Growth Hormone
Scott Chappel1 and William Murphy2,*
1
Serono Corp., 100 Longwater Circle, PO Box B, Norwell, MA 02061, USA
2
Transplantation Biology Section, SAIC Frederick, Building 567, Room 210 PO Box B,
Frederick, MD 21702-1201, USA
* corresponding author fax: 301-846-6641, e-mail: murphyw@ncifcrf.gov
DOI: 10.1006/rwcy.2000.03012.
SUMMARY
Growth hormone (GH), while primarily noted for its
anabolic effects, has also been demonstrated to have
effects on immune cell development and function.
Receptors for GH have been found to be present on a
variety of immune cell types and numerous effects on
immune cell functions have been reported. With the
advent of recombinant material, it has become pos-
sible to delineate the effects of GH under more
stringent conditions. However, GH may exert many
of its effects indirectly through the induction and
release of IGF-1. In addition, many of the immune
effects ascribed to GH in immune system develop-
ment and function have utilized neurendocrine
hormone-deficient dwarf animals, which are deficient
in hormones other than GH, making interpretation
concerning the role of GH in immune development
and function difficult. In addition, human GH can
bind the prolactin receptor. Recent data suggest that
GH may have effects on immune cell function under
periods of stress, either directly or through IGF-1,
and may work in concert with other cytokines.
BACKGROUND
, and TNF are released by immune cells in
Discovery
Growth hormone (GH) has long been considered a
pleiotropic molecule. Its ability to stimulate the
growth and differentiation of muscle, bone, and
cartilage is well known (Daniels and Martin, 1991). In
addition to the pituitary gland, GH is synthesized
within many other tissues, including the hematopoie-
tic system (Clark, 1997). This suggests that it may
have autocrine/paracrine mechanisms of action. As
a result of molecular analysis, the genes for GH and
its receptor have been classified as members of the
hematopoietic growth factor/receptor superfamily
(Hooghe et al., 1993). Despite literature to support
an effect of GH upon immune function, there are no
convincing data as to its significance or relevance as
a hematopoietic or immunomodulating agents in
humans. This review will summarize the biological
actions of GH as they relate to the immune system
and consider the clinical utility of GH as an immuno-
modulating agent.
Main activities and
pathophysiological roles
Communication between Organ Systems
Interactions between organ systems are essential for
survival of all species. When critical information is
received by one system, it is relayed to others to
ensure and coordinate optimal responses. Many
interactions have been described between the endo-
crine and immune systems (Weigent and Blalock,
1987; Berczi, 1994; Weigent, 1996).
Products of the immune system have a direct effect
upon endocrine function. Cytokines such as IL-1,
IL-6, IFN
response to an invading pathogen. Many of these
acute stress cytokines have been shown to induce the
release of pituitary hormones, including prolactin,
ACTH, and GH (Besedovsky and Del-Rey, 1996).
Thus, when the immune system reacts to an acute
stimulus, a portion of that response involves the
release of hormones, including GH.
Products of the endocrine system also affect the
activity of immune cells. Stressful situations elicit the
252 Scott Chappel and William Murphy
release of adrenal glucocorticoids, which are potent
inhibitors of the immune system. Pituitary GH is
also released during stress and influences the immune
system in many species (Berczi, 1994; Blalock and
Weigent, 1994; Besedovsky and Del-Rey, 1996).
Immune cells themselves appear to produce specific
endocrine hormones, including GH (Weigent et al.,
1988; Sabharwal and Varma, 1996; Wu et al., 1996),
prolactin (Gala, 1991; Kooijman et al., 1996) and
their receptors. The capacity of immune cells to
respond to pituitary GH and produce it locally argues
for a role of that hormone in normal immune
function.
Neural Regulation of Pituitary
GH Biosynthesis and Release
The hypothalamus receives and integrates neural
and humoral information from the internal and
external environment. Following integration of that
information, the hypothalamus initiates the body's
response. Often, that response involves the secretion
of hormone, such as GH. Due to its many metabolic
actions, the release of GH is very tightly regulated
(Thorner et al., 1997). Specifically, two hypothalamic
peptides, GHRH and somatostatin (SRIF), are
involved in the control of GH secretion (Figure 1).
GHRH stimulates GH biosynthesis and release from
the pituitary (Frohman et al., 1992). GH exerts a
negative feedback on future GH secretion by de-
creasing the production of additional GHRH and its
receptor (Frohman et al., 1992; Kamegai et al., 1998).
GH also increases the activity of SRIF neurons in
the hypothalamus to inhibit its own secretion (Zheng
et al., 1997). SRIF inhibits GH release from the
pituitary. Following inhibition of GH pulses, soma-
tostatin tone gradually declines (Thorner et al., 1990)
and pulses of GH are reinitiated. GH pulses cannot
Figure 1 Circuit diagram of
pituitary GH neuroendocrine
control and feedback.
GRF
Hypothalamus
SRIH
+ –
Pituitary
GH
Peripheral sites
Metabolic
effects
IGF-1
occur solely by a decrease in somatostatin tone.
Hypothalamic GHRH is required to stimulate each
GH pulse (Ocampo-Lim et al., 1996).
The Classical GH/IGF-1 Axis
The growth hormone/insulin-like growth factor
(IGF-1) axis has been well studied and plays a critical
role in growth and development of many different
organ systems within the body. Growth hormone
does not act alone to stimulate mitogenesis and
differentiation in all tissues. Specific receptors for GH
are found on the liver and following GH receptor
activation, hepatocytes produce IGF-1. IGF-1 con-
sists of 70 amino acids and is carried in the circulation
as a protein complex. IGF-1 is also produced locally
by a number of other tissues (Daniels and Martin,
1991). Both GH and IGF-1 exert growth-promoting
and metabolic effects on many different tissues
including the immune system.
GENE AND GENE REGULATION
Accession numbers
GenBank:
Growth hormone gene: J00148, K00612 (Martial
et al., 1979)
Growth hormone locus: J03071 (Chen et al., 1989)
Chromosome location
The growth hormone gene is a member of the four
helical bundle hematopoietic gene superfamily that is
comprised mostly of cytokines and hematopoietic
growth factors. The human chromosomal growth
hormone locus has evolved as a series of gene dupli-
cations and consists of a cluster of five genes that
have approximately 95% sequence identity. This gene
cluster spans 47 kb on chromosome 17(q22±q24).
DNA sequencing of the GH locus has revealed the
presence of hGH-N(ormal) which is transcribed in the
pituitary and in the lymphoid and myeloid families of
cells (Binder et al., 1994; Palmetshofer et al., 1995;
Rohn and Weigent, 1995). Four other genes have also
been identified (hCS-L, hCS-A, hCS-B, and hGH-
V(ariant)). These four genes are expressed primarily
in the placenta.
The hGH-N gene is interrupted by four intervening
sequences that have different splice sites. These
differences in splice sites allow for the generation of
hGH of different sizes found within the normal
pituitary gland (DeNoto et al., 1981). Splice variants

