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Is IGF-1 the ONLY true marker of increased GH activity?
...........................................................
4
Introduction ........................................................................
4
Is IGF-1 always increased by increases in GH production?
......................................................
4
Diagnosis of growth-hormone deficiency in adults. ..........................................................
4
Serum Levels of Insulin-like Growth Factor-I (IGF-I)
and IGF Binding Protein-3 (IGFBP-3) in Idiopathic Tall
Basketball Players ...........................................................................
5
A five day treatment with daily subcutaneous injections
of growth hormone-releasing peptide-2 causes response
attenuation and does not stimulate insulin-like growth
factor-I secretion in healthy young men. .....................................
5
Defining growth hormone deficiency in adults. ...................................................................................
6
Association of insulin-like growth factor-I with body
composition, weight history, and past health behaviors
in the very old: the Framingham Heart Study. ....................................................................................
6
Insulin-like growth factor measurements in the evaluation
of growth hormone secretion. .................... 7
IGF-I levels in different conditions of low somatotrope
secretion in adulthood: obesity in comparison with GH
deficiency. 7
Can IGF-1 production be stimulated by factors other
than GH? ........................................ 7
The measurement of insulin-like growth factor I: clinical
applications and significance. .....................
7
IGF-1 synthesis and release ..............................................................................
8
Feeding colostrum increases circulating insulin-like
growth factor I in newborn pigs independent of endogenous
growth hormone secretion. ........................................................
8
Independent effects of food intake and insulin status
on insulin-like growth factor-I in young pigs. ... 8
Clinical utility of insulin-like growth factor assays.
.......................................................................................
9
Nutritional regulation of insulin-like growth factor-I.
...................................................................................
9
By what methods is IGF-1 measured? ...........................................................................
10
Blood Panel ...............................................................
10
Saliva ..................................................................
10
Salivary insulin-like growth factor-I originates from
local synthesis. ..................................................................
10
normal population study of human salivary insulin-like
growth factor 1 (IGF 1) concentrations from birth through
puberty. 10
Free insulin-like growth factor I (IGF-I) and IGF-II
in human saliva. .................................................................
11
Urine .................................................................
12
Immunoreactive insulin-like growth factor II in urine.
.....................................................................
12
Urinary growth hormone excretion in post-menarcheal
adolescent girls with type 1 diabetes. ..........................
12
Changes in serum concentrations of growth hormone,
insulin, insulin-like growth factor and insulin-like
growth factor-binding proteins 1 and 3 and urinary growth
hormone excretion during the menstrual cycle. ...........................................................................
13
(IGFs) and IGF binding protein 3 in healthy volunteers
before and after stimulation with recombinant human
growth hormone. 14
Cerebro Spinal Fluid ............................................................................
14
Specific assay for insulin-like growth factor (IGF)
II using the IGF binding proteins extracted from human
cerebrospinal fluid. 14
Amniotic Fluid ..................................................................................
15
Insulin-like growth factors in amniotic fluid. .........................................................................
15
Bile ................................................................................
15
Presence of insulin-like growth factor I but absence
of the binding proteins in the bile of rats. .........................
15
Can IGF-1 be too high? ................................................................................
16
Prostate Cancer Risk ..............................................................................
16
Insulin-like growth factor 1 and prostate cancer risk:
a population-based, case-control study. .........................
16
Insulin-like growth factor 1 in relation to prostate
cancer and benign prostatic hyperplasia. .............................
17
Breast Cancer Risk ........................................................................
17
The insulin-like growth factors and breast cancer--revisited.
..............................................................................
18
IGF-I physiology and breast cancer. ...................................................................
18
Circulating concentrations of insulin-like growth factor-I
and risk of breast cancer. ...........................................
18
Insulin and related factors in premenopausal breast
cancer risk. .........................................................................
19
rBGH, IGF-1, and Cancer ..............................................................
20
(Think Before You Drink, by Ben Davis, Conscious Choice,
November/December 1995) ................................
20
Insulin-like growth factor-I in relation to premenopausal
ductal carcinoma in situ of the breast. .......................
21
Other Important Blood Panel biomarkers for GH production
....................................... 22
Sex Hormones ................................................
22
Osteocalcin ..............................................................
22
BP3/BP2 Ratios (IGF-Binding Proteins) ....................................................................
22
DHEA .....................................................
22
Pregnenolone .....................................................
22
Thyroid Stimulating Hormone ................................................................
22
Thyroid, free T3 ...........................................................
22
Thyroid, free T4 .............................................................
22
FSH .............................................................
22
LH. ...................................................................
22
Is Oral Growth Hormone Real or Rip-Off? ............................................................
22
Orally active growth hormone secretagogues: state of
the art and clinical perspectives. ....................
22
Sample Standard Blood Panel Protocol for measuring
GH production ...................................................
24
Hormonal Assays .......................................................
