REVIEW ARTICLE

Regulation of HumanGrowth HormoneSecretion and

Its Disorders
Yuzuru Kato, Yoshio Murakami, Motoi Sohmiya and Masateru Nishiki

Abstract focus on the regulation of humanGHsecretion and its disor-

ders, although there have been a number of basically related
Growth hormone (GH) secretion from anterior pituitary reports in more detail (1).
is regulated by the hypothalamus and the mediators of GH
actions. Major regulatory factors include GHreleasing GHSecretion in Normal Subjects
hormone (GHRH), somatostatin (SRIF), GHreleasing pep-
tide (ghrerin) and insulin-like growth factor (IGF-I). The Growth hormone
principal physiological regulation mechanisms of GHse- Pituitary GHis a polypeptide produced by the somatotrope
cretion are neural endogenousrhythm, sleep, stress, exer- cells in the pituitary. In humans, pituitary GHis encoded by
cise, and nutritional and metabolic signals. GHdeficiency GH-1gene on the long arm of chromosome17, which is com-
results from various hereditary or acquired causes, which posed of two exons and four introns (2). HumanGHis hetero-
may be isolated or combined with other pituitary hormone geneous, consisting of several molecular variants including 22
deficiencies. GHdeficiency can be treated with recombinant K and 20 K forms (3). The main form is a 191 amino acid,
humanGH, which results in accelerating growth in chil- single chain protein with a molecular weight of 22, 000, which
dren and normalization of intermediary metabolism in is most abundantly in pituitary GHand is referred to as 22 K
adults. GHhypersecretion mostly results from a pituitary GH. The second most abundant GHwith a molecular weight
tumor and causes acromegaly or gigantism. Hypersecre- of20, 000 is known as 20 K GH, a mRNAsplice variant which
tion of GHcan be treated by transshenoidal surgery. Medi- lacks an internal sequence of 15 amino acids, and accounts for
cal treatment with octreotide and analogs is also effective 5-7% of pituitary GH. GHhas a three-dimensional structure
to reduce GHsecretion in combination with or without the with a twist bundle of four oc-helixes (4) and two independent
surgery. receptor binding sites are located on opposite surfaces of GH.
(Internal Medicine 41: 7-13, 2002)
Developmentof somatotrope
Key words: GH, GHRH, SRIF, ghrelin, IGF-I, GH deficiency, Several pituitary transcription factors are involved in pitu-
acromeg aly itary somatotrope development. They include Prop- 1 , Pit- 1 and
GH-releasing hormone receptor (GHRH-R)genes. These genes
are expressed sequentially during anterior pituitary develop-
ment (5). Prop- 1 and Pit-1 are POU-homeodomaintranscrip-
Introduction tion factors and are critical for tissue differentiation during pi-
tuitary ontogeny. Prop-1 is important for development of the
Growth hormone (GH) plays the central role in the modula- gonadotrope, somatotrope, lactotrope and thyrotrope lineages.
tion of growth from birth until the completion of puberty. GH Pit- 1 is involved in the differentiation of somatotropes, lactotropes
also plays a role in the control of body composition, somatic and thyrotropes under the direction of Prop-1. GH-releasing
growth and intermediary metabolism in the body throughout hormone (GHRH)is markedly expressed in somatotropes un-
life. GHis a memberof a family of normones that includes der the direction of Pit-1, and it is critical for the normal ex-
pituitary prolactin (PRL) and human placental lactogen (hPL). pansion of the somatotrope population. The GHRH-receptor
GHis secreted from the anterior pituitary under both positive (GHRH-R)is also required for GHsynthesis and secretion.
and negative control of the hypothalamus as well as short and
long feedback control of the mediators of GHactions (Fig. 1). Hypophysio tropic hormones
GHis species specific in structure and functions, and GHregu- GHsecretion from the pituitary is under neural control from
lation also differs from other species. In this review article, we the hypothalamus through at least three hypophysiotropic fac-
From the First Division, Department of Medicine, Shimane Medical University, Izumo
Reprint requests should be addressed to Dr. Yuzuru Kato, the First Division, Department of Medicine^Shimane Medical University, Izumo 693-8501
7
Internal Medicine Vol. 41, No. 1 (January 2002)
 Kato et al

