylation. Mol. Endocrinol. 18, 1658–1669 (2004)
174. A.O. Gurol, G. Yillar, A.O. Kursun, B. Kiran, E. Aktas, S.
Salman, G. Deniz, M.T. Yilmaz, Effect of human Somatotropin
hormone on cultured rat islets. Transplant. Proc. 36, 1613–1614
175. B. Granados, C. Ariznavarreta, J.A.P. Tresguerres, Adrenal and
parotid tissue autotransplantation to the sell turcica are able to
partially recover gonadotropic function in hypophysectomized
rats. J. Endocrinol. Invest. 16, 116 (1993)
176. P. Fernandez, B. Granados, C. Ariznavarreta, A. Rodriguez-
Ramos, P. Gil-Loyzaga, J.A.F. Tresguerres, Rat parotid gland
tissue is able to assume pituitary functions under hypothalamic
extracts in culture. Neuroendocrinology 60, 36 (1994)
177. J.A. Tresguerres, C. Ariznavarreta, B. Granados, J.A. Costoya,
A. Perez-Romero, F. Salame, M. Hermanussen, Salivary gland
is capable of GH synthesis under GHRH stimulation. J. Endo-
crinol. 160, 217–222 (1999)
178. A. Perez-Romero, E. Dialynas, F. Salame, A. Amores, L. Vid-
arte, A. Bartke, C. Ariznavarreta, J.A. Tresguerres, GH gene
expression in the submaxillary gland in normal and Ames dwarf
mice. J. Endocrinol. 169, 389–396 (2001)
179. W.G. Yong, G.O. Ramirez-Yanez, T.J. Daley, J.R. Smid, K.T.
Coshigano, J.J. Kopchick, M.J. Waters, Growth hormone and
epidermal growth factor in salivary glands of giant and dwarf
transgenic mice. J. Histochem. Cytochem. 52, 1191–1197
180. T. Mori, R.H. Devlin, Transgene and host growth hormone gene
expression in pituitary and non-pituitary tissues of normal and
growth hormone salmon. Mol. Cell. Endocrinol. 149, 129–139
181. C. Ohlsson, B.A. Bengtsson, O.G. Isaksson, T.T. Andreassen,
M.C. Slootweg, Growth hormone and bone. Endocr. Rev. 19,
55–79 (1998)
182. T. Ueland, Bone metabolism in relation to alterations in systemic
growth hormone. Growth Horm. IGF Res. 14, 404–417 (2004)
183. T. Ueland, GH/IGF-1 and bone resorption in vivo and in vitro.
Eur. J. Endocrinol. 152, 327–332 (2005)
184. B.C. van der Eerden, M. Karperien, J.M. Wit, Systemic and
local regulation of the growth plate. Endocr. Rev. 24, 782–801
185. S. Mohan, C. Richman, R. Guo, Y. Amaar, L.R. Donahue, J.
Wergedal, D.J. Bayling, Insulin-like growth factor regulates
peak bone mineral density in mice by both growth hormone-
dependent and -independent mechanism. Endocrinology 144,
929–936 (2003)
186. J. Wang, J. Zhou, C.M. Cheng, J.J. Kopchick, C.A. Bondy,
Evidence supporting dual, IGF-I-independent and IGF-I-
dependent, roles for GH in promoting longitudinal bone growth.
J. Endocrinol. 180, 247–255 (2004)
187. O. Nilsson, R. Marino, F. De Luca, M. Phillip, J. Baron, Endo-
crine regulation of the growth plate. Horm. Res. 64, 157–165
188. O. Isaksson, GH, IGF-I and growth. J. Pediatr. Endocrinol.
Metab. 4, 1321–1326 (2004)
189. O.G. Isaksson, J.O. Jansson, I.A. Gause, Growth hormone stim-
ulates longitudinal bone growth directly. Science 216, 1237–1239
190. J. Isgaard, C. Moller, O.G. Isaksson, A. Nilsson, L.S. Mathews,
G. Norstedt, Regulation of insulin-like growth factor messenger
ribonucleic acid in rat growth plate by growth hormone. Endo-
crinology 122, 1515–1520 (1988)
191. N.L. Schlechter, S.M. Russell, E.M. Spencer, C.S. Nicoll,
Evidence suggesting that the direct growth-promoting effect
of growth hormone on cartilage in vivo is mediated by local
production of somatomedin. Proc. Natl Acad. Sci. USA 83,
7932–7934 (1986)
192. T.T. Andreassen, H. Oxlund, The effects of growth hormone on
cortical and cancellous bone. J. Musculoskelet. Neuronal Inter-
act. 2, 49–58 (2001)
193. K. De Jesus, X. Wang, J.L. Liu, A general IGF-I overexpression
effectively rescued somatic growth and bone deficiency in mice
caused by growth hormone receptor knockout. Growth Factors
27, 438–447 (2009)
194. C.W. Denko, B. Boja, C.J. Malemud, Intra-erythrocyte deposi-
tion of growth hormone in rheumatic diseases. Rheumatol. Int.
23, 11–14 (2003)
195. W.C. Denko, C.J. Malemud, Role of the growth hormone/
insulin-like growth factor-I paracrine axis in rheumatic diseases.