24
As members of the scientific community and a practitioner
of EverYoungScience, We answer this resolution
in the negative; no, IGF-1 is not recognized as the
ONLY true marker for GH activity.
We will use scientific abstracts as our source of authority.
They have the widest recognition and the highest level
of respect among the scientific community and they are
supported by the highest level of empirical data and
research.
This resolution does not concern whether or not IGF-1
is useful as one of several markers for GH activity,
which is widely known; it concerns IGF-1 as the ONLY
marker for GH activity. The question is, is IGF-1 con
sid ered by science to be the ONLY marker for GH activity,
not whether it is a marker or not.
This resolution also does not concern the way in which
IGF-1 is used as a marker for GH activity.
The usefulness of IGF-1 as an accurate and consistent
measure of increased GH activity in the body has been
hotly debated in recent journals. The growing body of
evidence seems to suggest that IGF-1 is not the ONLY
true marker of increased GH activity. In fact, it is
becoming increasingly clear to biochemists and allopaths
worldwide that IGF-1 may not even be a "dependable"
marker in measuring GH activity since its production
can be stimulated by factors other than GH production.
In the following sections, we will show that IGF-1 can
be effected by several events. Because of this, it is
cautioned that anyone seeking to understand true levels
of GH activity should follow a full blood panel protocol.
Dependence on IGF-1 alone has been shown to give false
markers.
It is well documented that IGF-1 levels can and do
decrease in many cases, even when GH activity increases.
Please see the following medical journal excerpts.
Hoffman DM, O'Sullivan AJ, Baxter RC, Ho KK
Garvan Institute of Medical Research, St Vincent's
Hospital, Sydney , NSW, Australia .
". There is no consensus as to the most appropriate
method of diagnosing growth-hormone (GH) deficiency
in adults . We have evaluated the relative diagnostic
merits of measuring peak GH response to insulin-induced
hypoglycaemia (insulin tolerance test), mean 24 h GH
concentration derived from 20 min sampling, serum insulin-like
growth factor I (IGF-I) concentrations, and serum IGF
binding protein 3 (IGFBP-3) concentrations. These tests
were undertaken in 23 patients con sid ered GH deficient
from extensive organic pituitary disease, and in 35
sex-matched normal subjects of similar age and body-mass
index. Hypopituitary subjects had significantly lower
stimulated peak GH, mean 24 h GH, IGF-I, and IGFBP-3
concentrations than normal subjects. The ranges of stimulated
peak GH responses were clearly separated between the
hypopituitary (< 0.2-3.1 ng/mL) and normal (5.3-42.5
ng/mL) groups, but mean 24 h GH, IGF-I, and IGFBP-3
concentrations overlapped. Mean 24 h GH concentrations
were below assay sensitivity in 80% of hypopituitary
subjects and 16% of normal subjects. 70% and 72%, respectively,
of the IGF-I and IGFBP-3 values in hypopituitary subjects
were within the range for normal subjects. We conclude
that GH deficiency in adults is most reliably identified
by stimulatory testing, and that IGF-I and IGFBP-3 are
poor diagnostic tests of adult GH deficiency"
G. E. Krassas, L. M. S. Carlsson, C. Karlsson, N. Pontikides,
Th. Kaltsas, R. Gunnarsson
".On the basis of these results one can hypothesize
that IGF-I levels appear to reflect high physical exercise
and food intake rather than differences in GH secretion
, while IGFBP-3 reflects most probably differences in
GH secretion and food intake."
Nijland EA; Strasburger CJ; Popp Snijders C; van der
Wal PS; van der Veen EA
Department of Endocrinology, Free University Hospital
, Amsterdam , The Netherlands .
Eur J Endocrinol, 1998 Oct, 139:4, 395-401
".The synthetic hexapeptide growth hormone-releasing
peptide (GHRP)-2 specifically stimulates GH release
in man. To determine the effects of prolonged treatment
and whether response attenuation occurs in man, we administered
to nine healthy subjects a daily s.c. injection of 100
microg GHRP-2 over 5 days. Every day blood samples were
taken to determine GH, IGF-I, IGF-binding protein (IGFBP)-3
and osteocalcin levels. On days 1,3 and 5, GH was measured
at -20,0,20,40,60,90,120 and 180 min using an immunometric
and an immunofunctional assay. Mean-/+S.D). peak GH
concentrations were 83+/-31, 59+/-22 and 51+/-13 microg/l
on days 1, 3 and 5 respectively. Mean+/-S.D. areas under
the curve for days 1, 3 and 5 were 6366+/-2514, 3987
+/- 1418 and 3392+/-1215 mU/l per min. Despite the maintained
GH release, analysis of variance revealed that significant
response attenuation occurred (P < 0.01). Mean serum
IGF-I concentration did not increase after a 5 day treatment
with GHRP-2. Mean basal levels were 22, 25,23,25,23,24
nmol/l measured on days 1 to 6. However, osteocalcin,
another serum marker of GH activity in tissue, increased
significantly from 3.2+/-1.0 to 4.2+/-0.4 microg/l (mean+S.D.)