have also been described in the other four transcripts
within the placenta (MacLeod, et al., 1992).
Relevant linkages
The five GH locus genes plus the thyroid hormone
receptor interacting protein (TRIP-1) are all found on
the same chromosome in the human, pig, and rat
genome and may be physically linked. There is also a
physical linkage to the CD79b gene which is B cell
specific (Bennani-Baiti et al., 1998).
Regulatory sites and corresponding
transcription factors
Tissue specificity of expression is provided by pro-
moter regions found upstream of coding sequences.
The pituitary-specific transcription factor, POU1F1
(the human homolog of murine pit-1/GHF-1) regu-
lates the expression of pituitary GH, prolactin, and
thyroid-stimulating hormone through binding to
specific regions of the promoters of these genes (Li
et al., 1990). GHF-1/Pit-1 binds the 50 flanking DNA
of the GH gene at two sites: ÿ96/ÿ70 and ÿ134/
ÿ106. GHF-1 transcription is autoregulated and is
also affected by factors that control cAMP levels
within cells, such as GH-releasing hormone binding
to its receptor. Upregulation of GHF-1 expression
induces an increase in the rate of transcription of the
GH gene. Mutations of the pit-1 gene are responsible
for the syndrome of combined pituitary hormone
deficiency (Radovick et al., 1992). Pit-1 gene expres-
sion is also found in lymphoid and thymic cells that
express GH (Delhase et al., 1993; Chen et al., 1997;
Kooijman et al., 1997a, 1997b).
Thyroid hormone also upregulates GH gene
expression. The TH receptor is part of the nuclear
receptor superfamily and when occupied, binds to
GH promoter sequences at its now well-characterized
consensus sequence. The GH gene also contains
upstream binding sites for the glucocorticoid recep-
tor. Two receptor binding sites have been identified,
one at ÿ290 bp and another at +251 bp (Eliard et al.,
1985). Glucocorticoids have been shown to rapidly
increase accumulation of GH mRNA. Retinoic acid
has also been shown to induce the expression of the
GH gene. The GH promoter contains a hormone
response element that binds TR/RXR and RAR/
RXR heterodimers located close to two binding sites
for GHF-1. Thus, many different factors regulate the
expression of the GH gene. A review of all factors
that affect GH gene expression can be found in Theill
and Karin (1993).
Growth Hormone 253
PROTEIN
Accession numbers
Human growth hormone: NM000515
Description of protein
Growth hormone is a polypeptide of 191 amino acids.
It is a member of a class of hematopoietic growth
factors that possess an antiparallel four  helix
bundle fold. Proteins of the hematopoietic growth
factor superfamily, such as GH, bind to specific
receptors that are single pass, transmembrane recep-
tors from class 1 of the hematopoietic receptor
superfamily.
The ligand has also been co-crystallized with its
receptor (Somers et al., 1994). High-resolution muta-
tional and structural analysis of GH have provided a
great deal of information about the ligand's binding
to its receptor. hGH binds to hGH receptor on cell
membranes through site 1 and subsequently forms
a dimer by binding a second monomeric receptor
through site 2. Dimerized receptors are able to inter-
act with intracellular components to transmit a signal
(Figure 2) (Wells et al., 1993).
Discussion of crystal structure
The crystal structure of hGH has been reported
(Ultsch et al., 1994).
Figure 2 GH induces dimerization
of its receptor in GH responsive
cells which stimulates intracellular
signaling.
GH
responsive
cell
GH
GH
responsive
cell
JAK-STAT
254 Scott Chappel and William Murphy
Important homologies
Hematopoietic growth factors play important roles
in immune cell development and function (Hooghe
et al., 1993). The receptors and their ligands in this
family include GM-CSF, G-CSF, erythropoietin,
IL-2, IL-3, IL-4, IL-6, IL-11, and IL-13 (Wells and
de Vos, 1993). The binding surfaces of hGH and its
receptor and that of IL-4 and its receptor show
complementary structures and electrostatic potentials
(Demchuk et al., 1994). In all cases, the ligand induces
cross-linking of the receptor, which induces the
activation of intracellular signaling pathways, includ-
ing the JAK/STAT system (Carter-Su et al., 1996).
CELLULAR SOURCES AND
TISSUE EXPRESSION
Cellular sources that produce
Extrahepatic Location of GH Receptors
Lymphoid tissue of chickens, mice, rats, cattle and
humans has been shown to express high-affinity
receptors for GH (Kiess and Butenandt, 1985; Hull
et al., 1996; Clark, 1997; Chen et al., 1998; Dardenne,
et al., 1998; de Mello-Coelho et al., 1998) and IGF-1
(Clark, 1997). The GH receptor gene is also expressed
in T cells, B cells, and monocytes from humans and
rats (Badolaro et al., 1994; Rapaport et al., 1995).
Not only is the GH receptor present in lymphoid
tissue, but its expression is increased following acti-
vation of murine or bovine lymphoid cells by lectins
or anti-CD3 antibodies (Gagnerault et al., 1996;
Postel-Vinay et al., 1997; Dardenne et al., 1998).
Receptors for GH and IGF-1 are also located on
thymic epithelial cells (Ban et al., 1991).
Extrapituitary Expression of GH
In addition to being responsive to GH, cells of the
rodent and human immune system (peripheral
lymphocytes, thymus, and spleen) have been shown
to produce the protein. GH appears to serve as a local
signaling molecule (Weigent et al., 1988; Baxter et al.,
1991; Hattori et al., 1994; Varma et al., 1993,
Maggiano et al., 1994; Wu et al., 1996; de Mello-
Coelho et al., 1998). Differences in the amount of
expression of GH have been observed in immune cells
of different states of activation (Weigent et al., 1988;
Hattori et al., 1994). GH expression has also been
detected in a thymoma, a T cell lymphoma, B cell
lymphoma (Wu et al., 1996), as well as lymphoid and
myelomonocytic cell lines (Palmetshofer et al., 1995).
As an immune modulator, GH may be delivered
either from the pituitary or it may be synthesized
and secreted locally by lymphoid tissue. This suggests
that the immunoregulatory action of GH may be
the result of endocrine, paracrine, and/or autocrine
communication.
RECEPTOR UTILIZATION
GH receptors (GHR) have been shown to be
expressed on a variety of cell types including immune
cells. GHR have been described on human B cells
(Badolaro et al., 1994), thymic cells (de Mello-Coelho
et al., 1998), and activated human tonsilar T cells
(Thellin (1998). In addition, murine GHR have been
found to be expressed on all hematopoietic lineages
and multiple lymphocyte subsets in all major organs
of the immune system to varying degrees (Gagnerault
et al., 1996). Upon binding GH, the receptor di-
merizes and signals through JAK2 kinase (Harding
et al., 1996). However, the expression of GH recep-
tors during immune cell development and particularly
during disease and periods of stress have not been
elucidated.
IN VITRO ACTIVITIES
In vitro findings
The Thymus
The thymus is a unique microenvironment that plays
a major role in T cell lymphopoiesis. Through both
cellular and humoral interactions, the thymus shapes
the T cell repertoire. GH and IGF-1, expressed locally
or delivered from the systemic circulation, can exert
an effect upon this function. This may be through an
effect upon the T cells that migrate through the
thymus or on the thymus itself (Figure 3).
T cell precursors are produced in the bone marrow
and migrate to the thymus where a small percentage
is allowed to develop. They are exported from the
thymus to the periphery to perform their functions.
Developing T cells are both positively and negatively
selected based on their ability to recognize peptides
bound to self major histocompatibility complex
(MHC) proteins. The majority of developing cells are
destroyed in the thymus. Thus, the thymus plays an
important role in the constant production and selec-
tion of naõÈ ve T cells to defend the body against invad-
ing pathogens. As the individual ages, the thymus
 Growth Hormone 255

Figure 3 The role of growth hormone, IGF-1, and somatostatin on immune development. GH and IGF-1
have been demonstrated to promote hematopoiesis, particularly the megakaryocyte and erythroid lineages,
both in vitro and in vivo. Somatostatin has been demonstrated to inhibit hematopoietic growth factor release
by lymphocytes and therefore may exert inhibitory effects on hematopoiesis in vivo. GH and IGF-1 have also
been demonstrated to promote early B cell development which occurs in the bone marrow (BM). There is
evidence that NK cell development, also believed to occur in the BM, is upregulated by GH. Both GH and
IGF-1 have been found to promote the survival of T cell progenitors. Both GH and IGF-1 have been
demonstrated to promote T cell development in the thymus, although the precise stage(s) have yet to be
delineated. GH and IGF-1 have been found to promote T cell chemotaxis and therefore may play a role in
normal lymphocyte circulation to the lymph nodes and spleen. At these lymphoid organs an immune response
can occur and both GH and IGF-1 can promote, whereas somatostatin may inhibit, antigen-specific immune
function.

†
+ ? IGF-1
T +
GH + ?
pre-T pre-T

Thymus T

Lymph node
GH +
+ T Mφ
IGF-1 pro-T GH B
+
+ ? IGF-1
+
? –
Bone PSC ? NK
IGF-1
marrow Somatostatin
GH +
MSC LSC + GH GH
+
IGF-1 ? –
RBC pre-B +
+ +
PMN sigM– Spleen
pre-B
PLT
GH Monocyte Mφ
sigMto B
+
IGF-1 ? B
+ – B220 ++ sigMn T
Somatostatin

involutes. Circulating levels of GH show a similar
age-related decline. As described below, administra-
tion of GH to aged individuals improves thymic
function. This decrease in thymic function reduces its
ability to support optimal T cell development. The
number of naõÈ ve T cells declines, with a resultant
increase in the relative number of memory T cells in
the periphery. Suboptimal function of the aged
immune system is due, in part, to thymic involution
and may be due at least in part by reductions in
pituitary GH release.
Effects of GH on Thymic Cells
Both GH and IGF-1 stimulate thymic growth,
cellularity, and function (Berczi et al., 1991; Gala,
1991; Murphy et al., 1992d; Berczi, 1994; Savino et al.,
1995; Montecino-Rodriguez et al., 1998), as well as
the function and proliferation of thymic epithelial
cells (TEC) (Timsit et al., 1992). Thymulin, a hor-
mone produced by the thymus that plays a role in
the development and maintenance of immune func-
tion, is synthesized and secreted in greater amounts
under the influence of GH and IGF-1 (Goff et al.,
1987; Timsit et al., 1992). Thymulin and other thymic
peptides have differentiating properties on T cell
maturation (Robert and Geenen, 1992). GH stimu-
lates DNA synthetic activity of thymic lymphocytes
directly or indirectly through its effects upon the
function of thymic epithelial cells (Sabharwal and
Varma, 1996; Fukushima et al., 1997; Lin et al.,
1997).
256 Scott Chappel and William Murphy

Effects of GH on Thymocytes and Thymic Function proliferation in rats and monkeys (Berzi, 1994; Kelley
et al., 1996; Kooijman et al., 1992; Binder et al., 1994;
Thymocytes have been shown to synthesize both GH
LeRoith et al., 1996; Geffner, 1997). Growth hor-
and IGF-1 (Sabharwal and Varma, 1996). A dose-
mone has been shown to increase the activity of
related increase in thymocyte proliferation has been
cytotoxic T cells in mixed lymphocyte cultures (Snow
demonstrated in cultures of cells by the addition of
et al., 1981; Benfield et al., 1994) (Figure 4).
GH or IGF-1 (Gala, 1991; Weigent, 1996; Murphy
GH promotes the differentiation of T helper cell
et al., 1995; Kelley et al., 1996). GH stimulates the
subsets from uncommitted TH0 cells and stimulates
transcription of cytokines within fetal thymocytes,
TH1-type immune responses (Gonzalo et al., 1996).
specifically, IL-1, IL-6, and GM-CSF (Chen et al.,
When administered at the time of immunization, GH
1998). These cytokines are involved in thymocyte
induces a TH1 cytokine response to HIV-1 envelope
development and proliferation. The expression of
protein gp120 compared with controls (Mellado et al.,
extracellular matrix ligands and their receptors, to
1998). Administration of human GH increases T cell
allow for increases in T cell trafficking, is increased by
progenitor development in mice that are deficient in
GH exposure. This improves thymocyte adhesion to
endogenous GH (Murphy et al., 1993).
thymic epithelial cells which play a key role in
intrathymic T cell differentiation (Taub et al., 1994;
de Mello-Coelho et al., 1997).2 Local Expression of GH and IGF-1 by T cells
T cells have the transcription factors necessary to
Effects of GH on Peripheral T Cells
express the mRNA for GH and produce biologically
Binding of GH to its high-affinity receptor expressed active GH and IGF-1 in culture (Weigent et al., 1988;
on T cells exerts a number of responses. These include Geffner et al., 1990; Baxter et al., 1991; Delhase et al.,
the expression of IGF-1, an increase in T cell prolif- 1993; Hooghe et al., 1993; Varma et al, 1993; Hattori
eration and augmented lectin- and anti-CD3-induced et al., 1994; Auernhammer and Strasburger, 1995;

Figure 4 Role of GH, IGF-1, and somatostatin on immune function.