Semin. Arthritis Rheum. 35, 24–34 (2005)
196. O.G. Isaksson, C. Ohlsson, A. Nilsson, J. Isgaard, A. Lindahl,
Regulation of cartilage growth by growth hormone and insulin-
like factor I. Pediatr. Nephrol. 5, 451–453 (1991)
197. V.H. Heemskerk, M.A. Daemen, W.A. Buurman, Insulin-like
growth factor-1 (IGF-1) and growth hormone (GH) in immunity
and inflammation. Cyt. Growth Factor Rev. 10, 5–14 (1999)
198. F. Silveri, P. Morosini, D. Brecciaroli, C. Cervini, Intra-articular
injection of somatostatin in knee osteoarthritis: clinical results
and IGF-1 serum levels. Int. J. Clin. Pharamacol. Res. 14, 79–85
199. F. Silveri, C. Lo Barco, D. Brecciaroli, Somatostatin in peri-
arthropathies of the shoulder: clinical effectiveness and tolera-
bility after sub-acromial administration. Clin. Ter. 148, 75–81
200. G. Coatri, M. Di Franco, A. Iagnocco, M.R. Di Novi, M.T.
Mauceri, A. Copcco, Intra-articular somatostatin 14 reduces
synovial thickness in rheumatoid arthritis: an ultrasonographic
study. Int. J. Clin. Pharmacol. Res. 15, 27–32 (1995)
201. C. Fernandez-Criado, A. Martos-Rodriogiez, I. Santos-Alvarex,
J.P. Garcia-Ruiz, E. Delgado-Baeza, The fate of chondrocyte in
osteroarthritic cartilage of transgenic mice expressing bovine
GH. Osteoarthr. Cartil. 12, 543–551 (2004)
202. C.Z. Zhang, H. Li, W.G. Young, P.M. Bartold, C. Chen, M.J.
Waters, Evidence for a local action of growth hormone in
embryonic tooth development in the rat. Growth Factors 14,
131–143 (1997)
Endocr (2010) 38:335–359 355
203. W.G. Young, C.Z. Zhang, H. Li, P. Osborne, M.J. Waters, The
influence of growth hormone on cell proliferation in odonto-
genic epithelia by bromodeoxyuridine immunocytochemistry
and morphometry in the Lewis dwarf rat. J. Dent. Res. 71,
1807–1811 (1992)
204. W.G. Young, J.V. Ruch, M.R. Stevens, C. Begue-Kirn, C.Z.
Zhang, H. Lesot, Comparison of the effects of growth hormone,
insulin-like growth fctor-1 and fetal calf serum on mouse molar
odontogenesis in vitro. Arch. Oral Biol. 40, 789–799 (1995)
205. W.G. Young, H. Li, Y. Xiao, M.J. Waters, P.M. Bartold, Growth
hormone-stimulated dentinogenesis in Lewis dwarf rat molars.
J. Dent. Res. 80, 1742–1747 (2001)
206. J.R. Smid, J.E. Rowland, W.G. Young, K.T. Coschigano, J.J.
Kopochick, M.J. Waters, Mouse molar dentin size/shape is
dependent on growth hormone status. J. Dent. Res. 86, 463–468
207. J.R. Smid, J.E. Rowland, W.G. Young, T.J. Daley, K.T. Cos-
chigano, J.J. Kopochick, M.J. Waters, Mouse cellular cementum
is highly dependent on growth hormone status. J. Dent. Res. 83,
35–39 (2004)
208. H. Li, P.M. Bartold, C.Z. Zhang, R.W. Clarkson, W.G. Young,
M.J. Waters, Growth hormone and insulin-like growth factor-I
induce bone morphogenetic proteins 2 and 4: a mediator role in
bone and tooth formation. Endocrinology 139, 3855–3862
209. H. Li, P.M. Bartold, W.G. Young, Y. Xiao, M.J. Waters, Growth
hormone induces bone morphogenetic proteins and bone-related
proteins in the developing rat periodontium. J. Bone Miner. Res.
16, 1068–1076 (2001)
210. A. Slominski, W.B. Malarkey, J. Wortsman, S.L. Asa, A.
Carlson, Human skin expression growth hormone but not the
prolactin gene. J. Lab. Clin. Med. 136, 476–481 (2000)
211. A. Palmetshofer, D. Zechner, T.A. Lugerf, A. Barta, Splicing
variants of the human growth hormone mRNA: detection in
pituitary, mononuclear cells and dermal fibroblasts. Mol. Cell.
Endocrinol. 113, 225–234 (1995)
212. S.R. Oakes, K.M. Haynes, M.J. Waters, A.C. Herington, G.A.
Werther, Demonstration and localization of growth hormone
receptor in human skin and skin fibroblasts. J. Clin. Endocrinol.
Metab. 75, 1368–1373 (1992)
213. A. Tavakkol, J.T. Elder, C.E. Griffiths, K.D. Cooper, H. Talwar,
G.J. Fisher, K.M. Keane, S.K. Foltin, J.J. Voorhees, Expression
of growth hormone receptor, insulin-like growth factor 1 (IGF-
1) and IGF-1 receptor mRNA and proteins in human skin.
J. Invest. Dermatol. 99, 343–349 (1992)
214. M. Ginarte, T. Garcia-Caballero, V. Fernandez-Redondo, A.
Beiras, J. Toribio, Expression of growth hormone receptor in
benign and malignant cutaneous proliferative entities. J. Cutan.