NE Stress
DA H ypoglycem ia
5-H T E xercise
O pioids S leep

'S
e ｩ
/^ *
G H RH SR IF
C+ ) H ypothalam us
G hrelin

GH P ituitary
rr
%d
Blood cells
GHBP r N utrition

G ut F FA

d
GHR
i Body Fat
r L iver M uscle
IG F -I B one

P rotease K idneys

Steroids

des(l-3)IGF-I 1 IGFBPs l 'e

Figure 1. Schematicregulation of pituitary GHsecretion by hypothalamicneuronal factors and feedback mecha-

nisms in humans.

tors: GHRH,s omatostatin (SRIF) and ghrelin. The GHRHneu-
rons are located in the arcuate and ventromedialnuclei, and
SRIFneuronsare located in the anterior periventricular area.
GHRHand SRIFrelease are controlled by a complexneuronal
network, in which oc-adrenergic, dopaminergic and serotoni-
nergic signals stimulate GHsecretion.
GHRHis a 40- to 44-amino acid peptide, of which the gene
is located on chromosome2 0 q and encodes a 108 aminoacid
precursor. GHRH i s released from the medianeminenceinto
the pituitary portal system, reaching the somatotropes. GHRH 5 are expressed in normalhumanpituitary (7). Thesereceptors
8
interacts with the GHRH-R, whichis a seven transmembrane,
Gsoc-coupledreceptor that signals the CAMPand Ca2+-channel
pathways, and stimulates GHrelease from secretary granules
as well as GHtranscription (6).
SRIF is a cyclical peptide that exists in two forms: SRIF-14
and SRIF-28.Both SRIFare encodedby a single gene on the
long arm of chromosome3, and a 92-aminoacid precursor is
predominantly processed to SRIF- 14 in the hypothalamus. Five
SRIFreceptor subtypes are known,of which subtypes 1 , 2 and
Internal Medicine Vol. 41, No. 1 (January 2002)
 Regulation of GHSecretion in Man
N H 2 G s S I F L S X P E H Q R

蝣 I I 蝣 蝣 V I I
0I Q
I s E K R Q
c = o
I K
H CH K
I
H CH p p A K L Q p R COO H
I I 蝣 蝣 m 蝣
HGH 蝣 蝣 蝣 蝣
I I I 蝣 蝣 蝣
H CH 蝣 蝣 蝣
蝣 I I I 蝣 蝣 蝣 蝣 蝣 蝣
H CH 蝣 蝣 蝣 蝣
I I 蝣 蝣 蝣
H CH 蝣 蝣 蝣 蝣
I I 蝣 蝣 蝣 蝣
蝣 H CH 蝣 蝣 蝣 蝣 蝣 蝣
I I I 蝣 蝣
蝣 H 蝣 蝣 蝣 蝣

Figure 2. Schematicstructure and aminoacid sequenceof humanghrelin.