(P< 0.01)."
Ho KK, Hoffman DM
Garvan Institute of Medical Research, St. Vincent's
Hospital, Sydney , Australia .
".The absence of a distinct clinical syndrome calls
for a strategy to reliably identify patients with hyposomatotropism.
However, there is no consensus as to the most appropriate
method of defining growth hormone (GH) deficiency in
adults. Since GH secretion falls with senescence and
is also reduced by obesity, both of these factors must
be controlled for in such an evaluation. We have investigated
the relative diagnostic merits of measuring (1) peak
GH response to insulin-induced hypoglycemia (ITT), (2)
mean 24-hour GH concentration derived from 20-minute
sampling (IGHC), (3) serum IGF-I levels, and (4) serum
insulin-like growth factor (IGF)-binding protein-3 (IGFBP-3)
levels. These tests were undertaken in 23 patients con
sid ered GH-deficient from extensive organic pituitary
disease and in 35-sex-matched normal subjects of similar
age and body mass index. The ITT was the only test capable
of distinguishing patients with organic GH deficiency
from matched normal subjects. The sensitivity of the
GH radioimmunoassay (0.2 ng/mL) limited the utility
of IGHC measurements, since many subjects from both
groups had undetectable values. Using a GH assay with
a 100-fold greater sensitivity, we found a better but
still incomplete separation of values between the two
groups. There was a significant overlap of IGF-I and
IGFBP-3 values, with only a third of GH-deficient subjects
having low IGF-I values. The limitation of IGF-I has
been confirmed by others , although its sensitivity
as a diagnostic test is greater in young adults. We
conclude that organic GH deficiency in adults can be
reliably diagnosed by the ITT."
Harris TB; Kiel D; Roubenoff R; Langlois J; Hannan
M; Havlik R; Wilson P
National Institute on Aging, Epidemiology, Demography
and Biometry Program, Bethesda , MD 20892-9205 , USA
.
J Am Geriatr Soc, 1997 Feb, 45:2, 133-9
".CONCLUSION: Although IGF-I declined with age, these
data from the Framingham Heart Study did not show expected
cross-sectional associations of weight, body fat, and
lean mass. The strongest associations were between IGF-I
and nutritional indicators. These results suggest caution
may be warranted with regard to use of IGF-I as an indicator
of growth horm one."
Furlanetto RW
".However, IGF-I levels are age dependent and subject
to regulation by other hormones and nutritional variables;
these features complicate the interpretation of IGF-I
levels in individual patients and limit the usefulness
of these measurements, particularly for determining
GH deficiency in young children. Circulating IGF-II
levels are not GH dependent and, therefore, their measurement
is of little clinical utility in assessing GH secretion."
Maccario M, Grottoli S, Aimaretti G, Gianotti L, Endrio
Oleandri S, Procopio M, Savio P, Tassone F, Ramunni
J, Camanni F, Ghigo E
Department of Internal Medicine, University of Turin
, Italy .
".CONCLUSIONS: In conclusion, present data confirm
that IGF-I levels depends on GH secretion as well as
on nutritional status, being negatively and independently
correlated with age and BMI. IGF-I assay is not a reliable
test for the diagnosis of GH deficiency in adulthood
though it gives good discrimination between GHD and
normal subjects up to 40 yrs of age. In spite of low
GH secretion, IGF-I levels are only slightly reduced
in obesity, probably as consequence of hyperinsulinism."
In this section, it will be shown that IGF-1 can indeed
be stimulated by factors other than GH production even
though among biochemists, it is used as the preliminary
marker. However, the growing body of respected science
is moving away from IGF-1 as a reliable marker of GH
activity. Since the production of IGF-1 is "reactionary"
to other processes in the body, it can be stimulated
by several factors that are "mimetic." This means that
if a substance that "mimes" GH is picked up by the receptor
sites of the Liver, it can trigger a rise in IGF-1 production
without triggering a rise in GH production and therefore
would not give a reliable reading of increased GH production
in those cases. Nutrition and Amino Acid supplementation,
in addition to protein intake can stimulate the elevation
of IGF-1 independent of GH increase. This may indicate
why IGF-1 levels rise in subjects ingesting "Amino Acid"
growth hormone compounds and this rise may not be indicative
of actual GH rise. Some Amino Acid precursors to GH
actually increase IGF-1 production directly without
acting on GH.
Teale JD, Marks V
".Apart from GH control, several other factors influence
circulating IGF-I levels . Nutritional status can be
assessed through reference to IGF-I analysis, overall
catabolic or anabolic processes being associated with
decreasing or increasing plasma IGF-I levels respectively."
Excerpted from the University of Virginia Endocrinology
syllabus
".nutritional status is the second most important regulator
of IGF-1." (GH release is the first)
Wester TJ, Fiorotto ML, Klindt J, Burrin DG
Children's Nutrition Research Center, ARS, USDA, Department
of Pediatrics, Baylor College of Medicine, Houston,
TX 77030, USA.