Antigen (Ag) is phagocytosed by antigen-presenting cells (APCs) and
proteolytically porcessed. It is then bound with class II MHC
molecules on the cell surface. GH and IGF-1 have been demonstrated
to augment macrophage function and therefore may affect Ag
processing. Somatostatin has been shown to inhibit inflammatory
responses. Both GH and IGF-1 have been found to promote T cell
proliferation and function (i.e. cytokine production or cytotoxicity).
Somatostatin may inhibit these activities. GH and IGF-1 have also
been shown to induce B cell proliferation and immunoglobulin (Ig)
production and act as switch factors for particular isotypes.

CD8 +
cytotoxic
T-cell GH
+ +
Somatostatin
GH IGF-1 – ?
+ +
Ag +?
IGF-1
Ag Proliferation
+
Somatostatin processing +

– – CD4 + IGF-1
T-helper
Inflammatory TCR cell
cascade
APC
Cytokines Class II Ag
presentation
GH
B
+
cell + IGF-1

GH IGF-1 + Ig
+ Proliferation
+
IGF-1
Isotype
switching
Ig production

Sabharwal and Varma, 1996; Wu et al., 1996).
Leukocytes, activated by a nonspecific mitogen such
as PHA, secrete greater amounts of GH and IGF-1
than unstimulated cells (Weigent et al., 1988;
Gagnerault et al., 1996).
Experimental reductions in GH release or signaling
affect T cell proliferation. Administration of GH
antisera prevents the proliferation of lymphocytes in
culture (Pierpaoli and Sorkin, 1968; Weigent et al.,
1988). Decreases in GH signaling can also be achieved
by preventing the transcription or translation of the
GH gene. Antisense oligonucleotides against GH
mRNA, when incubated with lymphocytes, reduces
their rate of proliferation (Weigent et al., 1991).
Effects of GH and IGF-1 on NK Cell Function
IGF-1 and GH bind with high affinity and specificity
to NK cells. Both of these hormones have been shown
to stimulate CD16+ natural killer cell activity
(Bidlingmaier et al., 1997). Natural killer cell activity
is depressed in aged rats and administration of GH
can restore function (Davila et al., 1987). A decrease
in NK cell function has been demonstrated in GH-
deficient patients (Crist et al., 1987; Bozzola et al.,
1990). Administration of recombinant GH corrected
the decrease in NK activity in GH-deficient children
(Berczi, 1994).
Effects of GH and IGF-1 on B Cells
GH stimulates thymidine incorporation into human
plasma cell lines and can increase the production of
immunoglobulins (Igs) in these cells (Yoshida et al.,
1992, Kimata and Yoshida, 1994; Kimata and
Fujimoto, 1994). In addition, GH has been shown
to enhance the production of many different classes of
Igs including IgGs, IgAs, and IgMs (Kimata and
Fujimoto, 1994). These effects are blocked by coincu-
bation of B cells with antibodies against human GH.
GH and IGF-1 have been shown to induce IgE and
IgG class switching (Geffner, 1997; Rapaport and
Bozzola, 1997). GH administration increased splenic
follicles and splenic B cell populations in aged
monkeys (LeRoith et al., 1996). In contrast, transient
decreases in B cell numbers have been reported in
children during GH administration (Wit et al., 1993;
Rapaport and Bozzola, 1997).
Effects of GH and IGF-1 on Monocytes,
Macrophages, and Polymorphonuclear Cells
Monocyte chemotaxis is stimulated in vitro by the
administration of GH (Wiedermann et al., 1993b).
GH has also been shown to induce superoxide anion
production in macrophages (Edwards et al., 1988,
Growth Hormone 257
1992). In this report, GH-primed alveolar macro-
phages both in vitro and in vivo. GH has been shown
to improve immune function in burned mice by
increasing the production of cytostatic macrophages
(Takagi et al., 1997). GH can protect the host from
a lethal bacterial infection by promoting the matu-
ration and function of macrophages and other
phagocytes (Saito et al., 1996). Both GH and IGF-1
are potent signals for priming human and porcine
PMNs to secrete superoxide anions (O2) (Fu et al.,
1991; Wiedermann et al., 1993a). It appears that these
molecules act in a paracrine fashion to prime PMNs
for enhanced respiratory bursts. GH is expressed in
human neutrophils (Balteskard et al., 1997; Kooijman
et al., 1997b; Melen et al., 1997). GH may act to
increase host resistance to disease by increasing the
release of toxic oxygen metabolites by the innate
immune system to combat infections.
GH and Cytokines
The effects of GH on lymphoid cell activity,
engraftment, and migration may be the result of
stimulation of cytokines known to contribute to these
activities. GH stimulates the expression of IL-2
(Schimpff and Repellin, 1990) and several cytokines
by thymic epithelial cells (Tseng et al., 1997; Chen
et al., 1998). Likewise, IGF-1 potentiates the pro-
duction of IL-2 from human T cells and enhances the
rate of differentiation of progenitor cells to mature
lymphocytes (Clark, 1997). While there may be a
direct effect of GH and IGF-1 on immune cell
function, it may also be stimulated indirectly through
an effect on cytokine expression in the responsive
tissue.
GH and Hematopoiesis
GH administration promotes the proliferation of
hematopoietic cells, particularly bone marrow-
derived progenitor cells. In combination with GM-
CSF, GH doubled the number of precursor cells that
differentiated into granulocytes and stimulated
granulopoiesis in vitro (Merchav et al., 1988) as well
as a variety of other hematopoietic lineages in vivo
(Murphy et al., 1992c). GH and IGF-1 have been
shown to inhibit apoptosis in hematopoietic progeni-
tors (Minshall et al., 1998) and stimulate the produc-
tion of murine and human red blood cells in vitro
(Golde et al., 1976; Christ et al., 1997). In numerous
animal species, as well as humans, administration of
GH causes an increase in hemoglobin levels (Ten
Have et al., 1997).
As summarized above, GH exhibits effects upon
a variety of cell types within the immune system.
258 Scott Chappel and William Murphy
In addition to enhancing the inherent activities of
the cells, GH also acts with other factors to stimulate
hematopoiesis and immune cell development and
function.
IN VIVO BIOLOGICAL
ACTIVITIES OF LIGANDS IN
ANIMAL MODELS
Normal physiological roles
Hypophysectomy and Other Methods to
Reduce GH Signaling
Since 1930, it has been known that hypophysectomy
(removal of the pituitary gland) suppresses both
hematopoiesis and immune cell proliferation (Smith,
1930). It also induces a state of immunodeficiency and
thymic hypoplasia in rodents (Nagy et al., 1987; Gala,
1991). Administration of antiserum to GH also
induces thymic atrophy and smaller spleens in mice
and rats (Fabris et al., 1971; Berczi et al., 1983). These
defects in immune function in rodents can be reversed
by the administration of GH (Berczi et al., 1983).
Hypophysectomized rats have additional evidence
for impaired immune function such as reduced rates
of survival after bacterial infections (Edwards et al.,
1992), contact sensitivity to allergens (Berczi et al.,
1983), and reduced ability to produce antibodies and
reject skin allografts (Fabris et al., 1971). GH may act
to protect the host by stimulating leukocyte matura-
tion and migration, production of cytokines and
other chemoprotectants (Saito et al., 1996).
Injections of both GH and its primary IGF-1
increase the weight of lymphoid organs and induce
the proliferation and activity of cells within many
different components of the immune system
(Auernhammer and Strasburger, 1995, LeRoith
et al., 1996).
Knockout mouse phenotypes
Growth hormone-deficient mice (Snell-Bagg and
Ames) have been used in many studies to determine
the effect of GH on immune function. These mice
lack somatotropes (GH-secreting cells) and other
cell types (lactotropes and thyrotropes) within the
anterior pituitary gland. The molecular basis for the
dwarfism is the absence of a nuclear transcription
factor, pit-1, that is required for GH gene transcrip-
tion (Li et al., 1990). Pit-1-deficient dwarf mice have
impaired cell-mediated immune responses and
atrophy of the thymus and spleen. Dwarf mice have
deficits in CD4+ CD8+ double positive thymic
cells. These deficiencies are partially reversed by
administration of GH (Baroni et al., 1969; Murphy
et al., 1992b, 1992d; Schurmann et al., 1995).
Administration of GH to dwarf mice resulted in a
significant increase in thymocyte proliferation
(Murphy et al., 1993).
Immune function can also be partially restored by
administration of GH-producing lymphocytes into
these dwarf animals (Weigent and Blalock, 1994).
These experiments support the contention that pitu-
itary GH plays a significant role in immune function.
Transgenic overexpression
As further evidence for a role for GH as a stimulator
of hematopoiesis, mice transgenic for either bovine
GH or human GH-releasing hormone (hGHRH)
exhibited splenic hyperplasia with increased num-
bers of erythroid and megakaryocytic progenitors.
Further, splenocytes from these transgenic animals
had a higher proliferative index than controls when
infused into irradiated nontransgenic controls (Blazar
et al., 1995).
Mice treated with azidothymidine (AZT) to induce
myelotoxicity, show a significant increase in splenic
and bone marrow progenitor cell content and hema-
tocrit after the administration of recombinant human
or ovine GH. Bone marrow cellularity, hematocrit
values, white blood cell count, and splenic hemato-
poietic progenitor cell counts were all significantly
increased in this model after GH administration
(Murphy et al., 1992c). A similar effect is observed
after treatment of this mouse model with IGF-1
(Tsarfaty et al., 1994; Montecino-Rodriguez et al.,
1998). GH has been shown to increase thymic
recovery in rats after cyclosporin administration
(Beschorner et al., 1991). Recombinant human GH
also stimulates the engraftment of human or murine
T cells into severe combined immunodeficient (SCID)
mice (Murphy et al., 1992a).
Pharmacological effects
These reports show that GH has a wide variety of
effects upon the immune system in animals models
and in vitro. GH administration has an effect upon
thymic function, T cell proliferation and colonization
within the thymus, migration, and engraftment (Taub
et al., 1994; Mackall and Gress, 1997; Montecino-
Rodriguez et al., 1998). Thus, these reports suggest
that GH administration may enhance hematopoietic