Pathol. 27, 276–282 (2000)
215. M. Sheffield-Moore, R.J. Urban, An overview of the endocri-
nology of skeletal muscle. Trends Endocrinol. Metab. 15,
111–115 (1994)
216. H.B. Segard, S. Moulin, S. Boumard, C. Augier de Cremiers,
P.A. Kelly, J. Finidori, Autocrine growth hormone production
prevents apoptosis and inhibits differentiation in C2C12 myo-
blasts. Cell. Signal. 15, 612–615 (2003)
217. J.A. Beyea, D.M. Olson, R.A. Vandergriend, S. Harvey,
Expression of growth hormone and its receptor in the lungs of
embryonic chicks. Cell Tissue Res. 322, 379–392 (2005)
218. J. Isgaard, A. Tivesten, P. Friberg, B.A. Bengtsson, The role of
the GH/IGF-I axis for cardiac function and structure. Horm.
Metab. Res. 31, 50–54 (1999)
219. J. Svensson, A. Tivesten, J. Isgaard, Growth hormone and
cardiovascular function. Min. Endocrinol. 30, 1–13 (2005)
220. A. Caelers, N. Maclean, G. Hwang, G.E. Eppler, M. Reinecke,
Expression of endogenous and exogenous growth hormone (GH)
messenger (m) RNA in a GH-transgenic tilapia (Oreochromis
niloticus). Transgenic Res. 14, 95–104 (2005)
221. J. Beyea, D.M. Olson, S. Harvey, Growth hormone-dependent
changes in rat lung proteome during alveorization. Mol. Cell.
Biochem. 321, 197–204 (2009)
222. A.T. Allen, C.A. Bloor, R.K. Kedia, R.A. Knight, M.A. Spiteri,
Expression of growth hormone-releasing factor, growth hor-
mone, insulin-like growth factor-1 and its binding proteins in
human lung. Neuropeptides 34, 98–107 (2000)
223. J. Beyea, G. Sawicki, D.M. Olson, E. List, J.J. Kopchick, S.
Harvey, Growth hormone (GH) receptor knockout mice reveal
actions of GH in lung development. Proteomics 6, 341–348 (2006)
224. J. Beyea, D.M. Olson, S. Harvey, Growth hormone (GH) action
in the developing lung: changes in lung proteins after adenoviral
GH overexpression. Dev. Dyn. 234, 404–412 (2005)
225. P. Klilerich, K. Kristiansen, S.S. Madsen, Hormone receptors in
gills of smolting Atlantic salmon, Salmo salar: expression of
growth hormone, prolactin, mineralocorticoids, and glucocorti-
coid receptors and 11beta-hydroxysteriod dehydrogenase type 2.
Gen. Comp. Endocrinol. 152, 295–303 (2007)
226. K.M. Meier, M.A. Figueiredo, M.T. Kamimura, J. Laurino,
R. Maggioni, L.S. Pinto, O.A. Dellagostin, M.B. Tesser,
L.A. Sampaio, L.F. Marins, Increased growth hormone (GH),
growth hormone receptor (GHR), and insulin-like factor I
(IGF-I) gene transcription after hyperosmotic stress in the
Brazilian flounder Paralichthys orbignyanus. Fish Physiol. Bio-
chem. 35, 501–509 (2008)
227. S. Tomy, Y.M. Chang, Y.H. Chen, J.C. Cao, T.P. Want, C.F.
Chang, Salinity effects on the expression of osmoregulatory
genes in the euryhaline black progy Acanthopagrus schlegeli.
Gen. Comp. Endocrinol. 161, 123–132 (2009)
228. T. Sakamoto, T. Hirano, Growth hormone receptors in the liver
osmoregulatory organs of rainbow trout: characterization and
dynamics during adaptation to seawater. J. Endocrinol. 130,
425–433 (1991)
229. M. Pantaleon, E.J. Whiteside, M.B. Harvey, R.T. Barnard, M.J.
Waters, P.L. Kaye, Functional growth hormone (GH) receptors
and GH are expressed by preimplantation mouse embryos: a role
for GH in early embryogenesis? Proc. Natl Acad. Sci. 94,
5125–5130 (1997)
230. S. Kolle, M. Stojkovic, K. Prelle, M. Waters, E. Wolf,
F. Sinowatz, Growth hormone (GH)/GH receptor expression and
GH-mediated effects during early bovine embryogenesis. Biol.
Reprod. 64, 1826–1834 (2001)
231. K.E. Markham, P.L. Kaye, Growth hormone, insulin-like factor
I and cell proliferation in the mouse blastocyst. Reproduction
125, 327–336 (2003)
232. A. Revol, M.L. Garza Rodriguez, V. Hernandez Montenegro,
C. Aguilera, H. Barrera Saldana, R. Mendoza, Cloning of
growth hormone cDNA of alligator gar Atractosteus spatula and
its expression through larval development. Comp. Biochem.
Phsyiol. A: Mol. Integr. Physiol. 140, 423–429 (2005)
233. M. Li, J. Greenway, J. Petrik, A. Hahnel, J. Leatherland, Growth
hormone and insulin-like growth factor gene expression prior
to the development of the pituitary gland in rainbow trout
(Oncorhynchus mykiss) embryos reared at two temperatures.
Physiol. A: Mol. Integr. Physiol. 143, 514–522 (2006)
234. M. Li, J.C. Raine, J.F. Leatherland, Expression profiles of
growth-related genes during the very early development of
rainbow trout embryos reared at two incubation temperatures.