Table 1. Effects of TRHon the Secretion of Pituitary Hor- hypothalamus,b ut a minoreffect is also present at the pitu-
monesin Humans itary level.
1) Stim ulation 2) Inhibition Thyrotropin (TSH) releasing hormone (TRH) plays not only
T SH GH in normal a stimulating role in TSHand prolactin (PRL), but also an in-
Prol actin basal hibitory action on GHsecretion inducedby a numbero f stimuli
GH in pathological states sleep-induced (1 1, 12) and during sleep (13) (Table 1). The inhibitory mecha-
acromag aly arginine-induced nismsremainsto be elucidated, but could be explained,at least
anorexia nervosa L -dopa-induced
depres sion
partly, by NOrelease from the pituitary in a paracrine/autocrine
fashion (14, 15).
liver dysfunction
renal dysfunction
ACTH in pathologic states
Growthhormoner eceptor
Cushing's disease The GHreceptor (GHR)is a 620-amino-acid, single chain
glycoproteinwith a single transmembrane domainand an ex-
tracellular domain involved in GHsignalling (16). The extra-
cellular domainalso occurs separately as a soluble GHbind-
are memberso f the seven transmembraned omain,G protein- ing protein (GHBP).
coupled class. Interaction of SRIFwith its receptors induces TheGHRis encodedby a single gene located on the short
coupling in Gj and Goproteins, which in turn inhibits CAMP arm of chromosome5. The gene includes 10 exons and 9 in-
production and Ca2+-channel fluxes, thereby blocking GHre- trons (17), of which exons 2-7 encode the extracellular do-
lease. main, exon 8 the transmembranedomain, and exons 9 and 10
GHreleasing peptides (GHRP)are a class of short peptides the intracellular domain. The GHRis expressed ubiquitously
that are extremely potent as pharmacologicalGHsecretagogues and mostenriched in the liver.
(GHS) (8). The cloning of a specific GHRPreceptor (GHRP- GHinitiates its action by binding to site 1 of the GHRon
R) was followed by recent identification of a natural ligand, one of its surfaces, then followed by binding to site 2 on the
ghrelin (9). Ghrelin is a 28-aminoacid peptide with an essen- other surface of GH(1 8). This results in a complexcontaining
tial n-octanoyl modification at Ser3 (Fig. 2). The GHRP-Ris a twoGHRsin association with GH.This GH-inducedd imer-
seven transmenbranedomain,Gprotein-coupledreceptor that ization of the GHRis critical for GHRsignaling and GHac-
interacts with Ga. Ghrelin is expressed in the hypothalamus tion. Intracellular signaling is initiated by binding of Janus ki-
and the pituitary as well as the stomach,and is consideredas a nase 2 (JAK2) to a proline-rich region (Box 1) in the proximal
potential physiological regulator of GHsecretion. The action intracellular part of the GHR,followed by a JAK2-mediated
of ghrelin on GHsecretion is dependent on a functional GHRH tyrosine phosphorylation cascade involving JAK2itself, the
system, and GHRH a nd ghrelin have synergic actions in vivo. GHR,s ignal transducers and activators of transcription (Stats) 1 ,
(10) The principal site of ghrelin action on GHrelease is the 3 and 5, insulin-receptor substances (IRS) 1 and 2, compo-
9
Internal Medicine Vol. 41, No. 1 (January 2002)
 Kato et al

