New approach to the diagnosis of growth hormone deficiency

Abstract

Ghigo E, Aimaretti G, Gianotti L, Bellone J, Arvat E, Camanni F. New approach to the diagnosis of growth hormone deficiency in adults. Eur J Endocrinol 1996;134:352–6. ISSN 0804–4643
Pyridostigmine (PD), a muscarinic cholinergic agonist, and arginine (ARG) clearly increase the growth hormone (GH) response to growth hormone-releasing hormone (GHRH) in man. The current study was undertaken to investigate the value and safety of PD + GHRH and ARG + GHRH tests as well as the measurement of serum insulin-like growth factor I (IGF-I) in diagnosing GH deficiency in adults. Fifty-four patients considered GH deficient from extensive organic or idiopathic pituitary disease and 326 healthy adults were studied. The IGF-I concentrations were lower than the 3rd percentile of normal values in only 31 of the 54 (57.4%) patients with hypopituitarism. However, the IGF-I levels in hypopituitary patients and in normal subjects overlapped more frequently between 41 and 60 years (50%) and between 61 and 80 years (92.3%) as opposed to between 20 and 40 years (8.6%). In contrast to the IGF-I measurement, the ranges of peak GH responses to PD + GHRH and ARG + GHRH tests were clearly differentiated between the hypopituitary (0.2–6.8 and 0.1–9.5 μg/l, respectively) and normal subjects 17.7–114 and 16.1–119 μg/l, respectively). However, the PD + GHRH test was reliable only in subjects of 20–40 years of age. In conclusion, IGF-I measurement had no value in the diagnosis of GH deficiency in adults aged over 40 years, but is reliable enough when young adults of 20–40 years of age are considered. Both PD + GHRH and ARG + GHRH testing should be considered more reliable biochemical measurements of GH deficiency. In contrast to the PD + GHRH test, the ARG + GHRH test is reliable throughout the adult lifespan and appears to be the most appropriate for patient compliance and safety.
F Camanni, Divisione di Endocrinologia, Ospedale Molinette, C.so Dogliotti 14, 10126 Torino, Italy

Full text

New
approach
to
the
diagnosis
of
growth
hormone
deficiency
in
adults
Ezio
Ghigo,
Gianluca
Aimaretti,
Laura
Gianotti,
Jaele
Bellone,
Emanuela
Arvat
and
Franco
Camanni
Division
of
Endocrinology,
Department
of
Internal
Medicine,
University
of
Turin,
Italy
Ghigo
E,
Aimaretti
G,
Gianotti
L,
Bellone
J,
Arvat
E,
Camanni
F.
New
approach
to
the
diagnosis
of
growth
hormone
deficiency
in
adults.
Eur
J
Endocrinol
1996;134:352-6.
ISSN
0804-4643
Pyridostigmine
(PD),
a
muscarinic
cholinergic
agonist,
and
arginine
(ARG)
clearly
increase
the
growth
hormone
(GH)
response
to
growth
hormone-releasing
hormone
(GHRH)
in
man.
The
current
study
was
undertaken
to
investigate
the
value
and
safety
of
PD
+
GHRH
and
ARG
+
GHRH
tests
as
well
as
the
measurement
of
serum
insulin-like
growth
factor
I
(IGF-I)
in
diagnosing
GH
deficiency
in
adults.
Fifty-four
patients
considered
GH
deficient
from
extensive
organic
or
idiopathic
pituitary
disease
and
326
healthy
adults
were
studied.
The
IGF-I
concentrations
were
lower
than
the
3rd
percentile
of
normal
values
in
only
31
of
the
54(
57.4%)
patients
with
hypopituitarism.
However,
the
IGF-I
levels
in
hypopituitary
patients
and
in
normal
subjects
overlapped
more
frequently
between
41
and
60
years
(50%)
and
between
61
and
80
years
(92.3%)
as
opposed
to
between
20
and
40
years
(8.6%).
In
contrast
to
the
IGF-I
measurement,
the
ranges
of
peak
GH
responses
to
PD
+
GHRH
and
ARG
+
GHRH
tests
were
clearly
differentiated
between
the
hypopituitary
(0.2-6.8
and
0.1-9.5
\g=m\g/l,
respectively)
and
normal
subjects
17.7\p=n-\114
and
16.1\p=n-\119\g=m\g/l,
respectively).