Gen. Comp. Endocrinol. 153, 302–310 (2007)
235. J.C. Gabillard, H. Duval, C. Cauty, P.Y. Rescan, C. Weil, P.Y.
Le Bail, Differential expression of the two GH genes during
embryonic development of rainbow trout Oncorhynchus mykiss
in relation with the IGFs system. Mol. Reprod. Dev. 64, 32–40
356 Endocr (2010) 38:335–359
236. M.J. Herrero-Turrion, R.E. Rodriguez, A. Velasco, R. Gonzalez-
Sarmiento, J. Aijon, J.M. Lara, Growth hormone expression in
ontogenic development in gilthead sea bream. Cell Tissue Res.
313, 81–91 (2003)
237. E.E. Deane, S.P. Kelly, P.M. Collins, N.Y. Woo, Larval
development of silver sea bream (Sparus sarba): ontogeny of
RNA-DNA ratio, GH, IGF-I, and Na(?)-K(?)-APTase. Mar.
Biotechnol. (NY) 5, 79–91 (2003)
238. Y. Ozaki, H. Fukada, H. Tanaka, H. Kagawa, H. Ohta, S. Adachi,
A. Hara, K. Yamauchi, Expression of growth hormone family
and growth hormone receptor during early development in the
Japanese eel (Anguilla japonica). Comp. Biochem. Physiol. B:
Biochem. Mol. Biol. 145, 27–34 (2006)
239. W.S. Li, D. Chen, A.O. Wong, H.R. Lin, Molecular cloning,
tissue distribution, and ontogeny of mRNA expression of growth
hormone in orange-spotted grouper (Epinephelus coioides).
Gen. Comp. Endocrinol. 144, 78–89 (2005)
240. K.L. Hull, S. Harvey, Growth Hormone and Cancer, in The
Molecular and Cellular Pathology of Cancer Progression and
Prognosis, ed. by G. Sherbet (Research Signpost, Trivandrum,
2006), pp. 97–138
241. J.K. Perry, B.S. Emerald, H.C.P.E. Lobie, The oncogenic
potential of growth hormone. Growth Horm. IGF Res. 16,
277–289 (2006)
242. J.B. Engel, G. Keller, A.V. Schally, G.L. Toller, K. Groot, A.
Havt, P. Armatis, M. Zarandi, J.L. Varga, G. Hallmos, Inhibition
of growth of experimental human endometrial cancer by an
antagonist of growth hormone-releasing hormone. J. Clin.
Endocrinol. Metab. 90, 3614–3621 (2004)
243. L. Zhao, T. Yano, Y. Osuga, S. Nakagawa, H. Oishi, O. Wada-
Hiraike, X. Tang, N. Yano, K. Kugu, A.V. Schally, Y. TAketani,
Cellular mechanisms of growth inhibition of human endometrial
cancer cell line by an antagonist of growth hormone-releasing
hormone. Int. J. Oncol. 32, 593–601 (2008)
244. S.T. Bustin, P.J. Jenkins, The growth hormone-insulin-like
factor-I axis and colorectal cancer. Trends Mol. Med. 7,
447–454 (2001)
245. L. Lauriola, N. Maggiano, F.G. Serra, S. Nori, M.L. Trdio, A.
Capelli, M. Piantelli, F.O. Ranelletti, Immunohistochemical and
in situ hybridization detection of growth-hormone-producing
cells in human thymoma. Am. J. Pathol. 151, 55–61 (1997)
246. J. Kirpensteijn, E.P. Timmermans-Sprang, E. van Garderen,
G.R. Rutteman, I.S. Lantinga-van Leeuwen, J.A. Mol, Growth
hormone gene expression in canine normal growth plates and
spontaneous osteosarcoma. Mol. Cell. Endocrinol. 197, 179–185
247. L.K. Chopin, Veveris-Lowe, A.F. Philipps, A.C. Herrington,
Co-expression of GH and GHR isoforms in prostate cancer cell
lines. Growth Horm. IGF Res. 12, 126–136 (2002)
248. Z. Wang, R.M. Luque, R.D. Kineman, V.H. Ray, K.T. Christov,
D.D. Lantvit, T. Shirai, S. Hedayat, T.G. Unterman, M.C.