".Our objective was to examine the influence of feeding
and endogenous GH secretion on circulating IGF-I in
colostrum-deprived newborn pigs fed colostrum (n = 4),
formula (control, n = 4), or water (n = 4). In another
four formula-fed pigs, GH was ablated (GRF-A) with two
intravenous injections of a GH releasing-factor antagonist
(N-Ac-Tyr1,D-Arg2)-GRF(1-29)-NH2. Blood was serially
sampled in all pigs to measure plasma IGF-I and GH profiles.
Feeding increased plasma IGF-I concentration two- to
fourfold and decreased GH secretion. Despite a more
than 80% decrease in the plasma GH in GRF-A pigs, the
circulating IGF-I concentration was similar to that
in control pigs. In colostrum-fed pigs, plasma IGF-I
was higher than that in control pigs , despite equal
nutrient intake and lower circulating GH . There were
no differences in plasma IGF binding protein (IGFBP)-3
levels among the treatment groups. However, the relative
abundance of plasma IGFBP-4 was lower, and that of IGFBP-1
higher, in unfed pigs than in any of the three fed groups.
The plasma insulin concentration was not different among
fed pigs, but it was lower in unfed pigs. Our results
indicate that the circulating IGF-I concentration is
more dependent on nutrient intake than on GH in newborn
pigs, despite relatively high GH concentrations. However,
because the nutrient content in the formula was developed
to match that of colostrum, a factor other than nutrient
intake and GH was responsible for the maximal increase
in circulating IGF-I concentration observed in colostrum-fed
pigs."
Taylor-Roth JL, Malven PV, Gerrard DE , Mills SE, Grant
AL
Lilly Research Laboratories, Greenfield , IN 46140
, USA .
".Reduction of food intake was associated with decreased
body weight gains, decreased serum IGF-I concentrations,
and increased serum GH concentrations . Nutrient restriction
also tended to decrease the relative abundance of IGF-I
mRNA in liver and skeletal muscle."
Lee PD, Rosenfeld RG
Department of Pediatrics, Children's Hospital, Denver
, Colo.
".Insulin-like growth I and II (IGF-I and II) mediate
many of the peripheral mitogenic actions of growth hormone
(GH). The marked dependence of IGF levels on GH adequacy
has led to the development of commercial immunoassays
for IGF-I (somatomedin-C), and the widespread use of
IGF-I levels in the evaluation of short stature. Proper
interpretation of IGF-I levels requires con sid eration
of assay methodology, age-related norms, clinical findings,
nutritional status, and concurrent hormonal and disease
processes. IGF-I levels alone cannot be used to predict
stimulated GH response , but may have value in directing
the clinical evaluation of a child with short stature.
Low IGF-I levels may also be characteristic of a subpopulation
of short children with neurosecretory GH deficiency.
The role of IGF-II levels in the evaluation of short
stature is uncertain, although the combination of low
IGF-I and IGF-II levels is more specific for GH deficiency
than either value alone. Other clinical applications
for IGF assays in pediatrics are also reviewed."
Ketelslegers JM, Maiter D, Maes M, Underwood LE, Thissen
JP
Department of Internal Medicine, School of Medicine
, Catholic University of Louvain , Brussels , Belgium
.
".Several lines of evidence indicate that in the human,
insulin-like growth factor-I (IGF-I) is nutritionally
regulated. Both energy and protein availability are
required for maintenance of IGF-I. Measurements of serum
IGF-I constitute a sensitive means for monitoring the
response of acutely ill patients to nutritional intervention.
Serum IGF-I may also serve as a marker for evaluation
of nutritional status. Our findings and those of others
in animal models suggest that nutrients influence synthesis
and action of IGF-I and its binding proteins (IGFBPs)
at multiple levels. In fasting, liver growth hormone
(GH) binding is decreased, providing one explanation
for decreased IGF-I. In protein restriction, GH receptors
are maintained, but there is evidence for a postreceptor
defects. The latter results from pretranslational and
translational defects. Amino acid availability to the
hepatocytes is essential for IGF-I gene expression .
Protein malnutrition not only decreases IGF-I production
rate, but also enhances its serum clearance and degradation.
Finally, there is evidence for selective organ tolerance
to the growth-promoting effects of IGF-I in protein-restricted
rats ."
It is already widely known that a measure of serum
IGF-1 can be accomplished by testing the blood. However,
testing IGF-1 alone is thought by many biochemists to
be inadequate in reflecting true GH levels.
Ryan J, Mantle T, McQuaid S, Costigan DC
Children's Research Centre, Our Lady's Hospital for
Sick Children, Crumlin, Dublin , Ireland .