However,
the
PD
+
GHRH
test
was
reliable
only
in
subjects
of
20\p=n-\40
years
of
age.
In
conclusion,
IGF-I
measurement
had
no
value
in
the
diagnosis
of
GH
deficiency
in
adults
aged
over
40
years,
but
is
reliable
enough
when
young
adults
of
20\p=n-\40
years
of
age
are
considered.
Both
PD
+
GHRH
and
ARG
+
GHRH
testing
should
be
considered
more
reliable
biochemical
measurements
of
GH
deficiency.
In
contrast
to
the
PD
+
GHRH
test,
the
ARG
+
GHRH
test
is
reliable
throughout
the
adult
lifespan
and
appears
to
be
the
most
appropriate
for
patient
compliance
and
safety.
F
Camanni,
Divisione
di
Endocrinologia,
Ospedale
Molinette,
C.so
Dogliotti
14,
10126
Torino,
Italy
The
diagnosis
of
growth
hormone
(GH)
deficiency
(GHD)
in
childhood
is
based
on
auxological
and
hormonal
investigations,
whereas
this
diagnosis
in
adults
is
based
on
hormonal
investigations
only,
i.e.
the
assessment
of
serum
insulin-like
growth
factor
I
(IGF-I)
and
serum
IGF
binding
protein
3
(IGFBP-3)
and
the
testing
of
GH
secretion
after
pharmacological
stimuli,
spontaneous
GH
secretion
or
a
combination
of
both.
However,
there
is
no
consensus
as
to
which
test
or
combination
of
tests
should
be
used
to
assess
GH
status.
The
ready
availability
of
recombinant
human
GH
has
led
to
many
studies
of
the
biological
consequences
of
GH
deficiency
and
the
benefits
of
treating
adults
with
this
drug.
To
date,
several
studies
in
GH-deficient
adults
report
a
beneficial
effect
of
GH
treatment
on
body
composition
and
cardiovascular
and
musculoskeletal
function
(1-5).
Thus,
accurate
diagnosis
of
GH
deficiency
becomes
imperative
to
select
adults
who
are
truly
GH
lacking.
Recently,
the
value
of
stimulated
GH
release,
spontaneous
secretion,
fGF-I
and
IGF-BP3
measure¬
ment
in
diagnosing
GH
deficiency
has
been
investigated
in
adults
(6).
Of
the
four
tests
used
to
assess
GH
secretory
status,
the
insulin
tolerance
test
(1TT)
was
the
only
one
able
to
differentiate
patients
with
organic
hypothalamic/pituitary
disease
from
their
matched
normal
counterparts.
Although
1TT
provided
100%
diagnostic
accuracy
in
defining
GH
deficiency,
this
test
has
potential
dangers.
In
addition,
ITT
is
contra-
indicated
in
patients
at
risk
of
epilepsy
in
major
neurosurgery.
On
the
other
hand,
the
risk
of
inducing
profound
hypoglycaemia
is
higher
in
patients
with
GH
deficiency
because
they
have
an
enhanced
sensitivity
to
the
action
of
insulin.
We
have
reported
previously
(7-9)
that
pyridostigmine
(PD),
a
muscarinic
cholinergic
agonist,
and
arginine
(ARG)
clearly
increase,
both
in
children
and
in
adults,
the
GH
response
to
GH-releasing
hormone
(GHRH).
In
contrast
to
GHRH
alone
(10),
PD
+
GHRH
and
ARG
+
GHRH
tests
have
been
reported
to
be
reliable
provocative
tests
for
the
diagnosis
of
primary
pituitary
GH
deficiency
in
children
(11-13).
The
current
study
was
undertaken
to
investigate
the
diagnostic
potential
and
safety
of
these
new
tests
of
GH
stimulation
in
adults.
The
related
value
of
the
measure¬
ment
of
serum
fGF-f
concentrations
in
diagnosing
GH
deficiency
has
also
been
evaluated.

Subjects
and
methods
Fifty-four
patients
with
hypopituitarism
(30
women
and
24
men
aged
20-80
years)
and
326
healthy
adults
(228
women
and
98
men
aged
20-80
years),
all
within
±15%
of
ideal
body
weight,
were
studied.
The
body
mass
index
in
hypopituitary
patients
ranged
from
18.2
to
27.1
kg/m".
After
an
explanation
of
the
protocol
and
the
test
procedures,
all
subjects
gave
their
consent
to
participate.
