EndocrinolJapon
1991,38(1),33-38
Growth Hormone (GH) Profiles with Successive Provocation by GH-releasing Hormone and Arginine in Children: A Clinical Appraisal TAMOTUSATO, NOBORUIGARASHI , KAZUHIKOMIYAGAWA, MAKOTOSHIMIZU ANDTAKESHINISHIKAWA DepartmentofPediatrics,SchoolofMedicine,Kanazawa University, Kanazawa920, Japan
Abstract.
To
examined
successive
hormone and
for
peak
tor
Arg
treatment.
which
two
in 60
children
GH
profiles
were
with
2 GH
stimuli
adolescents to Arg None
GHRH-Arg
as to differentiate
and
to
be a based
2 adults
test
pituitary makes
pituitary
short
(type
(48.7•}4.3
[SEM]ƒÊg/L
deficiency
responded to evaluate from
was
pattern. plasma response
which
appears to both
the
to
to
GHRH caused
stimuli
and
in
29
and
A).
younger
A
Single
children
(9.0•}1.1ƒÊg/L) by
as GH but
somatostatin and
between
7
32.2•}2.6
adults)(type
(4.5•}1.3
GHRH
dwarfism
25 children
of them were diagnosed and good response to
be
counterbalance
hypothalamic
in
we
releasing-
pituitary
GHRH
obtained Two GH
GH
4 types: for
secretion,
action, with
into
respectively
peak
(GH)
of
6 patients
classified
a blunted C),
hormone modes
stature,
Arg-induced
showed
dwarfism
growth
different
qualitatively
GHRH-dominant on a low nocturnal
it possible GH
with
30.1±9.2μg/L
an
(40.6•}9.5ƒÊg/L)
with
evaluating
of
peaks
and
without
for
agents
(Arg)
Their
is considered GHRH deficiency
test
by
(57.7•}4.6ƒÊg/L)
Six
the
reliable
Children;25.8±7i6μg/L
response
hypertonicity.
well
in
arginine
both
and
provocation
adults. to
GHRH
(type B), hypothalamic
normal
and
young
responded
μg/L
a single GH
(GHRH)
9 normal
adults
Thus,
establish
a
(SRIH)
2.3•}0.5ƒÊg/L).
GHRH
and
SRIH
as
dysfunction.
(Endocrinol
japon
38:
33-38,
1991)
IN ADDITION to the intrinsic complexity of growth hormone (GH) regulatory mechansims, the recent accumulation of knowledge about GH secretion in children further complicates the diagnosis of GH deficiency [ 1, 2]. It is mandatory to establish a simple and reliable test for evaluating GH secretion based on the major GH control mechanisms. Recent findings indicate that arginine (Arg)-induced GH secretion is not mediated by GH-releasing hormone (GHRH) but by suppressing endogenous somatostatin (SRIH) [3, 4]. Our previous study on mutual priming effects between GHRH and Arg on GH secretion also supports this concept [5]. Moreover, we found that
priming by GHRH potentiates the following Arginduced GH peak by 88% and the pattern of GH response to successive provocation by GHRH and Arg is fairly consistent in individuals. In the
Received: July 26, 1990 Accepted: December 12, 1990 Correspondence to: Dr. T. SATO, Department of Pediatrics, School of Medicine, Kanazawa University, 13-1 Takaramachi, Kanazawa 920, Japan.
patients with organic panhypopituitarism due to craniopharyngeoma or dysgerminoma. All of them had been treated with hGH for several years, but the therapy was stopped for at least 1 year
present study, we examined the clinical availability of the GHRH-Arg test in children of various ages and patients with pituitary dwarfism. Materials Sixty children
and Methods
of short
stature
aged
2 to
16
years, 9 healthy male volunteers aged 23-24 years and 6 patients with pituitary dwarfism were included in the study. GH deficient patients consisted of 4 with idiopathic pituitary dwarfism and 2
34
SATO
before
the
was
test.
based
height
on and
last
two
al
tests
without
In
GHRH(1-44)
the
90
test).
to
In
of
4
GH
GHRH on
at
30min
until
by the
by
response: (A),
to
to
but
stimuli
(D).
normal for
GHRH
in
children
For
and
deviation
GH in
(SD)
velocity
age
somatomedin
C
for
children
those
over
were
below
further
and
sleep
for
excretion
of
plasma GH and urinary defined
range.
The
The
age.
at
GH
in
the
GH
kit
all
the
the to
of of
child
of
of
(RIA)
the
of
a
evoked
was
Table
for The
GHRH
found. was the
in
D type type
and
but In
markedly
the
reduced
in
type
peak GH
peak
for for
(9.0•}1.0ƒÊg/L),
GH in
shown 48.7•} for
peak
appreciable
contrast,
Arg-induced
(40.6•}9.5ƒÊg/L)
GH no
are
A was
32.2•}3.6ƒÊg/L
GHRH-induced
57.7•}4.6ƒÊg/L was
peak
peak
type
C
was response.
definitely The
1.