Bosland, G.S. Pris, S.M. Swanson, Disruption of growth hor-
mone signaling retards prostate carcinogenesis in the probasin/
Tag rat. Endocrinology. 149, 1366–1376 (2008)
249. L.K. Chopin, A.C. Herington, A potential autocrine pathway for
growth hormone releasing hormone (GHRH) and its receptor in
human prostate cancer cell lines. Prostate 49, 116–121 (2001)
250. N. Barabutis, A.V. Schally, Antioxidant activity of growth hor-
mone-releasing hormone antagonists in LNCaP human prostate
cancer line. Proc. Natl Acad. Sci. 105, 20470–20475 (2008)
251. R. Hooghe, S. Merchav, G. Gaidano, F. Naessens, L. Matera, A
role for growth hormone and prolactin in leukaemia and lym-
phoma? Cell. Mol. Life Sci. 54, 1095–1101 (1998)
252. L.A. Baglia, D. Cruz, J.E. Shaw, Production of immunoreactive
forms of growth hormone by the Burkitt tumor serum-free cell
line sfRamos. Endocrinology 130, 2446–2454 (1992)
253. J.T. Farmer, D.A. Weigent, TGF-beta 1 expression in EL4
lymphoma cells overexpressing growth hormone. Cell. Immu-
nol. 240, 22–30 (2006)
254. R.E. Arnold, D.A. Weigent, The inhibition of superoxide pro-
duction in EL4 lymphoma cells overexpressing growth hor-
mone. Immunopharmacol. Immunotoxicol. 25, 159–177 (2003)
255. R.E. Arnold, D.A. Weigent, The inhibition of apoptosis in EL4
lymphoma cells overexpressing growth hormone. Neuroimmu-
nomodulation 11, 149–159 (2004)
256. D.A. Weigent, R.E. Arnold, Expression of insulin-like growth
factor-1 and insulin-like growth factor-1 receptors in EL4
lymphoma cells overexpressing growth hormone. Cell. Immu-
nol. 234, 54–66 (2005)
257. N. Liu, H.C. Mertani, G. Norstedt, J. Tornell, P.E. Lobie, Mode
of the autocrine/paracrine mechanism of growth hormone
action. Exp. Cell. Res. 237, 196–206 (1997)
258. K.K. Kaulsay, H.C. Mertani, K.O. Lee, P.E. Lobie, Autocrine
human growth hormone enhancement of human mammary
carcinoma cell spreading is Jak2 dependent. Endocrinology 141,
1571–1584 (2000)
259. K.K. Kaulsay, H.C. Mertani, J. Tornell, G. Morel, K.O. Lee,
P.E. Lobie, Autocrine stimulation of human mammary carci-
noma cell proliferation by human growth hormone. Exp. Cell
Res. 250, 35–50 (1999)
260. K.K. Kaulsay, T. Zhu, W. Bennett, K. Lee, P.E. Lobie, The
effects of autocrine human growth hormone (hGH) on human
mammary carcinoma cell behavior are mediated via the hGH
receptor. Endocrinology 142, 767–777 (2001)
261. X. Zhang, B.S. Emerald, S. Mukhina, K.M. Mohankumar, A.
Kraemer, A.S. Yap, P.D. Gluckman, K.O. Lee, P.E. Lobie,
HOXA1 is required for E-cadherin-dependent anchorage-inde-
pendent survival of human mammary carcinoma cells. J. Biol.
Chem. 281, 6471–6481 (2006)
262. F. Shafiei, F. Rahnama, L. Pawella, M.D. Mitchell, P.D.
Gluckman, P.E. Lobie, DNMT2A and DNMT3B mediate
autocrine hGH repression of plakoglobin gene transcription and
consequent phenotypic conversion of mammary carcinoma
cells. Oncogene 27, 2602–2612 (2008)
263. K.M. Mohankumar, X.Q. Xu, T. Zhu, N. Kannan, L.D. Miller,
E.T. Liu, P.D. Gluckman, S. Sukumar, B.S. Emerald, P.E.
Lobie, HOXA1-stimuated oncogenicity is mediated by selective
upregulation of components of the p44/42 MAP kinase pathway
in human mammary carcinoma cells. Oncogene 26, 3998–4008
264. K.M. Mohankumar, J.K. Perry, N. Kannan, K. Kohno, P.D.
Gluckman, B.S. Emerald, P.E. Lobie, Transcriptional activation
of signal transducer and activator of transcription (STAT)3 and
STAT5B partially mediate homeobox A1-stimulated oncogenic
transformation of the immortalized human mammary epithelial
cell. Endocrinology 149, 2219–2229 (2008)
265. X. Zhang, T. Zhu, Y. Chen, H.C. Mertani, K.O. Lee, P.E. Lobie,
Human growth hormone-regulated HOXA1 is a human mam-
mary epithelial oncogene. J. Biol. Chem. 278, 7580–7590
266. T. Zhu, B. Starling-Emerald, X. Zhang, K.O. Lee, P.D. Gluck-
man, H.C. Mertani, P.E. Lobie, Oncogenic transformation of
human mammary epithelial cells by autocrine human growth
hormone. Cancer Res. 65, 317–324 (2005)
267. Z. Zhu, S. Mukhina, T. Zhu, H.C. Mertani, K.O. Lee, P.E.
Lobie, p44/42 MAP kinase-dependent regulation of catalase by
autocrine human growth hormone protects human mammary
carcinoma cells from oxidative stress-induced apoptosis.
Oncogene 24, 3774–3785 (2005)
268. C.M. Vouyovitch, L. Vidal, S. Borges, M. Raccurt, C. Arnould,
J. Chiesa, P.E. Lobie, J. Lachuer, H.C. Mertani, Proteomic
analysis of autocrine/paracrine effects of human growth
Endocr (2010) 38:335–359 357
hormone in human mammary carcinoma. Adv. Exp. Med. Biol.
617, 493–500 (2008)
269. H.C. Mertani, T. Zhu, E.L. Goh, K.O. Lee, G. Morel, P.E. Lobie,
Autocrine human growth hormone (hGH) regulation of human
mammary carcinoma cell gene expression. Identification of
CHOP as a mediator of hGH-stimulated human mammary car-
cinoma cell survival. J. Biol. Chem. 279, 21464–21475 (2001)
270. R. Graichen, D.Z. Liu, Y. Sun, K.O. Lee, P.E. Lobie, Autocrine
human growth hormone inhibits placental transforming growth
factor-bgene transcription to prevent apoptosis and allow cell
cycle progression of human mammary carcinoma cells. J. Biol.