The
protocol
had
been
approved
by
our
Ethical
Committee.
Patients
with
a
history
of
a
structural
lesion
of
the
pituitary
or
hypothalamus
frequently
treated
with
surgery
and/
or
radiotherapy
(12
craniopharyngiomas,
17
non-
functioning
pituitary
adenomas,
five
prolactinomas,
two
Sheehan's
syndromes,
one
cyst
of
arachnoid,
one
meningioma,
one
hystiocitosis
and
one
cholesteatoma)
or,
in
the
absence
of
a
structural
lesion,
with
a
history
of
idiopathic
hypopituitarism
(N
=
7)
were
considered
to
be
GH
deficient.
Out
of
these
47
patients,
five
(10.6%)
were
gonadotrophin-
and
ACTH-deficient
and
three
(6.4%)
were
ACTH-
and
TSH-deficient;
in
the
remaining
39
patients
(83.0%),
three
anterior
pituitary
hormone
(gonadotrophin,
ACTH
and
TSH)
deficiencies
were
shown.
The
duration
of
hypopituitarism
ranged
from
2
to
12
years.
The
seven
patients
previously
diagnosed
as
having
isolated
GH
deficiency
for
short
stature
(<
3sd)
had
already
received
GH
replacement
therapy
during
childhood.
Hypopituitary
subjects
received
standard
substitutive
therapy
for
thyroid,
adrenal
or
gonadal
hypofunction,
which
included
75-100
µ%
of
thyroxine
per
day,
25-37.5
mg
of
cortisone
acetate
per
day,
ester
association
of
2
50
mg
of
testosterone
intramuscularly
once
a
month
for
men
and
standard
cyclical
oestrogen
replacement
for
women.
Measurement
of
serum
IGF-I
was
performed
on
all
controls
and
hypopituitary
subjects.
Eighty-four
controls
(46
females
and
38
males)
and
27
hypopituitary
subjects
underwent
a
PD
+
GHRH
test
and
73
controls
(34
females
and
39
males)
and
24
hypopituitary
subjects
underwent
an
ARG
+
GHRH
test.
Sixteen
of
the
hypopituitary
patients
underwent
both
tests.
Nineteen
hypopituitary
patients
also
underwent
an
insulin
tolerance
test
(ITT).
After
overnight
fasting,
tests
were
carried
out
starting
at
09.00
h,
30
min
after
an
indwelling
catheter
was
inserted
into
an
antecubital
vein,
kept
patent
with
a
slow
infusion
of
0.9%
saline.
Pyridostygmine
+
GHRH
test
Pyridostigmine
(120
mg;
Mestinon,
Hoffmann-Laroche,
Basel,
Switzerland)
was
administered
orally
60
min
before
GHRH
(1
/¿g/kg
as
iv
bolus).
Arginine
+
GHRH
test
Arginine
(30
g
in
100
ml)
was
infused
from
0
to
30
min
and
GHRH
(
1
pg/kg)
was
injected
as
an
iv
bolus
at
Omin.
Insulin
tolerance
test
Soluble
insulin
(0.1IU/kg
Actrapid;
Novo-Nordisk,
Copenhagen,
Denmark)
was
given
intravenously
at
Omin.
Blood
samples
were
taken
at
15-min
intervals,
starting
at
—15
to
120
min
for
GH
measurement.
During
ITT,
glucose
measurement
was
performed
and
a
minimum
plasma
glucose
level
of
2.2
nmol/1
or
less
was
detected.
Serum
GH
levels
were
measured
in
duplicate
by
immunoradiometric
assay
(HGH-CTK,
Sorin,
Italy).
All
samples
from
an
individual
subject
were
analysed
together.
The
sensitivity
of
the
assay
was
0.15/Lig/l.
The
inter-
and
intra-assay
coefficients
of
variation
were
4.9-6.5%
and
1.5-2.9%,
respectively.
The
IGF-I
levels
were
measured
in
duplicate
by
radioimmuno¬
assay
(Nichols
Institute
Diagnostics,
USA).
To
avoid
interference
by
binding
proteins,
all
plasma
samples
were
treated
with
acid-ethanol.
The
sensitivity
of the
assay
was
0.1
pg/\.
The
inter-
and
intra-assay
coefficients
of
variation
were
10.1-15.7%
and
7.6-
15.5%,
respectively.