and lymphoid reconstitution after myeloablation or
bone marrow transplantation (Tian et al., 1998).
PATHOPHYSIOLOGICAL ROLES
IN NORMAL HUMANS AND
DISEASE STATES AND
DIAGNOSTIC UTILITY
Role in experiments of nature and
disease states
Immunological Status of Individuals
with GH Deficiency
There are virtually no immunological abnormalities
reported in growth hormone-deficient patients and
data with GH administration is inconclusive. GH
administration does not affect (enhance) immune
function in these patients (Abbassi and Ballanti, 1985;
Rapaport et al, 1986, 1987; Petersen et al., 1990;
Spadoni et al., 1991; Wit et al., 1993, Kappel et al.,
1993; Carroll et al., 1998). Several studies have
suggested that adults and children with GH deficiency
have impaired NK cell killing activity (Abbassi and
Bellanti, 1985; Crist et al., 1987; Bozzola et al., 1990).
NK function can be partially restored by GH
administration. Conversely, a transient reduction in
circulating B cell numbers has also been reported in
children after GH treatment (Wit et al., 1993). Lower
plasma levels of thymulin were noted in GH-deficient
children compared with age-matched healthy chil-
dren. Administration of GH to GH-deficient children
resulted in an increase in plasma levels of thymulin
(Mocchegiani et al., 1990).
Most immune parameters are normal in GH-
deficient patients. Paracrine- and autocrine-produced
GH levels are not affected by a dysfunction in
pituitary GH synthesis and release. Further, a num-
ber of cytokines and growth factors are still available
to stimulate immune function in these individuals.
In light of the experimental evidence in rodents
reviewed above, how can GH deficiency in humans
result in such a modest effect upon immune function?
As shown above, there is a wealth of evidence to
document the presence of GH and its receptor
throughout the immune system. Nearly all agents that
influence immune or hematopoietic function are
redundant in their action with one or more other
peptides, hormones, or cytokines. It should be
recalled that IL-2 has long been considered to be a
cytokine central to T cell function. Interestingly, mice
lacking the IL-2 gene show normal primary and
secondary T cell responses as well as B cell activity
Growth Hormone 259
(Kundig et al., 1993). There is a growing consensus in
the scientific community that signaling paths critical
to the survival of the species are necessarily redun-
dant. Thus, the absence of a distinct immunological
phenotype in GH-deficient people could reflect com-
plementary effects from other cytokines or hormones
with which GH shares this responsibility.
Given the minimal effects of hypopituitarism or
GH deficiency on immune function in humans and
the supposition that GH acts in concert with other
immune modulators to assure normal function, why
should reductions in systemic GH by hypophysect-
omy or administration of GH antiserum to rats or
mice affect immune function? Clark (1997) has pro-
posed an interesting explanation based upon a com-
parison of circulating levels of GH in the rat and
human. Human GH levels are generally lower than
those in rats. Further, rat immune cells generally
produce lower amounts of GH compared with human
cells. The rat and mouse may have a greater
dependence upon systemic GH for immune function
compared with the human. Thus, removal of the
pituitary-derived component of GH may have a far
greater impact on immune function in the rodent.
Aged and Critically Ill Patients
A common feature in age-related alterations of the
immune system is thymic involution. Thymic involu-
tion is not an irreversible process. Regrowth of the
thymus and improvement in thymic function have
been observed after GH administration to mice
(Murphy et al., 1992d; Montecino-Rodriguez et al.,
1998), rats (Kelley et al., 1986; Goya et al., 1993;
Kelley, 1995), dogs (Goff et al., 1987), monkey
(LeRoith et al., 1996), and humans (Davila et al.,
1987; Mocchegiani et al., 1990). Age-related decreases
in thymic function are reversed by the administration
of growth hormone-secreting pituitary tumor cells
(Kelley et al., 1986). Further, treatment of aged men
and women with GH-releasing hormone elicited
significant increases in B cell number and responsive-
ness, IL-2 receptor expression on T cells (Khorram
et al., 1997a, 1997b).
Thymic involution occurs with aging, which is
presumed to affect immune function (Montecino-
Rodriguez et al., 1998). However, the exact contribu-
tion of this phenomenon to immune activity has not
been systematically assessed in older patients. Elderly
persons have increases in the rates of cancer,
infection, and fatality from pneumonia compared
with younger persons (Gelato, 1996). Elderly indivi-
duals also have dramatically reduced GH levels and
immune function. Other benefits of GH administra-
tion to elderly and critically ill patients are well
260 Scott Chappel and William Murphy
recognized. These include increases in nutrient utili-
zation, reduction of body fat, normalization of sen-
sitivity to insulin, and increases in lean tissue mass
(Vancer, 1990; Ziegler and Leader, 1994; Hwu et al.,
1997; Johannsson et al., 1997; Carroll et al., 1998).
Thymic regrowth, induced by GH administration
would be expected to stimulate many aspects of the
lymphoid system. GH's therapeutic utility in a variety
of NK-sensitive infections and neoplasias should also
be considered. The augmented killing ability of NK
cells (Crist et al., 1987), neutrophils (Fu et al., 1991;
Balteskard et al., 1997), and macrophages (Edwards
et al., 1988, 1992) treated with GH suggests that GH
therapy may be beneficial to patients at risk of
infection. These would include the elderly or immuno-
compromised persons (transplant recipients, HIV-
infected, myelosuppressed, myeloablated, etc.).
Due to GH's ability to stimulate lymphopoiesis
as well as its stimulatory effects upon the thymus, the
utility of this pleiotropic hormone as an immune
stimulant in the aged population should be critically
evaluated.
HIV-infected Individuals
Although the newly developed inhibitors of proteases
are effective in reducing the proliferation of the
human immunodeficiency virus (HIV ), rejuvenation
of the immune system of infected individuals remains
a new challenge. GH is now being used to improve
the lean body mass of HIV-infected cachectic
individuals (Larkin, 1998; Mulligan et al., 1998).
Recently, a pilot study suggested that GH has an
immunostimulatory effect in HIV-infected patients
(Nguyen et al., 1998). GH may be of therapeutic
value to promote T cell development, recirculation,
and activity in the HIV-infected immunocompro-
mised patient.
The thymus is a major target of HIV infection.
Thymic infection by HIV or SIV results in an
increased rate of thymic dysfunction and pro-
grammed cell death (apoptosis) of thymocytes
(McCune, 1997; Wykrzykowska et al., 1998). HIV-
infected patients with thymic dysfunction have a
significantly greater mortality than those without.
Therapies that can reverse thymic involution would
therefore be expected to dramatically improve
immune function following therapies to treat HIV
infection (Mackall and Gress, 1997; McCune, 1997).
In addition, GH effects on neutrophils, macro-
phages, and NK cells may have a benefit in the
reconstruction of the immune system of HIV-infected
individuals. GH has been reported to affect positively
thymocyte progenitors in the bone marrow at an early
stage of their development in the thymus (Knyszynski
et al., 1992). Due to its documented effects upon
hematopoiesis, thymic function, and immune cell
activity, the use of GH for immune reconstitution
certainly warrants indepth consideration (Hirschfeld,
1996; Geffner, 1997).
Immunocompromised Patients after Bone Marrow
Transplantation or Radiation or Chemotherapy
Due to age-related thymic involution, bone marrow
transplantation results in a sustained period of
immunodeficiency. GH and IGF-1 therapy has been
shown to be of benefit in bone marrow transplan-
tation due to its ability to stimulate the thymus
(Montecino-Rodriguez et al., 1998), to induce lym-
phocyte proliferation, and to increase splenic and
bone marrow hematopoietic progenitor cell content
and cellularity (Murphy et al., 1992c; Tian et al.,
1998). Following engraftment, administration of GH
may be expected to increase the rate of immune
reconstitution and decrease the duration of exposure
to opportunistic infections post transplantation.
However, as GH and IGF-1 have been shown to
promote the growth of some tumors in vitro,
additional studies will be required before one could
consider clinical use of GH in instances of neoplasia.
IN THERAPY
Clinical results
GH has been demonstrated to exert numerous sti-
mulatory effects on immune and hematopoietic
parameters. GH may therefore provide a therapeutic
benefit to individuals requiring rapid immune
reconstitution. This would be important after
chemotherapy, radiation therapy, bone marrow
transplantation, viral infection, or in aging. The
mechanism by which GH exerts these immunomodu-
latory effects is only now being elucidated. GH and
IGF-1 may stimulate thymic function and accelerate
immune reconstitution. Other effects on the bone
marrow and mature immune cell function would also
be expected to play a role. Pituitary secretion of GH
may not be of great importance in immune
competence in humans (unlike other species).
However, its administration during an immunocom-
promised period may be of great therapeutic and
economic value to decrease the length of time that a
patient is without the full protection of the immune
system. The precise physiological role(s) of GH on
immune parameters need to be studied in much
greater detail, regardless of clinical utility.