Chem. 277, 26662–26672 (2002)
271. S.E. Brunet-Dunand, C. Vouyovitch, S. Araneda, V. Pandey,
L.J.P. Vidal, C. Print, H.C. Mertani, P.E. Lobie, J.K. Perry,
Autocrine human growth hormone promotes tumor angiogenesis
in mammary carcinoma. Endocrinology 150, 1341–1352 (2009)
272. X.Q. Xu, B. Starling Emerald, E.L.K. Goh, N. Kannan, L.D.
Miller, P.D. Gluckman, E.T. Liu, P.E. Lobie, Gene expression
profiling to identify oncogenic determinants of autocrine human
growth hormone in human mammary carcinoma. J. Biol. Chem.
280, 23987–24003 (2005)
273. J.K. Perry, N. Kannan, P.M. Grandison, M.D. Mitchell, P.E.
Lobie, Are trefoil factors oncogenic? Trends Endocrinol. Metab.
19, 74–81 (2008)
274. J.K. Perry, K.M. Mohankumar, B.S. Emerald, H.C. Mertani,
P.E. Lobie, The contribution of growth hormone to mammary
neoplasia. J. Mammary Gland Biol. Neoplasia 13, 131–145
275. S. Pyronnet, C. Bousquet, S. Najib, R. Azar, H. Laklai, C. Su-
sini, Antitumor effects of somatostatin. Mol. Cell. Endocrinol.
286, 230–237 (2008)
276. A.V. Schally, J.L. Varga, Antagonistic analogs of growth hor-
mone-releasing hormone: new potential antitumor agents.
Trends Endocrinol. Metab. 10, 383–391 (1999)
277. M.J. van den Eijnden, G.J. Strous, Autocrine growth hormone:
effects on growth hormone receptor trafficking and signaling.
Mol. Endocrinol. 21, 2832–2846 (2007)
278. E. Tallet, V. Rouet, J.B. Jomain, P.A. Kelly, S. Bernichtein,
V. Goffin, Rational design of competitive prolactin/growth
hormone receptor antagonists. J. Mammary Gland Biol. Neo-
plasia 13, 105–117 (2008)
279. R. Dehari, Y. Nakamura, N. Okamoto, H. Nakayama, Increased
nuclear expression of growth hormone receptor in uterine cer-
vical neoplasms of women under 40 years old. Tohoku J. Exp.
Med. 216, 165–172 (2008)
280. B.L. Conway-Campbell, J.W. Wooh, A.J. Brooks, D. Gordon,
R.J. Brown, A.M. Lichanska, H.S. Chin, C.L. Barton, G.M.
Boyle, P.G. Parsons, D.A. Jans, M.J. Waters, Nuclear targeting
of the growth hormone receptor results in dysregulation of cell
proliferation and tumorigenesis. Proc. Natl Acad. Sci. USA 104,
13331–13336 (2007)
281. A.J. Brooks, J.W. Wooh, K.A. Tunny, M.J. Waters, Growth
hormone receptor; mechanism of action. Int. J. Biochem. Cell
Biol. 40, 1984–1989 (2008)
282. K.L. Hull, M. Luna, S. Harvey, C. Aramburo, Growth Hormone:
A Pituitary and Extrapituitary Chameleon During Development,
in Functional Avian Endocrinology, ed. by A. Dawson,
P.J. Sharp (Narosa Publishing House, New Delhi, 2005),
pp. 389–400
283. B.D. Anawalt, G.R. Merriam, Neuroendocrine aging in men.
Andropause and somatopause. Endocrinol. Metab. Clin. North
Am. 30, 647–669 (2001)
284. C.J. Rosen, Growth hormone and aging. Endocrine 12, 197–201
285. A.A. Toogood, S.M. Shalet, Conflicts with the somatopause.
Growth Horm. IGF Res. 8, 47–54 (1998)
286. D.A. Weigent, J.B. Baxter, W.E. Wear, L.R. Smith, K.L. Bost,
J.E. Blalock, Production of immunoreactive growth hormone by
mononuclear leukocytes. FASEB J. 2, 2812–2818 (1988)
287. Martinez-Moreno, M. Luna, C. Aramburo, Growth hormone
secretion in chicken testicular cell culture. Abstract P115, Pro-
ceedings of the 23rd Conference of European Comparative
Endocrinologists, Manchester, UK, p. 127 (2006)
288. D.A. Weigent, J.E. Blalock, Expression of growth hormone by
lymphocytes. Int. Rev. Immunol. 4, 193–211 (1989)
289. W.M. Rohn, D.A. Weigent, Cloning and nucleotide sequencing
of rat lymphocyte growth hormone cDNA. Neuroimmunomod-
ulation 2, 108–114 (1995)
290. C.L. Render, K.L. Hull, S. Harvey, Neural expression of the
pituitary GH gene. J. Endocrinol. 147, 413–422 (1995)
291. C.L. Render, K.L. Hull, S. Harvey, Expression of the growth
hormone gene in immune tissues. Endocrine 3, 729–735 (1995)
292. P.J. Selman, J.A. Mol, G.R. Rutteman, E. van Garderen, A.
Rijnberk, Progestin-induced growth hormone excess in the dog
originates in the mammary gland. Endocrinology 134, 287–292
293. Y.M. Bohlooly, B. Olsson, C.E. Bruder, D. Linden, K. Sjorgren,
M. Bjursell, E. Egecioglu, L. Svensson, P. Brodin, J.C. Water-
ton, O.G. Isaksson, F. Sundler, B. Ahren, C. Ohlsson, J.