Statistical
methods
Shapiro-Wilks'
w
test
was
applied
to
test
the
normality
of
the
population
distribution.
When
the
distribution
of
the
population
was
not
normal,
percentiles
were
calculated
with
conventional
methods.
The
results
were
expressed
by
median
values
and
ranges.
The
Kruskall-Wallis
ANOVA
test
was
used
to
test
the
sex
difference.
Linear
correlations
were
calculated
using
Spearman's
rank
correlation
test.
Results
Insulin-like
growth
factor
1
Serum
IGF-I
levels
in
normal
subjects
decreased
significantly
(r
=
-0.60,
<
0.0001)
during
their
lifespan,
with
no
significant
sex
difference
(Fig.
1).
The
IGF-I
concentrations
were
lower
than
the
3rd
percentile
of
normal
values
in
only
31
of
the
54
(57.4%)
patients
with
hypopituitarism.
However,
the
IGF-I
levels
in
hypopituitary
patients
and
in
normal
subjects
over¬
lapped
more
frequently
between
the
ages
of
41-60
years
(50%)
and
61-80
years
(92.3%),
as
opposed
to
20-40
years
(8.6%).
Pyridostigmine
+
GHRH
test
Figures
2
and
3
report
a
peak
GH
response
to
the
PD
+
GHRH
test
in
84
normal
subjects
and
in
27
patients
with
hypopituitarism
and
IGF-I
levels
ranging

I
u-
500
400
300
-
200
100
0
500
400
300
200
100
0
·+*
20
60
80
AGE
(years)
Fig.
1.
Age
distribution
of
serum
IGF-I
levels
in
326
healthy
adults
(20-80
years
old)
of
both
sexes
(upper
panel)
and
in
54
hypopituitary
patients
aged
20-80
years
(lower
panel).
Solid
triangles
are
IGF-I
levels
in
idiopathic
GH
deficiency.
The
shaded
area
depicts
the
95%
confidence
levels
in
normal
subjects
per
decade
of
age.
from
7
to
196
pg/\.
In
normal
subjects,
the
PD
+
GHRH
test
induced
peak
GH
responses
that
ranged
from
3.7
to
114.0µg/l
(median
27.2pg/\).
No
significant
sex
difference
was
highlighted,
but
the
median
GH
peak
was
lower
in
elderly
subjects
(60-80
years
of
age)
than
in
young
adults
(20-40
years
of
age)
(14.5
vs
54.5
pg/\\
<
0.05).
The
GH
peak
occurred
at
15-
90
min
after
GHRH
administration.
Peak
GH
responses
between
normal
and
hypopituitary
subjects
overlapped,
PD+GHRH
ARG+GHRH
120
100
-
Z¡
80
60
40
20
Oo
oo
o
o
oo
o"
„o°
udVÙa*
o
ooo
o
88
o
0°
0°
qOO
8
<?copo
°o8<¿l§
0o°8°¿
O0§°0
op.S§°
*»UAti
Fig.
2.
Peak
GH
responses
to
pyridostygmine
(PD)
+
GHRH
or
arginine
(ARG)
+
GHRH
tests
in
normal
(o)
and
hypopituitary
(·)
subjects.
Solid
triangles
are
GH
levels
in
idiopathic
GH
deficiency.
PD+GHRH
ARG+GHRH
I
60
-
<3
°o
o
<*0
o8
O
0)0
···
V·
20
30
40
50
60 70
80
o
oo
oo
oo
o
«
°*
°
*°
o08
o*
o
o
•
·...
¿v.
:v.
·
-1-1-1-1-1-1
20
30
40
50
60
70
80
Age
(yrsl
Fig.
3.
Peak
GH
responses
to
pyridostygmine
(PD)
+
GHRH
or
arginine
(ARG)
+
GHRH
tests
in
relation
to
age
in
normal
(o)
and
hypopituitary
(·)
subjects.
Solid
triangles
are
GH
levels
in
idiopathic
GH
deficiency.
with
18.5%
(five
out
of
27)
of
hypopituitary
patients
reporting
values
within
the
range
of
normal
subjects.
However,
if
only
young
adults
aged
between
20
to
40
years
of
age
are
considered,
a
clear
differentiation
in
the
range
of
peak
GH
responses
between
the
two
groups
is
highlighted,
with
the
hypopituitary
group
reporting
the
highest
value
of
6.8
/ig/1
as
opposed
to
a
range
of
17.7-
114.0/xg/l
(3rd
and
97th
percentiles
of
17.8
and
109.0µg/l,
respectively)
in
normal
subjects.