Etiology of short A to D.
stature
in relation
to GH profiles of
mean sleep
normal deficiency
and
the final
the
therapy.
was with
LKB,
GH
for
GH
urinary
The
GHRH
6 months
mean
A to
during or
limit
(Fig.2).
GHRH
(0.1
5ƒÊg/L during 10ng/g-creatinine
possible
Arg
provocation of
indices
insulin
samples.
concentration
(Pharmacia
of
GHRH-Arg profiles
1. The
whereas
0.7U/ml
intervals
lower
after
plasma
after
(SEM)ƒÊg/L
B was to
0.5U/ml
concentration
0.5U/kg/w
made
and
subject,
overnight
radioimmunoassay
available
age
Fig.
Arg
age
and
profiles Representative
4.3
growth
than
response
min
with
with
plasma
80%
a
indices
bone
lower
GH 20
in
as
was
below
When
GH
plasma
child
treated
diagnosis
GH type
standard
-25D, of
of
concentration GH excretion
were
by
of
for
h
D
test:
below
yrs
limits
the 4
to
clinical
the
ratio
level
10
examined
U/kg)
was
height
(BA/CA)
yrs
4 to
(SM-C)
the
15,ƒÊg/L
responses
A
deficiency,
under 10
GH
the
Causes of short stature and GH profiles Etiologies of short stature in 66 children are listed in Table 1 in relation to GH secretory profiles. All cases of pituitary dwarfism showed type D response, while 54 of 66 children revealed either a type A (38%) or type B (44%) pattern. Two children with type B had hypothalamic GHRH dysfunction, but there was no close correlation between the other causes of short stature and GH secretory profiles. Type C (9%) also appears to be a normal response.
in
5.0cm/y,
chronological
both
of as
Arg.
low
to
limit
into
addition
of
under
(B),
low
definition.
screening evaluated
and
Arg
and
defined for
of
GHRH
lower
classified
pro-
4 types
to
(C)
the
GH
evoke
low
Arg
10ƒÊg/L
this
imat -20•Ž
both
tentatively
were to
may
but
to
was
[6]
according
were
GHRH
Therefore,
response
stored
to
at
heparinized
combined Arg
normal
examined
separated
and
responses
normal
GHRH
a
was
Results
by
obtained
through
and
normal
was
were
Theoretically,
order
followed
test)
3h
GHRH
reverse
infusion
Plasma
infusion
sample at 0 time, thyroxine (T4) and the SM-C concentration were measured by RIA (Eiken Immunochemical Lab. Tokyo, Japan and Nichols Institute, California, U.S.A., respectively). The urinary GH concentration was determined by the highly sensitive enzyme immunoassay developed by Hashida et al. [7] (Otsuka Assay Lab. Tokushima, Japan). Bone age was evaluated by the method of Gruelich and Pyle [8]. Statistical analysis was carried out by the t-test with pooled variance estimated by the analysis of variance.
(GHRH-Arg the
centrifugation
assay.
vocations
Arg
for
Osafol-
Arg
GHRH
samples
catheter.
mediately
of
Arg-GHRH Blood
intervals
indwelling
synthetic Co.
0.5g/kg
(Arg
day.
of
intravenously,
after
90min:
another
plasma
stimulation
1ƒÊg/kg
3 children,
provocation
the
hypothyroidism.
of
of
and
in
for
GH
Pharmaceutical
120min
adults
SD
chronologic-
value
administered
infusion
-2
rate
to
primary
a bolus
was
by
from
peak
(Sumitomo
Japan)
lowed
of
subjects,
age
2 different
evidence
these
ka,
(3)
in
deficiency below
growth
bone
and
7ƒÊg/L
GH (1)
normal
delayed
80%
than
of
criteria:
70%
(2)
under
less
diagnosis
following
under
years,
age
GH
The
the
et al.
determined commercially
Sweden).
In
the
a) Precocious puberty, post irradiation b) Turner's syndrome.
and ulcerative colitis.
GHPROFILES
WITH
TypeA
GHRH
ARGININE
PROVOCATION
TypeB
TypeC
TypeD
Fig.3. Fig.1.
Effect of Arg priming GHRH-induced
Representative 4 types (A to D) of GH response to GHRH-Arg test.
adoiescent
induced the
with
(shaded
area,
other
adults
of Arg
an In
with
type
GH
secretory
B
values
(囗)and
of GH
(mean+SEM)
Arg(囗)in
type
for GHRH
A
to
D
of
response.