References
Abbassi, V., and Ballanti, J. A. (1985). Humoral and cell-mediated
immunity in growth hormone-deficient children: effect of
therapy with human growth hormone. Pediatr. Res. 19, 299±
301.
Auernhammer, C. J., and Strasburger, C. J. (1995). Effects of
growth hormone and insulin-like growth factor I on the immune
system. Eur J. Endocrinol. 133, 635±645.
Badolaro, R., Bond, H. M., Valerio, G., Petrella, A., Morrone, G.,
Waters, M. J., Venuta, S., and Tenore, A. (1994). Differential
expression of surface membrane growth hormone receptors on
human peripheral blood lymphocytes detected by dual fluoro-
chrome flow cytometry. J. Clin. Endocrinol. Metab. 79,
984±990.
Balteskard, L., Unneberg, K., Halvorsen, D., Ytrebo, L. M.,
Waage, A., Sjursen, H., and Revaug, A. (1997). The influence
of growth hormone on tumour necrosis factor and neutrophil
leukocyte function in sepsis. Scand. J. Infect. Dis. 29, 393±399.
Ban, E., Gagnerault, M. C., Jammes, H., Postel-Vinay, M. C.,
Haour, F., and Dardenne, M. (1991). Specific binding sites
for growth hormone in cultured mouse thymic epithelial cells.
Life Sci. 48, 2141±2148.
Baroni, C. D., Fabris, N., and Bertoli, G. (1969). Effects of hor-
mones on development and function of lymphoid tissue.
Synergistic action of thyroxin and somatotropic hormone in
pituitary dwarf mice. Immunology 17, 303±314.
Baxter, J. B., Blalock, J. E., and Weigent, D. A. (1991).
Characterization of immunoreactive insulin-like growth fac-
tor-I from leukocytes and its regulation by growth hormone.
Endocrinology 129, 1727±1734.
Benfield, M. R., Vail, A., and Weigent, D. A. (1994).
Recombinant human growth hormone augments responses in
the mixed leukocyte culture. Transplant. Proc. 26, 84.
Bennani-Baiti, I. M., Cooke, N. E., and Liebhaber, S. A. (1998).
Physical linkage of the human growth hormone gene cluster and
the CD79b (Ig beta/B29) gene. Genomics 48, 258±264.
Berczi, I. (1994). The role of the growth and lactogenic hormone
family in immune function. Neuroimmunodulation 1, 201±216.
Berczi, I., Nagy, E., Asa, S. L., and Kovacs, K. (1983). Pituitary
hormones and contact sensitivity in rats. Allergy 38, 325±330.
Berczi, I., Nagy, E., De Toledo, S. M., Matusik, R. J., and
Friesen, H. G. (1991). Pituitary hormones regulate c-myc and
DNA synthesis in lymphoid tissue. J. Immunol. 146, 2201±2206.
Beschorner, W. E., Divic, J., Pulido, H., Yao, X., Kenworthy, P.,
and Buce, G. (1991). Enhancement of thymic recovery after
cyclosporine by recombinant human growth hormone and
insulin-like growth factor-1. Transplantation 52, 879±884.
Besedovsky, H., and Del-Rey, A. (1996). Immune-neuroendocrine
interactions: facts and hypotheses. Endocr. Rev. 17, 64±102.
Bidlingmaier, M., Auernhammer, C. J., Feldmeier, H., and
Strasburger, C. J. (1997). Effects of growth hormone and
insulin-like growth factor I binding to natural killer cells. Acta
Paediatr. Suppl. 423, 80±81.
Binder, G., Revskoy, S., and Gupta, D. (1994). In vivo growth
hormone gene expression in neonatal rat thymus and bone mar-
row. J. Endocrinol. 140, 137±143.
Blalock, J. E., and Weigent, D. A. (1994). Pituitary control of
immune cells. Immunol. Today 15, 39.
Blazar, B. R., Brennan, C. A., Broxmeyer, H. E., Shultz, L. D.,
and Vallera, D. A. (1995). Transgenic mice expressing either
bovine growth hormone (bGH) or human GH releasing hor-
mone (hGRH) have increased splenic progenitor cell colony
formation and DNA synthesis in vitro and in vivo. Exp.
Hematol. 23, 1397±1406.
Growth Hormone 261
Bozzola, M., Valtorta, A., Moretta, A., Cisternino, M., Biscaldi, I.,
and Schimpff, R. (1990). In vitro and in vivo effect of growth hor-
mone on cytotoxic activity. J. Pediatr. 117, 596±599.
Carroll, P. V., Christ, E. R., Bengtsson, B. A., Carlsson, L.,
Christiansen, J. S., Clemmons, D., Hintz, R., Ho, K.,
Laron, Z., Sizonenko, P., Sonksen, P. H., Tanaka, T., and
Thorne, M. (1998). Growth hormone deficiency in adulthood
and the effects of growth hormone replacement: a review.
J. Clin. Endocrinol. Metab. 83, 382±395.
Carter-Su, C., Schwartz, J., and Smit, L. (1996). Molecular
mechanism of growth hormone action. Annu. Rev. Physiol. 58,
187±207.
Chen, E. Y., Liao, Y. C., Smith, D. H., Barrera-Saldana, H. A.,
Gelinas, R. E., and Seeburg, P. H. (1989). The human growth
hormone locus: nucleotide sequence, biology and evolution.
Genomics 4, 479±497.
Chen, H. T., Schuler, L. A., and Schultz, R. D. (1997). Growth
hormone and Pit-1 expression in bovine fetal lymphoid cells.
Domest. Anim. Endocrinol. 14, 399±407.
Chen, H., Schuler, L. A., and Schultz, R. D. (1998). Growth hor-
mone receptor and regulation of gene expression in fetal lym-
phoid cells. Mol. Cell. Endocrinol. 137, 21±29.
Christ, E. R., Cummings, M. H., Westwood, N. B., Sawyer, B. M.,
Pearson, T. C., Sonkesen, O. H., and Russel-Jones, D. L.
(1997). The importance of growth hormone in the regulation
of erythropoiesis, red cell mass and plasma volume in adults
with growth hormone deficiency. J. Clin. Endocrinol. Metab.
82, 2985±2990.
Clark, R. (1997). The somotogenic hormones and insulin-like
growth factor-1: stimulators of lymphopoiesis and immune
function. Endocr. Rev. 18, 157±179.
Crist, D. M., Peake, G. T., Mackinnon, L. T., Sibbitt, W. L., and
Kraner, J. C. (1987). Exogenous growth hormone treatment
alters body composition and increases natural killer cell activity
in women with impaired endogenous growth hormone secre-
tion. Metabolism 36, 1115±1117.
Daniels, G., and Martin, J. B. (1991). In ``Principles of Internal
Medicine''(ed Wilson et al.), Neuroendocrine regulation and
diseases of the anterior pituitary and hypothalamus, pp. 1660±
1664. McGraw-Hill, New York.
Dardenne, M., Mello-Coelho, V., Gagnerault, M. C., and Postel
Vinay, M. C. (1998). Growth hormone receptors and immuno-
competent cells. Ann. NY Acad. Sci. 840, 510.
Davila, D. R., Brief, S., Simon, J., Hammer, R. E., Brinster, R. L.,
and Kelley, K. W. (1987). Role of growth hormone in regulating
T-dependent immune events in aged, nude and transgenic
rodents. J. Neurosci. Res. 18, 108±116.
de Mello-Coelho, V., Villa-Verde, D. M., Dardenne, M., and
Savino, W. (1997). Pituitary hormones modulate cell±cell inter-
actions between thymocytes and thymic epithelial cells. J.
Neuroimmunol. 76, 39±49.
de Mello-Coelho, V., Ganerault, M. C., Souberbielle, J. C.,
Strasburger, C. J., Savino, W., Dardenne, M., and Postel-
Vinay (1998). Growth hormone and its receptor are expressed
in human thymic cells. Endocrinology 139, 3837±42.
Delhase, M., Vergani, P., Malur, A., Hooghe-Peters, E. L., and
Hooghe, R. J. (1993). The transcription factor Pit1/GHF-1 is
expressed in hemopoietic and lymphoid tissues. Eur. J.
Immunol. 23, 951±955.
Demchuk, E., Mueller, T., Oschkinat, H., Sebald, W., and
Wade, R. C. (1994). Receptor binding properties of four-
helix-bundle growth factors deduced from electrostatic analysis.
Protein Sci. 3, 920±935.
DeNoto, F. M., Moore, D. D., and Goodman, H. M. (1981).