".Insulin-like growth factor-I (IGF-I) is a GH-dependent
growth factor found in its highest concentrations in
plasma. It is also measurable in saliva . The origins
of salivary IGF-I concentrations were studied. Intracardial
administration of Sprague-Dawley rats with 125I-labelled
IGF-I and subsequent analysis of plasma and saliva samples
by exclusion gel chromatography and SDS-PAGE, followed
by autoradiography, demonstrated the apparent inability
of IGF-I to cross from the plasma pool through to saliva.
125I-Labelled IGF-I was not chromatographed immediately
before injection, resulting in administration of free
iodide along with the iodinated peptide. This free iodide
was demonstrable in saliva, indicating that movement
of substances from plasma to saliva was measurable using
the levels of 125I activity administered. Free iodide
in saliva was not contributed to by 125I-labelled IGF-I
degradation since 125I-labelled IGF-I was shown to be
stable in saliva over 24 h. These data indicated that
IGF-I in saliva is produced locally . Identification
of a 4.7 kb IGF-I mRNA transcript in rat parotid salivary
gland was consistent with IGF-I synthesis within that
tissue."
Ryan J, Mantle T, Costigan DC
Children's Research Centre, Our Lady's Hospital for
Sick Children, Crumlin, Dublin , Ireland .
".Insulin-like growth factor 1 (IGF 1) concentrations
in mixed saliva samples , collected from a normal population
(n = 327, ranging in age from birth to adolescence),
were determined by RIA . Salivary IGF 1 concentrations
remained steady over a 24-h period when collected at
basal rates, but were diminished in saliva samples collected
at a maximally stimulated flow rate. A similar pattern
was observed for males and females, when IGF 1 levels
in saliva were plotted as a function of age. The pattern
was that of low levels in early childhood, rising with
age, peaking in puberty and falling again in late adolescence
. Salivary IGF 1 measurement differed from plasma measurement
in three ways: 1) salivary IGF 1 concentrations (70
+/- 50 pM) were 100- to 200-fold less than plasma IGF
1 levels; 2) salivary IGF 1 levels in age-matched male
and female samples were not different out sid e of pubertal
influences ; 3) salivary IGF 1 levels in neonates were
highly variable with concentrations ranging up to pubertal
concentrations . The study provides salivary IGF 1 reference
data for a pediatric population ."
Costigan DC, Guyda HJ, Posner BI
Division of Endocrinology and Metabolism, Montreal
Children's Hospital-Research Institute, Quebec , Canada
.
". We found that human saliva contains both insulin-like
growth factor I (IGF-I) and IGF-II but no significant
binding proteins , and that salivary IGF-I levels correlated
with plasma GH levels . Mixed saliva had globular proteins
precipitated by freezing/thawing. After centrifugation
the clear supernatant was used directly in the IGF-I
RIA (Van Wyk and Underwood antibody) and in a human
placental membrane RRA for IGF-II. The lower limits
of detection for IGF-I and IGF-II were 0.7 ng/mL (micrograms/L)
and 1.2 ng/mL (micrograms/L), respectively. Iodinated
IGF added to saliva was not degraded, as assessed by
trichloroacetic acid precipitability and placental membrane
binding. In saliva from 14 normal subjects, IGF-I was
measurable in all . IGF-II was detectable only in 8
of 14 subjects; the mean value in these 8 subjects was
2.6 +/- 0.6 (+/- SE) ng/mL (micrograms/L). The mol wt
of salivary IGF was similar to that of free plasma IGF
after acid or neutral pH gel chromatography . Human
saliva contained no significant IGF-binding protein.
Eluates from neutral gel chromatography of concentrated
(20-fold) normal saliva did not inhibit IGF-II binding
to placental membrane receptors. Eluted proteins from
saliva samples subjected to prior acid gel chromatography
failed to bind radiolabeled IGF after neutralization.
Saliva samples assayed for binding protein using an
amniotic fluid binding protein RIA had values at or
below the lower limit of detection [less than 0.06 micrograms
eq/mL (mgeq/L)]. Salivary IGF-I concentrations did not
change with increasing salivary flow rates above normal,
with time of day, or with storage at room temperature
for up to 24 h before freezing . The mean IGF-I concentration
in mixed saliva from 14 normal young adults (8 men)
was 2.3 +/- 0.3 (+/- SE) ng/mL (micrograms/L), and their
mean plasma IGF-I level was 315 +/- 27 ng/mL (micrograms/L).
Mean salivary IGF-I was significantly lower in 15 patients
with GH deficiency [1.3 +/- 0.2 ng/mL (micrograms/L);
P less than 0.01] and 8-fold higher in 5 acromegalic
patients [17.2 +/- 6.3 ng/mL (micrograms/L); P less
0.01]. Removal of their GH adenomas led to a fall in
salivary IGF-I to 5.6 +/- 1.3 ng/mL (micrograms/L);
P less than 0.05). In summary, saliva contains free
IGFs but no significant quantities of specific binding
proteins. Salivary IGF-I levels reflect the GH status
of the donor ."