The
sensitivity
and
specificity
of
the
test
were
100%
and
94%,
respectively.
In
11
hypopituitary
patients
of
20-40
years
of
age,
the
peak
GH
response
to
the
PD
+
GHRH
test
(median
2.6
µg/l;
range
0.2-6.8
µg/I)
did
not
differ
significantly
20
15
>
a.
10
5
-
··
A·
A·
•iX
PD+GHRH
ITT
ARG+GHRH
ITT
Fig.
4.
Comparison
in
the
same
hypopituitary
subjects
between
peak
GH
responses
to
the
pyridostygmine
(PD)
+
GHRH
test
(aged
20-40
years)
or
to
the
arginine
(ARG)
+
GHRH
test
(aged
20-80
years)
and
the
insulin
tolerance
test
(ITT).
Solid
triangles
are
GH
levels
in
idiopathic
GH
deficiency.

from
those
to
insulin-induced
hypoglycaemia
(median
1.2
pg/\;
range
0.4-3.1
pg/\)
(Fig.
4).
The
responses
to
the
PD
+
GHRH
test
were
also
not
different
in
hypopituitary
and
isolated
GH-deficient
patients
and
were
not
correlated
with
the
duration
of
GH
deficiency.
Arginine
+
GHRH
test
Figures
2
and
3
also
report
peak
GH
responses
to
the
ARG
+
GHRH
test
in
73
normal
subjects
and
in
24
patients
with
hypopituitarism
and
IGF-I
levels
ranging
from
14
to
196µg/l.
In
normal
subjects,
the
ARG
+
GHRH
test
induced
peak
GH
responses
that
ranged
from
16.1
to
119.0
pg/\
(median
49.5/ig/I;
3rd
and
97th
percentiles
of
16.4
and
113.0/ig/l,
respectively),
with
no
significant
sex
difference.
The
GH
peak
occurred
at
15-90
min
after
GHRH
administration.
Contrary
to
the
PD
+
GHRH
test,
the
median
GH
peak
to
ARG
+
GHRH
did
not
differ
significantly
in
elderly
and
young
subjects
(47.6
vs
57.0
pg/\).
There
was
a
clear
differentiation
in
the
range
of
peak
GH
responses
between
normal
and
hypopituitary
subjects
(including
the
five
patients
who
had
overlapping
"normal"
peak
GH
levels
following
PD
+
GHRH),
with
the
highest
value
in
the
hypopitui¬
tary
group
reported
at
9.5
pg/\
as
opposed
to
a
range
of
16.1-119.0
pg/\
in
normal
subjects.
The
sensitivity
and
specificity
of
the
test
were
100%
and
95.8%,
respectively.
In
11
hypopituitary
patients,
the
peak
GH
responses
to
the
ARG
+
GHRH
test
(median
3.1
pg/h
range
0.1-
9.5µg/l)
did
not
differ
significantly
from
those
to
insulin-induced
hypoglycaemia
(median
1.2pg/i;
range
0.2-5.9
µg/l)
(Fig.
4).
The
responses
to
the
ARG
+
GHRH
test
were
also
not
different
in
hypopituitary
and
isolated
GH-deficient
patients
and
were
not
correlated
with
the
duration
of
GH
deficiency.
Side
effects
After
GHRH
administration,
transient
facial
flushing
was
reported
for
most
of
the
subjects.
Pyridostigmine
frequently
induced
mild
abdominal
pain
and
fascicula-
tions,
while
no
side
effects
were
observed
after
arginine
administration.
Discussion
The
present
results
confirm
previous
reports
(14,
15)
that
serum
IGF-I
concentrations
in
normal
subjects
decrease
significantly
during
the
lifespan,
with
no
significant
sex
difference.
The
increased
overlapping
between
normal
and
hypopituitary
patients
over
40
years
reduces
the
diagnostic
value
of
individual
age-
stratified
IGF-f
measurements.
On
the
other
hand,
our
results
show
that
IGF-I
measurement
is
reliable
enough
in
young
adults
aged
20-40
years,
with
91.4%
of
hypopituitary
patients
having
IGF-I
concentrations
below
the
3rd
percentile
of
normal
values.
These
latter
results
are
in
accordance
with
the
findings
of
de
Boer
et
al.