Oscarsson, J. Tornell, Growth hormone expression in the central
nervous system results in hyperphagia-induced obesity associ-
ated with insulin resistance and hyslipidemia. Diabetes 54,
51–62 (2005)
294. B. Olsson, Y.M. Bohlooly, S.M. Fitzgerald, F. Frick, A.
Ljungberg, B. Ahren, J. Tornell, G. Bergstrom, J. Oscarsson,
Bovine growth hormone transgenic mice are resistant to diet-
induced obesity but develop hyperphagia, dyslipidemia, and
diabetes on a high-fat diet. Endocrinology 146, 920–930 (2005)
295. D.E. Berryman, E.O. List, K.T. Coshcigano, K. Behar, J.K. Kim,
J.J. Kopchick, Comparing adiposity profiles in three mouse
models with altered GH signaling. Growth Horm. IGF Res. 14,
309–318 (2004)
296. P.G. Hollingshead, L. Martin, S.L. Pitts, T.A. Stewart, A dom-
inant phenocopy of hypopituitarism in transgenic mice resulting
from central nervous system synthesis of human growth hor-
mone. Endocrinology 125, 1556–1564 (1989)
297. D.M. Flavell, T. Wells, S.E. Wells, D.F. Carmignac, G.B.
Thomas, I.C.A.F. Robinson, Dominant dwarfism in transgenic
rats by targeting human growth hormone (GH) expression to
hypothalamic GH-releasing factor neurons. EMBO J. 15,
3871–3879 (1996)
298. T. Wells, D.M. Flavell, S.E. Wells, D.F. Carmignac, I.C.A.P.
Robinson, Effects of growth hormone secretagogues in the trans-
genic growth-retarded (Tgr) rat. Endocrinology 138, 580–587
299. E. Pellegrini, D.F. Carmignac, M.T. Bluet-Pajot, F. Mounier, P.
Bennett, J. Eqelbaum, I.C.A.F. Robinson, Intrahypothalamic
growth hormone feedback: from dwarfism to acromegaly in the
rat. Endocrinology 138, 4543–4551 (1997)
300. S.E. Wells, D.M. Flavell, G.W. Bisset, P.A. Houston, H.
Christian, K.M. Fairhall, I.C.A.F. Robinson, Transgenesis and
neuroendocrine physiology: a transgenic rat model expression
growth hormone in vasopressin neurons. J. Physiol. 55, 323–336
301. D. Le Roith, Clinical relevance of systemic and local IGF-1:
lessons from animal models. Pediatr. Endocrinol. Rev. 5(supp),
12739–12743 (2008)
302. S. Yakar, Y. Wu, J. Setser, C.J. Rosen, The role of circulating
IGF-1: lessons from human and animal models. Endocrine 19,
239–248 (2002)
303. J. Bernichtein, P. Touraine, V. Goffin, New concepts in prolactin
biology. J. Endocrinol. 206, 1–11 (2010)
358 Endocr (2010) 38:335–359
304. K. Foitzik, E.A. Langan, R. Paus, Prolactin and the skin: a
dermatological perspective on an ancient pleiotropic peptide
hormone. J. Invest. Dermatol. 129, 1071–1087 (2009)
305. N. Ben-Jonathan, K. Liby, M. McFarland, M. Zinger, Prolactin
as an autocrine/paracrine growth factor in human cancer. Trends
Endocrinol. Metab. 13, 245–250 (2002)
306. D. Shoback, J.L. Funk, Ectopic Hormone and Receptor Syn-
dromes, in Greenspan’s Basic & Clinical Endocrinology, ed. by
F.S. Greenspan, D.G. Gardner (Lange Medical Books, McGraw
Hill, New York, 2001), pp. 778–791
307. P.C. Kohler, D.L. Trump, Clinical science review: ectopic
hormone syndromes. Cancer Invest. 4, 543–554 (1986)
308. M. Terzolo, G. Reimondo, A. Ali, S. Bovio, F. Daffara, P.
Paccotti, A. Angeli, Ectopic ACTH syndrome. Ann. Oncol. 12,
S83–S87 (2001)
309. R.C. Osthus, B. Karim, J.E. Prescott, B.D. Smith, M. McDevitt,
D.L. Huso, C.V. Dang, The Myc target gene JP01/CDCA7 is
frequently overexpressed in human tumors and has limited
transforming activity in vivo. Cancer Res. 65, 5620–5627 (2005)
310. N.R. Smalheiser, Proteins in unexpected locations. Mol. Biol.
Cell 7, 1003–1014 (1996)
311. S. Harvey, Y. Azumaya, K.L. Hull, Pituitary and extrapituitary
growth hormone: Pit-1 dependence? Can. J. Physiol. Pharmacol.
78, 1013–1028 (2000)
312. N. Hattori, Expression regulation and biological actions of
growth hormone (GH) and ghrelin in the immune system.
Growth Horm. IGF Res. 19, 187–197 (2009)
313. M. Ballesteros, K.C. Leung, R.J. Ross, T.P. Lismaa, K.K. Ho,
Distribution and abundance of messenger ribonucleic acid for
growth hormone receptor isoforms in human tissue. J. Clin.