Human growth hormone DNA sequence and mRNA structure:
possible alternative splicing. Nucleic Acids Res. 9, 3719±3730.
262 Scott Chappel and William Murphy
Edwards, C. K., Ghiasuddin, S. M., Schepper, J. M.,
Yunger, L. M., and Kelley, K. M. (1988). A newly defined
property of somatotropin: priming of macrophages for produc-
tion of superoxide anion. Science 239, 767±771.
Edwards, C. K., Arkins, S., and Yunger, L. M. (1992). The
macrophage-activating properties of growth hormone. Mol.
Neurobiol. 12, 499±504.
Eliard, P. H., Marchand, M. J., Rousseau, G. G., Formstecher, P.,
Mathy-Hartert, M., Belayew, A., and Martial, J. A. (1985).
Binding of the human glucocorticoid receptor to defined regions
in the human growth hormone and placental lactogen genes.
DNA 4, 409±417.
Fabris, N., Pierpaoli, W., and Sorkin, E. (1971). Hormones and
the immunological capacity. III. The immunodeficiency disease
of the hypopituitary Snell-Bagg dwarf mouse. Clin. Exp.
Immunol. 9, 209±225.
Frohman, L. A., Downs, T. R., and Chomczynski, P. (1992).
Regulation of growth hormone secretion. Front. Neuro-
endocrinol. 13, 344±405.
Fu, Y. K., Arkins, S., Wany, B. S., and Kelley, K. W. (1991). A
novel role of growth hormone and insulin-like growth factor-I.
Priming neutrophils for superoxide anion secretion. J. Immunol.
146, 1602±1608.
Fukushima, R., Hato, F., Kinoshita, Y., Tsuji, K., and Kitano, A.
(1997). Effect of exogenous growth hormone on in vitro prolif-
eration of thymic lymphocytes from the hypophysectomized
rats. Cell. Mol. Biol. 43, 567±579.
Gagnerault, M. C., Postel Vinay, M. C., and Dardenne, M. (1996).
Expression of growth hormone receptors in murine lymphoid
cells analyzed by flow cytofluorometry. Endocrinology 137,
1719±1726.
Gala, R. R. (1991). Prolactin and growth hormone in the regula-
tion of the immune system. Proc. Soc. Exp. Biol. Med. 198, 513±
527.
Geffner, M. (1997). Effects of growth hormone and insulin-like
growth factor I on T- and B-lymphocytes and immune function.
Acta Paediatr.Suppl. 423, 76±79.
Geffner, M. E., Bersch, N., Lippe, B. M., Rosenfeld, R. G.,
Hintz, R. L., and Golde, D. W. (1990). Growth hormone
mediates the growth of T-lymphoblast cell lines via locally
generated insulin-like growth factor-I. J. Clin. Endocrinol.
Metab. 71, 464±469.
Gelato, M. C. (1996). Aging and immune function: a possible role
for growth hormone. Horm. Res. 45, 46±49.
Goff, B. L., Roth, J. A., Arp, L. H., and Incefy, G. S. (1987).
Growth hormone treatment stimluates thymulin production in
aged dogs. Clin. Exp. Immunol. 68, 580±587.
Golde, D. W., Bersch, N., and Li, C. H. (1976). Growth hormone:
species specific stimulation of erythropoiesis in vitro. Science
196, 1112±1114.
Gonzalo, J. A., Mazuchelli, R., Mellado, M., Frade, J. M. R.,
Carrera, A. C., von Kobbe, C., Merida, I., and Martinez, C.
(1996). Enterotoxin septic shock protection and deficient
T helper 2 cytokine production in growth hormone transgenic
mice. J. Immunol. 157, 3298±3304.
Goya, R. G., Gagnerault, M. C., Sosa, Y. E., Bevilacqua, J. A.,
and Dardenne, M. (1993). Effects of growth hormone and thy-
roxine on thymulin secretion in aging rats. Neuroendocrinology
58, 338±343.
Harding, P. A., Wang, X., Okada, S., Chen, W. Y., Wan, W., and
Kopchick, J. J. (1996). Growth hormone (GH) and a GH
antagonist promote GH receptor dimerization and internaliza-
tion. J. Biol. Chem. 271, 6708±6712.
Hattori, N., Ikekubo, K., Ishihara, T., Moridera, K., Hino, M.,
and Kurahachi, H. (1994). Spontaneous growth hormone (GH)
secretion by unstimulated human lymphocytes and the effects
of GH-releasing hormone and somatostatin. J. Clin. Endocrinol.
Metab. 79, 1678±1680.
Hirschfeld, S. (1996). Use of human recombinant growth hormone
and human recombinant insulin-like growth factor-I in patients
with human immunodeficiency virus infection. Horm. Res. 46,
215±221.
Hooghe, R., Delhase, M., Vergani, P., Malur, A., and Hooghe-
Peters, E. L. (1993). Growth hormone and prolactin are para-
crine growth and differentiation factors in the haemopoietic
system. Immunol. Today 14, 212±214.
Hull, K. L., Thiagarajah, A., and Harvey, S. (1996). Cellular loca-
lization of growth hormone receptors/binding proteins in
immune tissues. Cell Tissue Res. 286, 69±80.
Hwu, C., Kwok, C. F., Lai, T., Shih, K., Lee, T., Hsiao, L., Lee, S.,
Fang, V. S., and Ho, L. (1997). Growth hormone (GH) replace-
ment reduces total body fat and normalized insulin sensitivity
in GH-deficient adults: a report of one-year clinical experience.
J Clin. Endocrinol. Metab. 82, 3285±3292.
Johannsson, G., Marin, P., Lonn, L., Ottosson, M., Stenlof, K.,
Bjorntorp, P., Sjostrom, L., and Bengtsson, B. (1997). Growth
hormone treatment of abdominally obese men reduces abdom-
inal fat mass, improves glucose and lipoprotein metabolism,
and reduces diastolic blood pressure. J. Clin. Endocrinol.
Metab. 82, 727±734.
Kamegai, J., Unterman, T. G., Frohman, L. A., and
Kneman, R. D. (1998). Hypothalamic/pituitary axis of the
spontaneous dwarf rat: autofeedback regulation of growth hor-
mone (GH) includes suppression of GH releasing hormone
receptor messenger ribonucleic acid. Endocrinology 139, 3554±
3560.
Kappel, M., Hansen, M. B., Diamant, M., Jorgensen, J. O. L.,
Gyhrs, A., and Pedersen, B. K. (1993). Effects of an acute bolus
growth hormone infusion on the human immune system. Horm.
Metab. Res. 25, 579±585.
Kelley, K. W. (1995). Immunologic roles of two metabolic hor-
mones, growth hormone and insulin-like growth factor-I, in
aged animals. Nutr. Rev. 53, S95±S103.
Kelley, K. W., Brief, S., Westly, H. J., Novakofski, J., Bechtel, P. J.,
and Simon, J. (1986). GH3 pituitary adenoma cells can reverse
thymic aging in rats. Proc. Natl Acad. Sci. USA 83,
5663±5667.
Kelley, K. W., Arkins, S., Minshall, C., Liu, Q., and Dantzer, R.
(1996). Growth hormone, growth factors and hematopoiesis.
Horm. Res. 45, 38±45.
Khorram, O., Laughlin, G. A., and Yen, S. S. (1997a). Endocrine
and metabolic effects of long-term administration of [NIe27]
growth hormone-releasing hormone-(1-29)-NH2 in age-advanced
men and women. J. Clin. Endocrinol. Metab. 82, 1472±1479.
Khorram, O., Yeung, M., Vu, L., and Yen, S. (1997b). Effects
of [norleucine27] growth hormone-releasing hormone
(GHRH) (1-29)-NH2 administration on the immune system of
aging men and women. J. Clin. Endocrinol. Metab. 82, 3590±
3596.
Kiess, W., and Butenandt, O. (1985). Specific growth hormone
receptors on human peripheral mononuclear cells: reexpression,
identification and characterization. J. Clin. Endocrinol. Metab.
60, 740±746.
Kimata, H., and Fujimoto, M. (1994). Growth hormone and insu-
lin-like growth factor I induce immunoglobin (Ig)E and IgG4
production by human B cells. J. Exp. Med. 180, 727±732.
Kimata, H., and Yoshida, A. (1994). Differential effect of growth
hormone and insulin-like growth factor-I, insulin-like growth
factor-II, and insulin on Ig production and growth in human
plasma cells. Blood 83, 1569±1574.