nents of the mitogen-activated protein kinase (MAPK),the pro- blocking agents, whereas oral administration of glucose and
tein kinase C, and phosphatidyl inositol-3 kinase pathways, increased serum FFAlevels rather suppress GHsecretion. GH
and
(19).
several other intracellular signaling and adaptor proteins secretion is also blunted in obesity and by aging (22). Exact
roles of GHRH,SRIF and ghrelin in regulating GHsecretion
in response to these stimuli are not fully elucidated in humans.
GHBP The principal physiologic short-term regulation mechanisms
The GHBPis the soluble, extracellular domain of the GHR, of GH secretion are 1) neural endogenous rhythm, 2) sleep, 3)
and is generated from the GHRby proteolysis (20). The GHBP stress, 4) exercise and 5) nutritional and metabolic signals. GH
circulates in plasma in nanomolar concentrations, sufficient secretion is regulated by the interaction of GHRHand SRIF
enough to complex a substantial part of plasma GH. Plasma and is released in 10-20 pulses in each 24-h cycle. Recent obser-
GHBPlevels reflect the GHRabundance in the liver. The GHBP vations in humans indicate that the timing of GHpulses is pri-
modulates GHaction through a variety of mechanisms. It in- marily supervised by intermittent SRIF withdrawal, and the
hibits GHaction by competing with the GHRfor ligand and amplitude of GHpulses is driven by GHRH(23).
by generating unproductive heterodimers with the GHRat the The highest peaks in plasma GHare found during slow wave
cell surface. The GHBPprolongs the half-life of GHin the sleep, typically one to two hr after falling asleep. GHpulses of
circulation by complexing GH, and by delaying its elimina- smaller amplitude occur throughout the day, on average ap-
tion. After secretion, GHbinds to GHBPin the circulation,
proximately every 2 hours (24). Womenof reproductive age
depending on the GHBPlevel and the GHconcentration, and have higher GHamplitudes as well as higher interpeak plasma
an average of 40-50% of plasma GH is bound to the GHBP. GHlevels. There is no knowndifferential secretion of specific
stimulus for any of the GHvariants, indicating that they are
Insulin-like growth factor cosecreted in response to a variety of physiological and phar-
The action of GHis mediated by GH-dependent factors. macological stimuli (25). However, they have different plasma
Amongthem, insulin-like growth factor I (IGF-I) is produced half lives, and the 20 K variant and oligometric forms have
in manytissues in response to GHand other regulators. IGF-I longer half lives than 22 K GHof 17 minutes (25, 26).
acts locally as in a paracrine/autocrine fashion and distantly in
a hormone-like mode. IGF-I has mitogenic and metabolic ac-
tivities. Six binding proteins for IGF (IGFBP) and three IGFBP-
GHsecretion in patients
related proteins are present in serum and interstitial fluid (21). GHdeficiency
IGFBP-3 is the major IGFBP in serum and is highly GH de- GHdeficiency results from various causes, hereditary or
pendent, circulating by forming a 150-kDa ternary complex acquired. GHdeficiency may be isolated or combined with
involving IGF, IGFBP-3 and another GH-dependent protein other pituitary hormone deficiencies. Congenital GHdeficiency
called acid-labile subunit (ALS). IGF-I is proteolytically con- partly occurs on a genetic basis. A numberof genetic causes
verted to des (1-3) IGF-I, which has more potent biological are known in combined pituitary hormone deficiency. Inacti-
activity due to reduced affinity to serum IGFBPs. vating mutations in the Prop-1 gene results in TSH, LH, FSH,
GHand PRL deficiency (27). Mutations in the Pit-1 gene re-
Insulin-like growth factor receptor sults in patients with GH, PRLand TSHdeficiency (28).
IGF-I binds to the type 1 IGF receptor, which is structurally Isolated GHdeficiency may be caused by inactivating mu-
homologousto the insulin receptor and has a tetrametric struc- tations in the GHRH-Rgene and in the GH-1 gene. GHRHis
ture with two extracellular oc-subunits covalently connected to required for somatotrope proliferation and for GHsynthesis
two (3-subunits through disulfide bonds. The p-subunits have and secretion. The patients with defective GHRH-Rare mani-
intrinsic tyrosine kinase activity and signal through a phos- fested by pituitary hypoplasia and isolated GH deficiency (29).
phorylation cascade involving IRS-1 and IRS-2, P113-path- Inactivating mutations in GH-1 gene directly affect GHpro-
ways. The IGF-I receptor is widely expressed in tissues, with
duction (30). Typical deletions of 6.7, 7.0 and 7.6 kb of GH-1
the exception of liver. gene, and other nonsense and frameshift mutations result in
severe GH deficiency (type IA). Less disabling mutations of
Feedback con trol GH-1 gene cause a milder GHdeficiency (type IB), in which
Negative feedback on GHsecretion is exerted by IGF-I and some abnormal GH is produced. Biologically inactive GH is
by GH itself. IGF-I inhibits GH secretion by influencing GHRH produced in a special case (31). In patients with type IA, sec-
and SRIF production in the hypothalamus and by influencing ondary resistance to exogenous GHadministration is frequently
GHRHaction in the pituitary. GHinhibits its ownsecretion in observed, because serum anti-GH antibodies to the exogenous
the hypothalamus. These feedback effects are superimposed GHare highly produced, whereas patients with type IB respond
on the neural control. well to exogenous GH.
Dominantly inherited GH-1gene mutations (type II) are
Other control mechanisms caused by splice-site mutations in one alle that result in skip-
GHsecretion is stimulated by insulin-induced hypoglyce- ping of exon 3, resulting in producing abnormal GHprotein
mia, arginine infusion, L-dopa administration, and p-adrenegic exerting a dominant negative influence on the normal GHpro-
10
Internal Medicine Vol. 41, No. 1 (January 2002)
 Regulation of GHSecretion in Man
Table 2. Serum Anti-human Pituitary Antibodies in 13 Patients with Au-
toimmune Lymphocytic Hypophysitis (Modified from 34)
P a tie n ts A ge S ex D u r atio n R e la tio n to G H D A n ti-p itu ita ry
N o. (y r) p re g n a n c y a nt ib od y *