Zumkeller W, Hall K
Department of Endocrinology, Karolinska Hospital and
Institute, Stockholm , Sweden .
". Insulin-like growth factor II and insulin-like growth
factor binding protein-1 were identified and quantified
in the urine of 23 healthy subjects between 17 and 76
years of age . IGF-II was measured after separation
by gel chromatography at low pH and compared with IGF-I
levels in the same samples, whereas IGF binding protein-1
was measured in dialysed urine. Urinary IGF-II was found
at much higher concentrations than IGF-I (mean +/- SEM:
717 +/- 69 vs 110 +/- 5 ng/mmol creatinine). The chromatographic
profile indicates that pro-IGF-II may also be present.
The concentrations of IGF-II appear to be less variable
than the other reported parameters. The mean IGF binding
protein-1 concentrations in these urine samples was
414 +/- 83 ng/mmol creatinine. IGFs in the urine are
in part bound to binding proteins..."
Aman J, Kroon M, Jones I, Segnestam K, Snellman K
Department of Paediatrics, Orebro Medical Centre Hospital
, Sweden .
".The aim of the present study was to compare measurements
of urinary growth hormone (GH), serum insulin-like growth
factor I (IGF-I) and IGF binding protein 3 (IGFBP3)
between two groups of post-menarcheal girls, 13-18 y
of age, one comprising 64 type 1 diabetic patients and
the other 64 healthy girls matched for age and stage
of puberty. GH was determined on two occasions in nocturnal
urine samples by using a modification of an immunoradiometric
method for serum . Significantly higher urinary GH concentrations
but lower IGF-I and IGFBP3 levels were found in diabetic
girls than in controls (p < 0.001) . A significant
correlation was found between urinary GH concentrations
and the daily dose of insulin (U kg[-1]) (r = 0.426,
p = 0.003). Urinary GH concentrations were also significantly
related to HbA1c (r = 0.380, p = 0.003). In conclusion,
disturbances of the GH-IGF-I axis may be evaluated by
the use of non-invasive urinary GH measurements , which
is a simple alternative to frequent sampling of serum
GH. Increased GH secretion seems to be related to a
great need for insulin and poor metabolic control. More
knowledge about underlying causal factors in the disturbed
GH-IGF-I axis is required."
Juul A, Scheike T, Pedersen AT, Main KM, Andersson
AM, Pedersen LM, Skakkebaek NE
Department of Growth and Reproduction, Rigshospitalet,
Copenhagen , Denmark .
".Few studies exist on the physiological changes in
the concentrations of growth hormone (GH), insulin-like
growth factors (IGF) and IGF-binding proteins (IGFBP)
within the menstrual cycle, and some controversy remains.
We therefore decided to study the impact of endogenous
sex steroids on the GH-IGF-IGFBP axis during the ovulatory
menstrual cycle in 10 healthy women (aged 18-40 years).
Blood sampling and urinary collection was functioned
every morning at 0800 h for 32 consecutive days. Every
second day the subjects were fasted overnight before
blood sampling. Follicle stimulating hormone, luteinizing
hormone (LH), oestradiol, progesterone, IGF-I, IGFBP-3,
sex hormone-binding globulin, dihydroepiandrosterone
sulphate and GH were determined in all samples, whereas
insulin and IGFBP-1 were determined in fasted samples
only. Serum IGF-I concentrations showed some fluctuation
during the menstrual cycle, with significantly higher
values in the luteal phase compared to the proliferative
phase (P < 0.001). Mean individual variation in IGF-I
concentrations throughout the menstrual cycle was 13.2%
(SD 4.3; range 0.1-18.3%). There were no cyclic changes
in IGFBP-3 serum concentrations and no differences in
IGFBP-3 concentrations between the luteal and the proliferative
phases. Mean individual variation in IGFBP-3 concentrations
throughout the menstrual cycle was 8.8% (SD 2.7; range
3.2-14.1). IGFBP-1 concentrations were inversely associated
with insulin concentrations, and showed a significant
pre-ovulatory increase that returned to baseline at
the day of the LH surge. Fasting insulin concentrations
showed large fluctuations throughout the menstrual cycle
without any distinct cyclic pattern. No cyclic changes
in urinary GH excretion during menstrual cycle were
detected . We conclude that, although IGF-I concentrations
are dependent on the phase of the menstrual cycle, the
variation in IGF-I concentrations throughout the menstrual
cycle is relatively small. Therefore, the menstrual
cycle does not need to be con sid ered when evaluating
IGF-I or IGFBP-3 serum values in women suspected to
have GH deficiency."
Tonshoff B, Blum WF, Vickers M, Kurilenko S, Mehls
O, Ritz E
Department of Pediatrics, University Hospital of Heidelberg
, Germany .