Endocrinol. Metab. 85, 2865–2871 (2000)
314. H.C. Mertani, G. Morel, In situ gene expression of growth
hormone (GH) receptor and GH binding protein in adult male rat
tissues. Mol. Cell. Endocrinol. 109, 47–61 (1995)
315. T.S. Tiong, A.C. Herington, Tissue distribution, characteriza-
tion, and regulation of messenger ribonucleic acid for growth
hormone receptor and serum binding protein in the rat. Endo-
crinology 129, 1628–1634 (1991)
316. C.J. Strasburger, M.T. Dattani, New growth hormone assays:
potential benefits. Acta Paediatr. Suppl. 423, 5–11 (1997)
317. E.A. Chaler, P. Travaglino, S. Pagani, E. Bozzola, R. Marino,
E. Berensztein, M. Maceiras, M. Tauber, M.A. Rivarola,
A. Belgorosky, M. Bozzola, Dose dependency of the serum bio/
immuno GH ratio in children during pharmacological secretion
tests. J. Endocrinol. Invest. 29, 109–114 (2006)
318. M.E. Geffner, The growth without growth hormone syndrome.
Endocrinol. Metab. Clin. North Am. 25, 649–663 (1996)
Endocr (2010) 38:335–359 359
... In these extrapituitary tissues, the locally produced GH acts to regulate the proliferation, differentiation and metabolism of the adjacent cells in an autocrine or paracrine manner even prior to the ontogeny of the pituitary gland (16). Recent studies have demonstrated the significant roles of extrapituitary GH in physiology, pathophysiology, and oncogenesis (17). ...
... Similarly, Ghr mRNA has also been detected in the uterine cells of cattle, cows, and pigs (27, 29, 30). In humans, GHR is expressed in the myometrium and decidua of the uterus (17,31). Additionally, GHR mRNA transcripts are detected in leiomyoma and its surrounding myometrium obtained from premenopausal women (32). ...
Full-text available
Secreted by the anterior pituitary gland, growth hormone (GH) is a peptide that plays a critical role in regulating cell growth, development, and metabolism in multiple targeted tissues. Studies have shown that GH and its functional receptor are also expressed in the female reproductive system, including the ovaries and uterus. The experimental data suggest putative roles for GH and insulin-like growth factor 1 (IGF-1, induced by GH activity) signaling in the direct control of multiple reproductive functions, including activation of primordial follicles, folliculogenesis, ovarian steroidogenesis, oocyte maturation, and embryo implantation. In addition, GH enhances granulosa cell responsiveness to gonadotropin by upregulating the expression of gonadotropin receptors (follicle-stimulating hormone receptor and luteinizing hormone receptor), indicating crosstalk between this ovarian regulator and the endocrine signaling system. Notably, natural gene mutation of GH and the age-related decline in GH levels may have a detrimental effect on female reproductive function, leading to several reproductive pathologies, such as diminished ovarian reserve, poor ovarian response during assisted reproductive technology (ART), and implantation failure. Association studies using clinical samples showed that mature GH peptide is present in human follicular fluid, and the concentration of GH in this fluid is positively correlated with oocyte quality and the subsequent embryo morphology and cleavage rate. Furthermore, the results obtained from animal experiments and human samples indicate that supplementation with GH in the in vitro culture system increases steroid hormone production, prevents cell apoptosis, and enhances oocyte maturation and embryo quality. The uterine endometrium is another GH target site, as GH promotes endometrial receptivity and pregnancy by facilitating the implantation process, and the targeted depletion of GH receptors in mice results in fewer uterine implantation sites. Although still controversial, the administration of GH during ovarian stimulation alleviates age-related decreases in ART efficiency, including the number of oocytes retrieved, fertilization rate, embryo quality, implantation rate, pregnancy rate, and live birth rate, especially in patients with poor ovarian response and recurrent implantation failure.
... Although pituitary-derived endocrine GH is a key driver of the musculoskeletal effects of GH, locally produced autocrine/ paracrine GH, also known as extrapituitary GH, also plays a major role in the growth and development of muscle and bone (Harvey, 2010). Evidence for the local production of GH is the increased (relative to serum) concentration of GH in the cartilage and synovial fluid of joints (Isaksson et al., 1991;Denko and Malemud, 2005), as well as in skeletal muscle (Kyle et al., 1981;Costa et al., 1993). ...
Full-text available
Growth hormone (GH) is a peptide hormone that can signal directly through its receptor or indirectly through insulin-like growth factor 1 (IGF-1) stimulation. GH draws its name from its anabolic effects on muscle and bone but also has distinct metabolic effects in multiple tissues. In addition to its metabolic and musculoskeletal effects, GH is closely associated with aging, with levels declining as individuals age but GH action negatively correlating with lifespan. GH’s effects have been studied in human conditions of GH alteration, such as acromegaly and Laron syndrome, and GH therapies have been suggested to combat aging-related musculoskeletal diseases, in part, because of the decline in GH levels with advanced age. While clinical data are inconclusive, animal models have been indispensable in understanding the underlying molecular mechanisms of GH action. This review will provide a brief overview of the musculoskeletal effects of GH, focusing on clinical and animal models.
... Elle est le principal régulateur du facteur de croissance de type insulinique 1 (IGF1), qui est sécrété par les tissus cibles, en particulier le foie. L'augmentation de la GH et de l'IGF1 sériques produit des circuits de rétroaction qui entraînent l'inhibition de la GHRH, la libération de somatostatine et, par conséquent, l'inhibition de la sécrétion de GH par l'hypophyse (Harvey 2010 ;Perry et al. 2013). ...