1 42 M 3 +
2 30 F 7 +
3 57 F 2 + 68 kD, 4 9kD
4 2 1 F 1 68 kD, 4 3kD
5 35 F 19 + +
6 38 F 1 + 68 kD, 49 kD
7 69 F 1 + 68 kD, 49 kD
8 67 F 6 +
9 3 1 F 2 + +
10 42 F 7 + +
ll 60 M 3
12 28 F 5 +
13 64 M 4 + 68k D, 49 kD

*: Serum antibodies to 68, 49, 43 kD human pituitary membrane antigens.

duced by the intact allele. A mutant GHacts as an antagonist at Table 3. Effects of GHTreatment for 12 Months on Plasma Levels
the level of the GHRin a patient with dwarfism (32). Another of GH, IGF-I and Erythropietin (EPO), Hb, and Serum
type of isolated GHdeficiency is inherited in an X-linked man- Levels of LDL Cholesterol (LDL.cho), Triglyceride (TG),
ner (type III), which is usually associated with hypo- or agam- Nonesterified Fatty Acids (NEFA), Creatinine (Cr) and
maglobulinemia. Urea Nitrogen (UN) in the Patients with Adult GHD
Most patients with congenital GHdeficiency are sporadic, (Modified from 38)
and caused by birth trauma and congenital malformations or be fo r e tr e at me n t af te r tr ea tm en t p
tumors affecting hypothalamic-pituitary function. MRI may GH (ng/ml) 0 . 2 4+ 0. 09 3 . 3 2 + 0. 5 4 <0.05
reveal abnormal scans such as septo-optic dysplasia and pitu- IG F -I (n g /m l) 7 0 . 1+ 1 3. 8 246.6+43.7 <0.05
itary stalk transection (33). The incidence of GHdeficiency is EP O (ml U/ ml ) 2 5 .9 ｱ 2 . 6 3 7 . 6 ｱ 4. 2 <0.05
considered to be one per 10, 000 births. H b (g / dl ) 1 0 . 3+ 0 .5 10 . 8 + 0. 5 <0.05
Acquired GHdeficiency may be obtained at any time dur- LDL ch o (mg/dl) 1 2 6 . 5 + 9. 2 1 2 4 . 3 +9 . 8 <0.05
ing the life span by hypothalamic-pituitary lesions, including NEF A ( mg/d l) 0 . 1 9+0.0 2 0.31+0.05 <0.05
such tumors as craniophryngioma and non-functioning pitu- UN (m g/dl) 1 9 .0 ｱ 2 .2 16 . 0 + 1. 2 < 0 . 01
itary adenoma. Autoimmunehypophisitis could be involved in C re a tin in e (m g /d l) 1. 1 + 0 .1 8 0.9 6+ 0. 1 <0.05
adult GHdeficiency in which serum anti-pituitary antbodies B o dy f a t ( % ) 26 . 4 + 2 . 6 22 . 8 + 3. 1 <0.05
are specifically detectable (34) (Table 2). In patients with pitu-
itary lesions, GH, gonadotropin and PRLare lost earlier than *: mean (±SE) values are shown.
ACTH and TSH.
In childhood, GHdeficiency is suspected by growth retar-
dation, which begins at or shortly after birth. Patients with id- sponse to insulin-induced hypoglycemia as severe GH defi-
iopathic GHdeficiency have blunted, but not absent, serum ciency and a gray zone between 3 and 5 ng/ml, using a
GHresponses to secretagogues. In adults, GHdeficiency may polyclonal GHassay (37).
not be recognized or considered clinically important because GHdeficiency can be treated with recombinant human GH
of the lack of subjective manifestations. Adult GHdeficiency given sc once daily at bed time. The usual dose of GHis 25-50
could be suspected by any hypothalamic-pituitary lesion or by |Lig/kg/day for children, whereas it is 3-12 |Lig/kg/day for adults.
the personal history of childhood GHdeficiency, although about GHtherapy is highly effective in children in accelerating growth
two-thirds of idiopathic GHdeficiency during childhood have to obtain normal or even catch-up growth velocity. In adults,
normal GHsecretion as adults (35). the principal effects are normalization of body composition,
GHdeficiency is diagnosed by the demonstration of an un- an increase in lean body mass, body fluid, and bone mineral
derlying cause, provocative tests of GHsecretion, and serum density, and a decrease in serum LDL-cholesterol (Table 3).
IGF-I measurement (36). A normal peak GHlevel in response Improved anemia (38), renal function (39), muscular strength,
to provocative tests is greater than 7 ng/ml. According to the energy and psychosocial well-being may be obtained. The GH
Growth Hormone Research Society Consensus Guidelines, dose is monitored by observation of growth velocity and/or
adult GHdeficiency is defined by a cut off of 3 ng/ml in re- serum IGF-I levels to maintain the age-appropriate normal