Knyszynski, A., Adler-Kunin, S., and Globerson, A. (1992).
Effects of growth hormone on thymocyte development from
progenitor cells in bone marrow. Brain Behav. Immunol. 6,
327±340.
Kooijman, R., Willems, M., Rijkers, G. T., Brinkman, A., van
Buul-Offers, S. C., Heijnen, C. J., and Zegers, B. J. (1992).
Effects of insulin-like growth factors and growth hormone on
the in vitro proliferation of T lymphocytes. J. Neuroimmunol. 38,
95±104.
Kooijman, R., Hooghe-Peters, L., and Hooghe, R. (1996).
Prolactin, growth hormone, and insulin-like growth factor-I in
the immune system. Adv. Immunol. 63, 377±454.
Kooijman, R., Malur, A., Van Buul-Offers, S. C., and Hooghe-
Peters, E. L. (1997a). Growth hormone expression in murine
bone marrow cells is independent of the pituitary transcription
factor, Pit-1. Endocrinology 138, 3949±3955.
Kooijman, R., Berus, D., Malur, A., Delhase, M., and Hooghe-
Peters, E. L. (1997b). Human neutrophils express GH-N gene
transcripts and the pituitary transcription factor Pit-1b.
Endocrinology 138, 4481±4484.
Kundig, T. M., Schorle, H., Bachmann, M. F., Hengartner, H.,
Zinkernagel, R. M., and Horak, I. (1993). Immune responses in
interleukin-2-deficient mice. Science 262, 1059±1061.
Larkin, M. (1998). Thwarting the dwindling progression of
cachexia. The Lancet 351, 1336.
LeRoith, D., Yanowski, J., Kaldjian, E. P., Jaffe, E. S.,
LeRoith, T., Purdue, K., Cooper, B. D., Pyle, R., and
Adler, W. (1996). The effects of growth hormone and insulin-
like growth factor I on the immune system of aged female
monkeys. Endocrinology 137, 1071±1079.
Li, S., Crenshaw, E. B., Rawson, E. J., Simmons, D. M.,
Swanson, L. W., and Rosenfeld, M. G. (1990). Dwarf locus
mutants lacking three pituitary cell types result from mutations
in the POU-domain gene, pit-1. Nature 347, 528±533.
Lin, B., Kinoshita, Y., Hato, F., and Tsuji, Y. (1997).
Enhancement of DNA synthetic activity of thymic lympho-
cytes by the culture supernatant of thymus epithelial cells
stimulated by growth hormone. Cell. Mol. Biol. 43, 351±359.
McCune, J. M. (1997). Thymic function in HIV-1 disease. Semin.
Immunol. 9, 397±404.
Mackall, C. L., and Gress, R. E. (1997). Thymic aging and T-cell
regeneration. Immunol. Rev. 160, 91±102.
MacLeod, J. N., Lee, A. K., Liebhaber, S. A., and Cooke, N. E.
(1992). Developmental control and alternative splicing of the
placentally expressed transcripts from the human growth hor-
mone gene cluster. J. Biol. Chem. 267, 14219±14226.
Maggiano, N., Piantelli, M., Ricci, R., Larocca, L. M., Capelli, A.,
and Ranelletti, F. O. (1994). Detection of growth hormone-
producing cells in human thymus by immunohistochemistry
and non-radioactive in situ hybridization. J. Histochem.
Cytochem. 42, 1349±1354.
Martial, J. A., Hallewell, R. A., Baxter, J. D., and
Goodman, H. M. (1979). Human growth hormone: comple-
mentary DNA cloning and expression in bacteria. Science
205, 602±607.
Melen, L., Hennen, G., Dullaart, R. P., Heinen, E., and Igout, A.
(1997). Both pituitary and placental growth hormone tran-
scripts are expressed in human peripheral blood mononuclear
cells (PBMC). Clin. Exp. Immunol. 110, 336±340.
Mellado, M., Llorente, M., Rodriguez-Frade, M., Lucas, P.,
Martinez-A. C., and del Real, G. (1998). HIV-1 envelope pro-
tein gp120 triggers a Th2 response in mice that shifts to Th1 in
the presence of human growth hormone. Vaccine 15, 1111±1115.
Merchav, S., Tatarsky, I., and Hochberg, Z. (1988). Enhancement
of human granulopoiesis in vitro by biosynthetic insulin like
Growth Hormone 263
growth factor/somatomedin C and human growth hormone.
J. Clin. Invest. 81, 791±797.
Minshall, C., Arkins, S., Straza, J., Conners, J., Dantzer, R.,
Freund, G. G., and Kelley, K. W. (1998). IL-4 and insulin-
like growth factor-I inhibit the decline in Bcl-2 and promote
the survival of IL-3-deprived myeloid progenitors. J. Immunol.
159, 1225±1232.
Mocchegiani, E., Paolucci, P., Balsamo, A., Cacciari, E., and
Fabris (1990). Influence of growth hormone on thymic endo-
crine activity in humans. Hormone Res. 33, 248±255.
Montecino-Rodriguez, E., Clark, R., and Dorshkind, K. (1998).
Effects of insulin-like growth factor administration and bone
marrow transplantation on thymopoiesis in aged mice.
Endocrinology 139, 4120±4126.
Mulligan, K., Tai, V. W., and Schambelan, M. (1998). Effects of
chronic growth hormone treatment on energy intake and resting
energy metabolism in patients with human immunodeficiency
virus-associated wasting ± A clinical research center study.
J. Clin. Endocrinol. Metab. 83, 1542±1547.
Murphy, W. J., Durum, S. K., and Longo, D. L. (1992a). Human
growth hormone promotes engraftment of murine or human
T cells in severe combined immunodeficient mice. Proc. Natl
Acad. Sci. USA 89, 4481±4485.
Murphy, W. J., Durum, S. K., Anver, M. R., and Longo, D. L.
(1992b). Immunologic and hematologic effects of neuroendo-
crine hormones. Studies on DW/J dwarf mice. J. Immunol.
148, 3799±3805.
Murphy, W. J., Tsarfaty, G., and Longo, D. L. (1992c). Growth
hormone exerts hematopoietic growth-promoting effects in vivo
and partially counteracts the myelosuppressive effects of azido-
thymidine. Blood 80, 1443±1447.
Murphy, W. J., Durum, S. K., and Longo, D. L. (1992d). Role
of neuroendocrine hormones in murine T cell development.
Growth hormone exerts thymopoietic effects in vivo.
J. Immunol. 149, 3851±3857.
Murphy, W. J., Durum, S. K., and Longo, D. L. (1993).
Differential effects of growth hormone and prolactin on murine
T cell development and function. J. Exp. Med. 178, 231±236.
Murphy, W. J., Rui, H., and Longo, D. L. (1995). Effects of
growth hormone and prolactin immune development and func-
tion. Life Sci. 57, 1±14.
Nagy, E., Berczi, I., and Friesen, H. G. (1987). Regulation
of immunity by lactogenic and growth hormones. Acta
Endocrinol. 102, 351±357.
Nguyen, B., Clerici, M., Venzon, D. J., Bauza, S., Murphy, W. J.,
Longo, D. L., Baseler, M., Gesundheit, N., Broder, S.,
Shearer, G., and Yarchaon, R. (1998). Pilot study of effects
of recombinant insulin-like growth factor in HIV-infected
patients. AIDS 12, 895±904.
Ocampo-Lim, B., Guo, W., DeMott-Friberg, R., Barkan, A. L.,
and Jaffe, C. A. (1996). Nocturnal growth hormone (GH) secre-
tion is eliminated by infusion of GH-releasing hormone antag-
onist. J. Clin. Endocrinol. Metab. 81, 4396±4399.
Palmetshofer, A., Zechner, S., Luger, T. A., and Barta, A. (1995).
Splicing variants of the human growth hormone mRNA:
detection in pituitary, mononuclear and dermal fibroblasts.
Mol. Cell. Endocrinol. 113, 225±234.
Peterson, B. H., Rapaport, R., Henry, D. P., Huseman, C., and
Moore, W. V. (1990). Effect of treatment with biosynthetic
human growth hormone (GH) on peripheral blood lymphocyte
populations and function in growth hormone-deficient children.
J. Clin. Endocrinol. Metab. 70, 1756±1760.
Pierpaoli, W., and Sorkin E. (1968). Hormones and immunologic
capacity. I. Effect of heterologous anti-growth hormone
(ASTH) antiserum on thymus and peripheral lymphatic tissue
264 Scott Chappel and William Murphy
in mice. Induction of a wasting syndrome. J. Immunol. 101,
1036±1043.
Postel-Vinay, M. C., de Mello-Cohelho, V., Gagnerault, M. C.,
and Dardenne, M. (1997). Growth hormone stimulates the pro-
liferation of activated mouse T lymphocytes. Endocrinology 138,
1816±1820.
Radovick, S., Nations, M., Du, Y., Berg, L. A., Weintraub, B. D.,
and Wondisford, F. E. (1992). A mutation in the POU-homeo-
domain of pit-1 responsible for combined pituitary hormone
deficiency. Science 257, 1115±1118.
Rapaport, R. G., and Bozzola, M. (1997). Role of B-cells in
growth hormone-immune interactions. Acta Paediatr. Suppl.
423, 82±83.
Rapaport, R., Oleske, J., Ahdieh, H., Solomon, S., Delfaus, C.,
and Denny, T. (1986). Suppression of immune function in
growth hormone-deficient children during treatment with
human growth hormone. J. Pediatr. 109, 434±439.
Rapaport. R., Oleske, J., Ahdieh, H., Skuza, K., Holland, B. K.,
Passannante, M. R., and Denny, T. (1987). Effects of human
growth hormone on immune functions: in vitro studies on cells
of normal and growth hormone-deficient children. Life Sci. 41,
2319±2324.
Rapaport, R., Sills, I. N., Barrett, P., Labus, J., Skuza, K. A.,
Chartoff, A., Goode, L., Stene, M., and Petersen, B. H.
(1995). Detection of human growth hormone receptors on
IM-9 cells and peripheral blood mononuclear cell subsets by
flow cytometry: correlation with growth hormone binding pro-
tein levels. J. Clin. Endocrinol. Metab. 80, 2612±2619.
Robert, F., and Geenen, V. (1992). Thymic neuropeptides and
T cell development. Ann. NY Acad. Sci. 650, 99±104.
Rohn, W. M., and Weigent, D. A. (1995). Cloning and nucleotide
sequencing of rat lymphocyte growth hormone cDNA. Neuro-
immunomodulation 2, 108±104.
Vancer, M. L. (1990). Growth hormone for the elderly? N. Engl.
J. Med. 232, 52±54.
Sabharwal, P., and Varma, S. (1996). Growth hormone synthe-
sized 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.
Saito, H., Inoue, T., Fukatsu, K., Inoue, T., Fukatsu, K., Ming-
Tsan, L., Inaba, T., Fukushima, R., and Muto, T. (1996).
Growth hormone and the immune response to bacterial infec-
tion. Horm. Res. 45, 50±54.
Savino, W., de Mello-Coelho, V., and Dardenne, M. (1995).
Control of the thymic microenvironment by growth hormone/
insulin-like growth factor-I-mediated circuits. Neuroimmuno-
modulation 2, 313±318.
Schimpff, R. M., and Repellin, A. M. (1990). Production of inter-
leukin 1 alpha and interleukin-2 by mononuclear cells in healthy
adults in relation to different experimental conditions and to
the presence of growth hormone. Horm. Res. 33, 171±176.
Schurmann, A., Spencer, G. S., and Berry, C. J. (1995). Growth
hormone alters lymphocyte sub-populations and antibody
production in dwarf rats in vivo. Experientia 51, 780±785.
Smith, P. E. (1930). Effect of hypophysectomy upon the involu-
tion of the thymus in the rat. Anat. Rec. 47, 119±126.
Snow, E. C., Feldbush, T. L., and Oakes, J. A. (1981). The
effect of growth hormone and insulin upon MLC responses
and the generation of cytotoxic lymphocytes. J. Immunol. 126,
161±164.
Somers, W., Ultsch, M., De vos, A. M., and Kossiakoff, A. A.
(1994). The X-ray structure of a growth hormone-prolactin
receptor complex. Nature 372, 478±481.
Spadoni, G. L., Rossi, P., Ragno, W., Galli, E., Cianfarani, S.,
Galasso, C., and Boscherini, B. (1991). Immune function in
growth hormone-deficient children treated with biosynthetic
growth hormone. Acta Paediatr. Scand. 80, 75±79.
Takagi, K., Suzuki, F., Barrow, R. E., Wolf, S. E., Kobayashi, M.,
and Herndon, D. N. (1997). Growth hormone improves
immune function and survival in burned mice infected with
herpes simplex virus type 1. J. Surg. Res. 69, 166±170.
Taub, D. D., Tsarfaty, G., Lloyd, A. R., Durum, S. K.,
Longo, D. L., and Murphy, W. J. (1994). Growth hormone
promotes human T cell adhesion and migration to both
human and murine matrix proteins in vitro and directly pro-
motes xenogeneic engraftment. J. Clin. Invest. 94, 293±300.
Ten Have, S. M., van der Lely, A. J., and Lamberts, S. W. (1997).
Increase in haemoglobin concentrations in growth hormone
deficient adults during human recombinant growth hormone
replacement therapy. Clin. Endocrinol. 47, 565±570.
Theill, L. E., and Karin, M. (1993). Transcriptional control of
GH expression and anterior pituitary development. Endocr.
Rev. 14, 670±689.
Thellin, O., Coumans, B., Zorzi, W., Barnard, R., Hennen, G.,
Heinen, E., and Igout A. (1998). Expression of growth hor-
mone receptors by lymphocyte subpopulations in the human
tonsil. Dev. Immunol. 6, 295±304.
Thorner, M. O., Vance, M. L., Hartman, M. L., Holl, R. W.,
Evans, W. S., Veldhuis, J. D., et al. (1990). Physiological role
of somatostatin on growth hormone regulation in humans.
Metabolism 39, 40±42.
Thorner, M. O., Chapman, I. M., Gaylinn, B. D., Pezzoli, S. S.,
and Hartman, M. L. (1997). Growth hormone-releasing hor-
mone and growth hormone-releasing peptide as therapeutic
agents to enhance growth hormone secretion in disease and
aging. Rec. Progr. Horm. Res. 52, 215±244.
Tian, Z. G., Woody, M. A., Sun, R., Welniak, L. A.,
Raziuddin, A., Funakoshi, S., Tsarfaty, G., Longo, D. L.,
and Murphy, W. J. (1998). Recombinant human growth hor-
mone promotes hematopoietic reconstitution after syngenic
bone marrow transplantation in mice. Stem Cells 16, 193±199.
Timsit, J., Savino, W., Safieh, B., Chanson, P., Gagnerault, M. C.,
Bach, J. F., and Dardenne, M. (1992). Growth hormone and
insulin-like growth factor-I stimulate hormonal function and
proliferation of thymic epithelial cells. J. Clin. Endocrinol.
Metab. 75, 183±188.
Tsarfaty, G., Longo, D. L., and Murphy, W. J. (1994). Human
insulin-like growth factor I exerts hematopoietic growth-pro-
moting effects after in vivo administration. Exp. Hematol. 22,
1273±1277.
Tseng, Y. H., Kessler, M. A., and Schuler, L. A. (1997).
Regulation of interleukin (IL)-1alpha, IL-1beta, and IL-6
expression by growth hormone and prolactin in bovine thymic
stromal cells. Mol. Cell. Endocrinol. 128, 117±127.
Ultsch, M. H., Somers, W., Kossiakoff, A. A., and de Vos, A. M.
(1994). The crystal structure of affinity-matured human growth
hormone at 2A resolution. J. Mol. Biol. 236, 286±299.
Varma, S., Sabharwal, P., Sheridan, J. F., and Malarkey, W. B.
(1993). Growth hormone secretion by human peripheral blood
mononuclear cells detected by an enzyme-linked immuno-
plaque assay. J. Clin. Endocrinol. Metab. 76, 49±53.
Weigent, D. A., and Blalock, J. E. (1987). Interactions between
the neuroendocrine and immune systems: common hormones
and receptors. Immunol. Rev. 100, 79±108.
Weigent, D. A., and Blalock, J. E. (1994). Effect of the adminis-
tration of growth-hormone-producing lymphocytes on weight
gain and immune function in dwarf mice. Neuroimmuno-
dulation 1, 50±58.
Weigent, D. A. (1996). Immunoregulatory properties of growth
hormone and prolactin. Pharmacol. Ther. 69, 237±257.
 Growth Hormone 265