". We examined excretion of urinary insulin-like growth
factors I and II (IGF-I and IGF-II) and their major
binding protein IGFBP-3 in comparison to their respective
serum concentration in nine healthy female volunteers
(median age 25 years, range 22-27) under baseline conditions
and after stimulation with recombinant human growth
hormone (rhGH), 4.5 IU twice daily subcutaneously for
a period of 3 days. The IGFs were measured in unconcentrated
urine by use of recently developed, highly sensitive
radioimmunoassays. The IGFBP-3 was measured by a specific
radioimmunoassay. The mean (+/- SD) urinary concentrations
of IGF-I (0.08 +/- 0.07 micrograms/l), IGF-II (1.02
+/- 0.47 micrograms/l) and IGFBP-3 (19.1 +/- 6.9 micrograms/l)
were two to three orders of magnitude lower than in
serum. The ratio of IGF-II over IGF-I concentration
in urine (13:1) was five times higher than in serum
(2.5:1), and the ratio of IGFBP-3 over the sum of IGF-I
and IGF-II in urine (17:1) was four times higher than
in serum (4:1). Urinary excretion was 63.3 +/- 46.6
ng.m-2.24h-1 for IGF-I, 1002 +/- 598 ng.m-2.24h-1 for
IGF-II and 18039 +/- 4983 ng.m-2.24h-1 for IGFBP-3.
Using fast protein liquid exclusion chromatography,
only immunoreactive IGFBP-3 components of less than
60 kD were detected in urine, with a major peak at 20
kD. Urinary IGFBP-3 excretion correlated with serum
IGFBP-3 (r = 0.61, p < 0.01) and the glomerular filtration
rate (r = 0.56, p < 0.05) measured by steady-state
inulin infusion clearances."
Binoux M, Lassarre C, Gourmelen M
".A protein-binding assay for insulin-like growth factor
II (IGF II) is described. The assay uses IGF binding
proteins extracted from human cerebrospinal fluid which
have selective affinity for IGF II. IGF I was 9 times
less potent than IGF II in displacing [125I]IGF II,
and when mixtures of the IGFs were assayed at IGF I/IGF
II ratios of 2, 5, and 10, interference from IGF I in
the assay was 0%, 5%, and 9%, respectively. Given the
serum concentrations of IGF I and IGF II estimated by
RIA and by this protein-binding assay, IGF I can be
said to have had no cross-reaction when IGF II was assayed
in human serum and at most 5% cross-reaction in the
case of rat serum. After separation of IGFs from their
binding proteins by acidic gel filtration, serum IGF
II levels (mean +/- SE) measured by this method were
1322 +/- 66 ng/ml in normal adults, 500 +/- 65 ng/ml
in patients with total GH deficiency, 1327 +/- 69 ng/ml
in untreated acromegalic patients, and 1817 +/- 145
ng/ml in uremic patients undergoing chronic hemodialysis.
In postpubertal young rats, the mean serum IGF II level
was 43 +/- 2.6 ng/ml and after hypophysectomy it was
16 +/- 2.4 ng/ml. Although the IGF II levels in man
and in the rat were different, they appeared to be similarly
GH dependent, although less so than IGF I. In view of
the sensitivity (0.03 ng IGF II) and the specificity
of this assay, the small quantities of cerebrospinal
fluid required (1 mu leq/assay tube) and its applicability
for IGF II measurement in several species, the use of
this assay for measuring IGF II in a variety of biological
media can be envisaged."
Merimee TJ, Grant M, Tyson JE
".The concentrations of insulin-like growth factors
I and II (IGF-I and IGF-II) in amniotic fluid were determined
by specific immunoassays in 58 women. IGF-I concentrations
were constant throughout gestation at approximately
20 ng/ml ; the mean IGF-II concentration was 114 +/-
13 (+/- SE) ng/ml at the earliest period of gestation
studied and remained unchanged at 26 to 33 weeks despite
a greater than 50% decrease in amniotic fluid total
protein. A precipitous decrease in IGF-II concentration
occurred at term which was not explainable by alterations
in total amniotic fluid protein concentration. The concentrations
of IGF-I and IGF-II in amniotic fluid did not correlate
with concentrations of these factors in maternal serum
(r = 0.08 and 0.09, respectively). [125I]IGF-I and [125I]IGF-II,
after incubation with amniotic fluid, bound to a 40-45
K protein (or proteins). A carrier protein of greater
mol wt, as in serum, was not detected. These findings
indicate that there is dynamic control of IGF in amniotic
fluid during normal pregnancy ."
Kong W, Philipps AF, Dvorak B, Anderson GG, Lake M
, Koldovsky O
Department of Pediatrics, Steele Memorial Children's
Research Center, Furrow Research Laboratory, University
of Arizona College of Medicine, Tucson 85724.
". Whereas insulin-like growth factor I (IGF-I) has
been found in various body fluids from different species
, the presence or absence of IGF and associated binding
proteins (IGFBPs) in bile has not been clearly defined.