Internal Medicine Vol. 41, No. 1 (January 2002) ll

 Kato et al
Table 4. Potential Clinical Use of GH Administration in Subjects onset is insidious and not recognized until the striking changes
with Absolute or Relative GH Deficiency (GHD) in connectivetissue and appearanceoccur.
I.GHD In acromegaly, GHsecretion remains pulsatile, with in-
1) Child GHDwith short stature creased amplitude and failure to completely cease between
2) Adult GHD pulses (42). The mixture of GHmolecular variants secreted in
II. Short stature without GHD acromegaly does not differ from the mixture secreted normally
1 ) Renal failure (25, 43). GHlevels are not normally suppressed by glucose to
2) Turner syndrome <1 ng/ml. Frequently, patients with acromegaly have a para-
3) Intrauterine growth retardation doxical GHresponse to TRHor LHRH.Bromocriptine and
III. Catabolic conditions other dopaminergic agents suppress GHsecretion during the
1 )2) Malnutrition
Sepsis
daytime in most patients with acromegaly (42). Acromegaly
may be caused by ectopic hypersecretion of GHRHassociated
3) Surgery with somatotroph hyperplasia (44). The involvement of ghrelin
4) Trauma in the hypersecretion of GHremains to be elucidated although
5) Hemodialysis ghrelin and GHRP-RmRNAare expressed in the somatotroph
6)Diets adenomas (45, 46).
7) Corticoid treatment Octreotide, a SRIF agonist, is quite effective for decreasing
IV. Others
1 ) Motor neuron disease GHsecretion by sc injection three times a day or by intermit-
2) Immunedeficiency tent sc infusion with a portable pump (47). Long acting formu-
3) Osteoporosis lations (octreotde LAR) or analogs (lanreotide) have been de-
4) Anemia veloped and are effective when injected in 20- to 40-mg doses
5) Sterility biweekly or monthly (48, 49). A GHantagonist at the GHRis
6) CNS dysfunction also effective in blocking GHaction in patients with acrome-
7)Aging
galy, by the disabling of binding site 2 in the GHmolecule,
and by preventing productive GHRdimerization (50), whereas
circulating GHlevels are rather increased due to blunted nega-
range. Furthermore, the potential use of GHin the treatment of tive feedback by GHand IGF-I.
patients with relative GHdeficiency maybe considered in a
variety of clinical situations (Table 4). Acknowledgements:This work was supported in part by grants from the
Ministry of Health and Welfare, Japan, Renal Anemia Foundation, Japan, and
GHinsensitivity Growth Science Foundation, Japan. Weare indebted to Akiko Kawakamifor
GHinsensitivity clinically resembles GHdeficiency. It may her secretarial help and Akiko Kanayamafor her technical assistance.
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Internal Medicine Vol. 41, No. 1 (January 2002)