Weigent, D. A., Baxter, J. B., Wear, W. E., Smith, L. R., immunoglobulin synthesis and proliferation in serum-free
Bost, K. L., and Blalock, J. E. (1988). Production of immunor- media. Acta Endocrinol. (Copenhagen) 126, 524±529.
eactive growth hormone by mononuclear leukocytes. FASEB J. Zheng, H., Bailey, A., Jiang, M. H., Honda, K., Chen, H. Y.,
2, 2812±2818. Trumbauer, M. E., VanderPloeg, L. H., Schaeffer, J. M.,
Weigent, D. A., Blalock, J. E., and LeBoeuf, R. D. (1991). An Leng, G., and Smith, R. G. (1997). Somatostatin receptor sub-
antisense oligodeoxynucleotide to growth hormone messenger type 2 knockout mice are refractory to growth hormone
ribonucleic acid inhibits lymphocyte proliferation. Endo- negative feedback on arcuate neurons. Mol. Endocrinol. 11,
crinology 128, 2053±2057. 1709±1717.
Wells, J. A., and de Vos, A. M. (1993). Structure and function of Ziegler, T. R., and Leader, I. (1994). Adjunctive human growth
human growth hormone: Implications for the hematopoietins. hormone therapy in nutrition support: potential to limit septic
Annu. Rev. Biophys. Biomol. Struct. 22, 329±351. complications in intensive care unit patients. Semin. Resp.
Wells, J. A., Cunningham, B. C., Fuh, G., Lowman, H. B., Infect. 9, 240±247.
Bass, S. H., Mulkerrin, M. G., Ultsh, M., and deVos, A. M.
(1993). The molecular basis for growth hormone-receptor inter-
actions. Recent Progr. Horm. Res. 48, 253±275.
Wiedermann, C. J., Reinisch, N., Niedermuhlbichler, M., and
Braunsteiner, H. (1993a). Inhibition of recombinant human
LICENSED PRODUCTS
growth hormone-induced and prolactin-induced activation of
neutrophils by octreotide. Naunyn Schmiedegbergs Arch.
Pharmacol. 347, 336±341. Product name/Company Therapeutic use
Wiedermann, C. J., Reinisch, N., and Braunsteiner, H. (1993b).
Stimulation of monocyte chemotaxis by human growth hor- Protropin/Genentech GH inadequacy in children
mone and its deactivation by somatostatin. Blood 82, 954±960.
Wit, J. M., Kooijman, R., Rijkers, G. T., and Zegers, B. J. (1993). Nutropin/Genentech GH deficiency
Immunological findings in growth hormone-treated patients. NutropinAQ/Genentech Liquid version of Nutropin
Horm. Res. 39, 107±110.
Wu, H., Devi, R., and Malarkey, W. B. (1996). Localization of Humatrope/Eli Lilly Somatotropin deficiency
growth hormone messenger ribonucleic acid in the human syndrome
immune system ± a clinical research center study. J. Clin. Saizen/Ares-Serono GH deficiency
Endocrinol. Metab. 81, 1278±1282.
Wykrzykowska, J. J., Rosenzweig, M., Veazey, R. S., Norditropin/Novo Nordisk Growth failure in children
Simon, M. A., Halvorsen, K., Desrosiers, R. C., Genotropin/Pharmacia/ Growth hormone deficiency
Johnson, R. P., and Lackner, A. A. (1998). Early regeneration Upjohn
of the thymic progenitors in rhesus macaques infected with
simian immunodeficiency virus. J. Exp. Med. 187, 1767±1778. Serostim/Ares-Serono Wasting associated
Yoshida, A., Ishioka, C., Kimata, H., and Mikawa, H. (1992). with AIDS
Recombinant human growth hormone stimulates B cell