Numbers in parenthesis: numbers of children or adult controls.*P
1991,38(1),33-38
Growth Hormone (GH) Profiles with Successive Provocation by GH-releasing Hormone and Arginine in Children: A Clinical Appraisal TAMOTUSATO, NOBORUIGARASHI , KAZUHIKOMIYAGAWA, MAKOTOSHIMIZU ANDTAKESHINISHIKAWA DepartmentofPediatrics,SchoolofMedicine,Kanazawa University, Kanazawa920, Japan
Abstract.
To
examined
successive
hormone and
for
peak
tor
Arg
treatment.
which
two
in 60
children
GH
profiles
were
with
2 GH
stimuli
adolescents to Arg None
GHRH-Arg
as to differentiate
and
to
be a based
2 adults
test
pituitary makes
pituitary
short
(type
(48.7•}4.3
[SEM]ƒÊg/L
deficiency
responded to evaluate from
was
pattern. plasma response
which
appears to both
the
to
to
GHRH caused
stimuli
and
in
29
and
A).
younger
A
Single
children
(9.0•}1.1ƒÊg/L) by
as GH but
somatostatin and
between
7
32.2•}2.6
adults)(type
(4.5•}1.3
GHRH
dwarfism
25 children
of them were diagnosed and good response to
be
counterbalance
hypothalamic
in
we
releasing-
pituitary
GHRH
obtained Two GH
GH
4 types: for
secretion,
action, with
into
respectively
peak
(GH)
of
6 patients
classified
a blunted C),
hormone modes
stature,
Arg-induced
showed
dwarfism
growth
different
qualitatively
GHRH-dominant on a low nocturnal
it possible GH
with
30.1±9.2μg/L
an
(40.6•}9.5ƒÊg/L)
with
evaluating
of
peaks
and
without
for
agents
(Arg)
Their
is considered GHRH deficiency
test
by
(57.7•}4.6ƒÊg/L)
Six
the
reliable
Children;25.8±7i6μg/L
response
hypertonicity.
well
in
arginine
both
and
provocation
adults. to
GHRH
(type B), hypothalamic
normal
and
young
responded
μg/L
a single GH
(GHRH)
9 normal
adults
Thus,
establish
a
(SRIH)
2.3•}0.5ƒÊg/L).
GHRH
and
SRIH
as
dysfunction.
(Endocrinol
japon
38:
33-38,
1991)
IN ADDITION to the intrinsic complexity of growth hormone (GH) regulatory mechansims, the recent accumulation of knowledge about GH secretion in children further complicates the diagnosis of GH deficiency [ 1, 2]. It is mandatory to establish a simple and reliable test for evaluating GH secretion based on the major GH control mechanisms. Recent findings indicate that arginine (Arg)-induced GH secretion is not mediated by GH-releasing hormone (GHRH) but by suppressing endogenous somatostatin (SRIH) [3, 4]. Our previous study on mutual priming effects between GHRH and Arg on GH secretion also supports this concept [5]. Moreover, we found that
priming by GHRH potentiates the following Arginduced GH peak by 88% and the pattern of GH response to successive provocation by GHRH and Arg is fairly consistent in individuals. In the
Received: July 26, 1990 Accepted: December 12, 1990 Correspondence to: Dr. T. SATO, Department of Pediatrics, School of Medicine, Kanazawa University, 13-1 Takaramachi, Kanazawa 920, Japan.
patients with organic panhypopituitarism due to craniopharyngeoma or dysgerminoma. All of them had been treated with hGH for several years, but the therapy was stopped for at least 1 year
present study, we examined the clinical availability of the GHRH-Arg test in children of various ages and patients with pituitary dwarfism. Materials Sixty children
and Methods
of short
stature
aged
2 to
16
years, 9 healthy male volunteers aged 23-24 years and 6 patients with pituitary dwarfism were included in the study. GH deficient patients consisted of 4 with idiopathic pituitary dwarfism and 2
34
SATO
before
the
was
test.
based
height
on and
last
two
al
tests
without
In
GHRH(1-44)
the
90
test).
to
In
of
4
GH
GHRH on
at
30min
until
by the
by
response: (A),
to
to
but
stimuli
(D).
normal for
GHRH
in
children
For
and
deviation
GH in
(SD)
velocity
age
somatomedin
C
for
children
those
over
were
below
further
and
sleep
for
excretion
of
plasma GH and urinary defined
range.
The
The
age.
at
GH
in
the
GH
kit
all
the
the to
of of
child
of
of
(RIA)
the
of
a
evoked
was
Table
for The
GHRH
found. was the
in
D type type
and
but In
markedly
the
reduced
in
type
peak GH
peak
for for
(9.0•}1.0ƒÊg/L),
GH in
shown 48.7•} for
peak
appreciable
contrast,
Arg-induced
(40.6•}9.5ƒÊg/L)
GH no
are
A was
32.2•}3.6ƒÊg/L
GHRH-induced
57.7•}4.6ƒÊg/L was
peak
peak
type
C
was response.
definitely The
1.