(16)
and
Bates
et
al.
(17).
In
contrast
to
IGF-I
measurement,
the
PD
+
GHRH
and
ARG
+
GHRH
tests
used
to
assess
GH
secretory
status
were
able
to
differentiate
clearly
between
normal
subjects
and
patients
with
hypopituitarism.
Thus,
the
subnormal
peak
GH
response
to
these
tests
had
a
diagnostic
accuracy
of
100%
in
the
differentiation
of
hypopituitary
patients
from
normal
subjects.
However,
the
PD
+
GHRH
test
was
reliable
only
in
subjects
aged
20-40
years.
These
provocative
tests
using
GHRH
are
able
to
probe
the
real
secretory
capacity
of
the
somatotrope
cells.
Possible
hypothalamic
defects
should
be
verified
by
the
study
of
spontaneous
GH
secretion,
which
seems
to
be
reliable
in
children
but
not
in
adults
(6).
In
patients
with
hypopituitarism
who
underwent
both
the
PD
+
GHRH
(or
ARG
+
GHRH)
test
and
ITT,
the
peak
GH
responses
overlapped
in
the
two
tests.
However,
in
normal
subjects
the
peak
GH
response
to
GHRH
combined
with
pyridostigmine
or
arginine
is
markedly
higher
than
that
to
the
insulin-induced
hypoglycaemia
reported
by
Hoffman
et
al.
(6),
the
minimum
normal
GH
peak
being
17.7
and
16.1
µg/l
for
the
PD
+
GHRH
and
ARG
+
GHRH
tests,
respectively,
and
5.3
µg/l
for
ITT.
Therefore,
a
clearer
differentiation
is
present
in
the
range
of
peak
GH
responses
between
normal
and
hypopituitary
subjects
through
PD
+
GHRH
and
ARG
+
GHRH
tests
than
through
ITT.
As
the
patients
included
in
this
study
suffered
from
severe
hypopituitarism,
it
may
be
hypothesized
that
these
new
tests
may
also
be
able
to
detect
minor
defects
in
GH
secretion
not
necessarily
revealed
by
insulin.
In
agreement
with
this
hypothesis,
the
GH
status
of
an
adult
with
non-acromegalic
pituitary
disease
has
been
reported
to
be
related
to
the
degree
of
hypopituitarism
present
(18).
In
contrast
to
ITT,
GHRH
combined
with
pyrido¬
stigmine
or
arginine
is
basically
a
well-tolerated
test.
However,
the
possible
contraindication
to
the
use
of
cholinergic
agonists
and
the
finding
of
low
GH
responses
to
the
PD
+
GHRH
test
in
elderly
subjects
indicate
ARG
+
GHRH
to
be
the
safest
and
most
reliable
test
throughout
the
adult
Iifespan.
Arginine,
but
not
pyridostigmine,
is
able
to
restore
totally
the
reduced
GH
responsiveness
to
GHRH
in
elderly
subjects,
making
it
overlap
with
that
in
young
adults
(19, 20).
Confirming
previous
data
(21),
our
results
show
that
the
GH
response
to
the
PD
+
GHRH
test
is
lower
in
the
elderly
than
in
the
young,
while
the
GH
response
to
the
ARG
+
GHRH
test
remains
unchanged
throughout
the
adult
Iifespan.
Because
the
GH-releasing
effect
ofboth
pyridostygmine
and
arginine
is
likely
to
be
mediated
by
inhibition
of
hypothalamic
somatostatin
release
(22-24),
the
reduced
GH
response

to
the
PD
+
GHRH
test
in
aging
would
point
to
the
existence
of
an
impaired
tuberoinfundibular
cholinergic
function
in
aging.
On
the
other
hand,
the
existence
of
an
impaired
function
of
the
cholinergic
nervous
system
in
old
people
has
been
evidenced
by
others
(25,
26).
In
conclusion,
IGF-I
measurement
is
sufficiently
reliable
to
diagnose
GH
deficiency
for
individuals
aged
20-40
years
but
has
no
value
for
those
over
40
years.
Pyridostigmine
+
GHRH
or
ARG
+
GHRH
testing
should
be
considered
a
very
reliable
biochemical
measurement
of
GH
deficiency.
These
tests
are
also
able
to
probe
the
real
secretory
capacity
of
somatotrope
cells.