Etiology of short A to D.
stature
in relation
to GH profiles of
mean sleep
normal deficiency
and
the final
the
therapy.
was with
LKB,
GH
for
GH
urinary
The
GHRH
6 months
mean
A to
during or
limit
(Fig.2).
GHRH
(0.1
5ƒÊg/L during 10ng/g-creatinine
possible
Arg
provocation of
indices
insulin
samples.
concentration
(Pharmacia
of
GHRH-Arg profiles
1. The
whereas
0.7U/ml
intervals
lower
after
plasma
after
(SEM)ƒÊg/L
B was to
0.5U/ml
concentration
0.5U/kg/w
made
and
subject,
overnight
radioimmunoassay
available
age
Fig.
Arg
age
and
profiles Representative
4.3
growth
than
response
min
with
with
plasma
80%
a
indices
bone
lower
GH 20
in
as
was
below
When
GH
plasma
child
treated
diagnosis
GH type
standard
-25D, of
of
concentration GH excretion
were
by
of
for
h
D
test:
below
yrs
limits
the 4
to
clinical
the
ratio
level
10
examined
U/kg)
was
height
(BA/CA)
yrs
4 to
(SM-C)
the
15,ƒÊg/L
responses
A
deficiency,
under 10
GH
the
Causes of short stature and GH profiles Etiologies of short stature in 66 children are listed in Table 1 in relation to GH secretory profiles. All cases of pituitary dwarfism showed type D response, while 54 of 66 children revealed either a type A (38%) or type B (44%) pattern. Two children with type B had hypothalamic GHRH dysfunction, but there was no close correlation between the other causes of short stature and GH secretory profiles. Type C (9%) also appears to be a normal response.
in
5.0cm/y,
chronological
both
of as
Arg.
low
to
limit
into
addition
of
under
(B),
low
definition.
screening evaluated
and
Arg
and
defined for
of
GHRH
lower
classified
pro-
4 types
to
(C)
the
GH
evoke
low
Arg
10ƒÊg/L
this
imat -20•Ž
both
tentatively
were to
may
but
to
was
[6]
according
were
GHRH
Therefore,
response
stored
to
at
heparinized
combined Arg
normal
examined
separated
and
responses
normal
GHRH
a
was
Results
by
obtained
through
and
normal
was
were
Theoretically,
order
followed
test)
3h
GHRH
reverse
infusion
Plasma
infusion
sample at 0 time, thyroxine (T4) and the SM-C concentration were measured by RIA (Eiken Immunochemical Lab. Tokyo, Japan and Nichols Institute, California, U.S.A., respectively). The urinary GH concentration was determined by the highly sensitive enzyme immunoassay developed by Hashida et al. [7] (Otsuka Assay Lab. Tokushima, Japan). Bone age was evaluated by the method of Gruelich and Pyle [8]. Statistical analysis was carried out by the t-test with pooled variance estimated by the analysis of variance.
(GHRH-Arg the
centrifugation
assay.
vocations
Arg
for
Osafol-
Arg
GHRH
samples
catheter.
mediately
of
Arg-GHRH Blood
intervals
indwelling
synthetic Co.
0.5g/kg
(Arg
day.
of
intravenously,
after
90min:
another
plasma
stimulation
1ƒÊg/kg
3 children,
provocation
the
hypothyroidism.
of
of
and
in
for
GH
Pharmaceutical
120min
adults
SD
chronologic-
value
administered
infusion
-2
rate
to
primary
a bolus
was
by
from
peak
(Sumitomo
Japan)
lowed
of
subjects,
age
2 different
evidence
these
ka,
(3)
in
deficiency below
growth
bone
and
7ƒÊg/L
GH (1)
normal
delayed
80%
than
of
criteria:
70%
(2)
under
less
diagnosis
following
under
years,
age
GH
The
the
et al.
determined commercially
Sweden).
In
the
a) Precocious puberty, post irradiation b) Turner's syndrome.
and ulcerative colitis.
GHPROFILES
WITH
TypeA
GHRH
ARGININE
PROVOCATION
TypeB
TypeC
TypeD
Fig.3. Fig.1.
Effect of Arg priming GHRH-induced
Representative 4 types (A to D) of GH response to GHRH-Arg test.
adoiescent
induced the
with
(shaded
area,
other
adults
of Arg
an In
with
type
GH
secretory
B
values
(囗)and
of GH
(mean+SEM)
Arg(囗)in
type
for GHRH
A
to
D
of
response.
Numbers in parenthesis: numbers of children or adult controls.*P