However,
the
PD
+
GHRH
test
is
reliable
only
in
young
adults,
whereas
the
ARG
+
GHRH
test
is
reliable
throughout
the
adult
Iifespan
and
appears
to
be
the
most
appropriate
for
patient
compliance
and
safety.
Acknowledgment
This
study
was
supported
in
part
by
a
grant
from
the
Consiglio
Nazionale
delle
Ricerche.
Progetto
Finalizzato
Invecchia¬
mento.
Inv.
95
3638.
References
1.
Jorgensen
JOL,
Thuesen
L,
Ingemann-Hansen
T,
Pedersen
SA.
Jorgensen
J.
Skakkebaek
NE.
et
al.
Beneficial
effects
of
growth
hormone
treatment
in
GH-deficient
adults.
Lancet
1989;i:1221-5
2.
Salomon
F,
Cuneo
RC,
Hesp
RC,
Sonksen
PH.
The
effects
of
treatment
with
recombinant
human
growth
hormone
on
body
composition
and
metabolism
in
adults
with
growth
hormone
deficiency.
Engl
J
Med
1989;321:1979-803
3.
Cuneo
RC,
Salomon
F.
Mark
Wiles
C,
Hesp
R.
Sonkesn
PH.
Growth
hormone
treatment
in
growth
hormone-deficient
adults.
II.
Effects
on
exercise
performance.
Am
J
Physiol
1991:70:695-700
4.
Amato
G,
Carella
C,
Fazio
S.
La
Montagna
G,
Cittadini
A.
Sabatini
D,
et
al.
Body
composition,
bone
metabolism
and
heart
structure
and
function
in
growth
hormone
(GH)-deficient
adults
before
and
after
GH
replacement
therapy
at
low
doses.
J
Clin
Endocrinol
Metab
1993;77:1671-6
5.
Merola
B,
Cittadini
A,
Colao
A,
Longobardi
S,
Fazio
S,
Sabatini
D,
et
al.
Cardiac
structural
and
functional
abnormalities
in
adult
patients
with
growth
hormone
deficiency.
J
Clin
Endocrinol
Metab
1993;77:1658-61
6.
Hoffmann
DM.
O'Sullivan
AJ,
Baxter
RC,
Ho
KY.
Diagnosis
of
growth
hormone
deficiency
in
adults.
Lancet
1994;i:1064-8
7.
Massara
F,
Ghigo
E,
Demislis
,
Tangolo
D,
Mazza
E.
Locatelli
V,
et
al.
Cholinergic
involvement
in
the
growth
hormone
releasing
hormone-induced
growth
hormone
release.
Studies
in
normal
and
acromegalie
subjects.
Neuroendocrinology
1986:43:670-5
8.
Ghigo
E.
Mazza
E,
Imperiale
E,
Rizzi
G,
Benso
L,
Muller
EE,
et
al.
The
enhancement
of
the
cholinergic
tone
by
pyridostigmine
promotes
both
basal
and
growth
hormone
(GH)-releasing
hormone-induced
GH
secretion
in
children
of
short
stature.
J
Clin
Endocrinol
Metab
1987:65:452-6
9.
Ghigo
E,
Bellone
J.
Mazza
E,
Imperiale
E.
Procopio
M,
Valente
F.
et
al.
Arginine
potentiates
the
GHRH-
but
not
the
pyridostigmine-
induced
GH
secretion
in
normal
short
children.
Further
evidence
for
a
somatostatin
suppressing
effect
of
arginine.
Clin
Endocrinol
1990:32:763-7
10.
Rogol
AD,
Blizzard
RM,
Johanson
AJ,
Furlanetto
RW,
Evans
WS,
Rivier
J,
et
al.
GH
release
in
response
to
human
pancreatic
tumor
GHRH-40
in
children
with
short
stature.
J
Clin
Endocrinol
Metab
1984:99:580-6
11.
Ghigo
E,
Imperiale
E,
Buffano
GM,
Mazza
E,
Bellone
J,
Arvat
E,
et
al.
A
new
test
for
the
diagnosis
of
growth
hormone
deficiency
due
to
primary
pituitary
impairment:
combined
administration
of
pyridostigmine
and
growth
hormone-releasing
hormone.
J
Endocrinol
Invest
1990:13:307-16
12.
Dammacco
F,
Boghen
MF.
Camanni
F.Cappa
M.
Ferrari
C.
Ghigo
E.
et
al.
and
the
Italian
collaborative
group
of
neuroendocrinology.
Somatotropic
function
in
short
stature:
evaluation
by
integrated
auxological
and
hormonal
indices
in
214
children.
J
Clin
Endocrinol
Metab
1993;77:68-72
13.
Bellone
J,
Valente
F,
Aimaretti
G,
Loche
S,
Cappa
M,
Bartolotta
E,
et
al.
Peak
GH
response
to
various
provocative
stimuli
in
children
with
normal
and
familial
short
stature.
Pediatr
Res
Suppl
1993:5:S25
14.
Clemmons
DR.
Van
Wyk
JJ.
Factors
controlling
blood
concentration
of
somatomedin
C.
Clin
Endocrinol
Metab
1984;13:113-43
1
5.
Juul
A,
Bang
P.
Hertel
NT,
Main
K,
Dalgaard
P.
Jorgensen
K,
et
al.
Serum
insulin-like
growth
factor-I
in
1030
healthy
children,
adolescents,
and
adults:
relation
to
age,
sex,
stage
of
puberty,
testicular
size,
and
body
mass
index.
J
Clin
Endocrinol
Metab
1994;78:744-52
16.
de
Boer
H.
Blok
G-J,
Poo-Snijders
C.
Van
der
Veen
EA.
Diagnosis
of
growth
hormone
deficiency
in
adults.
Lancet
1994:343(11):
1645-6
17.
Bates
AS.
Evans
AJ,
Jones
P.
Clayton
RN.
Assessment
of
GH
status
in
adults
with
GH
deficiency
using
serum
growth
hormone,
serum
insulin-like
growth
factor-I
and
urinary
growth
hormone
excretion.
Clin
Endocrinol
1995;42:425-30
18.
Toogod
AA,
Beardwell
CG.
Shalet
SM.
The
severity
of
growth
hormone
deficiency
in
adults
with
pituitary
disease
is
related
to
the
degree
of
hypopituitarism.
Clin
Endocrinol
1994:41:511-6
19.
Ghigo
E,
Goffi
S,
Nicolosi
M,
Arvat
E,
Valente
F,
Mazza
E,
et
al.
Growth
hormone
(GH)
responsiveness
to
combined
administration
of
arginine
and
GH-releasing
hormone
does
not
vary
with
age
in
man.
J
Clin
Endocrinol
Metab
1990:71:1481-5
20.
Ghigo
E,
Goffi
S.
Arvat
E,
Nicolosi
M.
Procopio
M,
Bellone
J,
et
al.
Pyridostigmine
partially
restores
the
GH
responsiveness
to
GHRH
in
normal
aging.
Acta
Endocrinol
(Copenh)
1990:123:169-74
21.
Ghigo
E,
Goffi
S,
Arvat
E,
Imperiale
E,
Boflano
GM.
Valetta
MR.
et
al.
A
neuroendocrinological
approach
to
evidence
an
impairment
of
central
cholinergic
function
in
aging.
J
Endocrinol
Invest
1992;15:665-70
22.
Alba-Roth
J,
Albrecht
A,
Müller
O.
Schopol
J.
Von
Werder
.
Arginine
stimulates
growth
hormone
secretion
by
suppressing
endogenous
somatostatin
secretion.
J
Clin
Endocrinol
Metab
1988;67:1186-90
2 3.
Locatelli
V.
Toresello
A.
Redaelli
M,
Ghigo
E,
Massara
F,
Muller
EE.
Cholinergic
agonist
and
antagonist
drugs
modulate
the
growth
hormone
response
to
growth
hormone-releasing
hormone
in
the
rat:
evidence
for
mediation
of
somatostatin.
J
Endocrinol
1986;11:271-8
24.
Casanueva
FF.
Villanueva
C,
Dieguez
J.
Atropine
blockade
of
growth
hormone
(GH)-releasing
hormone-induced
GH
secretion
in
man
is
not
exerted
at
pituitary
level.
J
Clin
Endocrinol
Metab
1986:62:186-91
25.
Bartus
RT,
Dean
RL,
Beer
B,
Lippa
AS.
The
cholinergic
hypothesis
of
geriatric
memory
dysfunction.
Science
1988:217:408-1
7
26.
Gibson
GE.
Peterson
C.
Jender
DJ.
Brain
acetylcholine
synthesis
declines
with
senescence.
Science
1981:213:674-6
Received
May
18th,
1995
Accepted
November
21st,
1995