Bile concentration of IGF-I was measured in this study
and found to be highest in the neonate and lowest in
adult rats [133 +/- 15.9, 79.4 +/- 10.5, 45.3 +/- 12.7
ng/ml (mean +/- SE) in 12-day-old, 33-day-old, and adult
rats, respectively]. When bile delivery rates of IGF-I
(i.e., the product of IGF-I concentration in bile and
the biliary flow rate) were calculated, IGF-I delivery
was highest in weanling rats (469 pg.h-1.g body wt-1).
When expressed as amount of IGF-I in bile delivered
per day, however, delivery rates rose from 0.2 micrograms/day
in the suckling and remained constant at 1.6-1.7 micrograms/day
in both weanling and adult animals. Bile samples exposed
to a placental membrane IGF receptor preparation showed
significant dose-dependent inhibition of binding of
native IGF-I. Because no IGF binding proteins were identified
by Western ligand blot or by Sephadex gel chromatography,
the results suggest the presence of biologically significant
quantities of bioactive IGF-I in bile . We speculate
that IGF-I in bile may play an important role in the
growth of the gastrointestinal tract, both in the suckling
as well as later in life."
Wolk A, Mantzoros CS, Andersson SO, Bergstrom R, Signorello
LB, Lagiou P, Adami HO, Trichopoulos D
Department of Medical Epidemiology, Karolinska Institute,
Stockholm , Sweden . Alicja.Wolk@mep.ki.se
".BACKGROUND: Recent epidemiologic investigations have
suggested an association between increased blood levels
of insulin-like growth factor 1 (IGF-1) and increased
risk of prostate cancer . Our goal was to determine
whether an association exists between serum levels of
IGF-1 and one of its binding proteins, insulin-like
growth factor-binding protein 3 (IGFBP-3), and prostate
cancer risk. METHODS: An immunoradiometric assay was
used to quantify IGF-1 levels and IGFBP-3 levels in
serum samples as part of a population-based, case-control
study in Sweden . The study population comprised 210
patients with newly diagnosed, untreated prostate cancer
and 224 frequency-matched control subjects. Data were
analyzed by use of unconditional logistic regression
to calculate odds ratios (ORs) and 95% confidence intervals
(CIs). Reported P values are two- sid ed. RESULTS: The
mean serum IGF-1 level for case patients (158.4 ng/mL)
was significantly higher than that for control subjects
(147.4 ng/mL) (P = .02); corresponding mean serum IGFBP-3
levels were not significantly different between case
patients (2668 ng/mL) and control subjects (2518 ng/mL)
(P =.09). We found a moderately strong and statistically
significant (P = .04) positive association between serum
levels of IGF-1 levels and risk of prostate cancer (OR
= 1.51; 95% CI = 1.0-2.26 per 100 ng/mL increment) ;
the association was particularly strong for men younger
than 70 years of age (OR = 2.93; 95% CI = 1.43-5.97).
No association was found between serum IGF-1 levels
and disease stage. Serum IGFBP-3 levels were not significantly
associated with increased risk of disease, and adjustment
for IGFBP-3 had little effect on the association between
IGF-1 levels and risk of prostate cancer. CONCLUSION:
Elevated serum IGF-1 levels may be an important predictor
of risk for prostate cancer . However, our results do
not support an important role for serum IGFBP-3 as a
predictor of risk for this disease."
Mantzoros CS, Tzonou A, Signorello LB, Stampfer M,
Trichopoulos D, Adami HO
Department of Epidemiology and Harvard Center for Cancer
Prevention, Harvard School of Public Health, Boston,
Massachusetts 02115, USA.
".Blood samples were collected from 52 incident cases
of histologically confirmed prostate cancer, an equal
number of cases of benign prostatic hyperplasia (BPH)
and an equal number of apparently healthy control subjects.
The three groups were matched for age and town of re
sid ence in the greater Athens area. Steroid hormones,
sex hormone-binding globulin, and insulin-like growth
factor 1 (IGF-1) were measured in duplicate by radioimmunoassay
in a specialized US centre. Statistical analyses were
functioned using multiple logistical regression. The
results for IGF-1 in relation to prostate cancer and
BPH were adjusted for demographic and anthropometric
factors, as well as for the other measured hormones.
There was no relation between IGF-1 and BPH, but increased
values of this hormone were associated with increased
risk of prostate cancer; an increment of 60 ng ml(-1)
corresponded to an odds ratio of 1.91 with a 95% confidence
interval of 1.00-3.73 . There was also some evidence
for an interaction between high levels of testosterone
and IGF-1 in relation to prostate cancer . This finding
suggests that, in addition to testosterone, IGF-1 may
increase the risk of prostate cancer in humans ."
It has been consistently shown that sustained rises
in IGF-1, rises like those claimed by amino acid based,
IGF-1 stimulating HGH compounds, can contribute to a
heightened risk of Breast, Colon and Pancreatic cancers
among others. Please see the following abstracts.
Yee D
University of Texas Health Science Center at San Antonio
, 78284-7884, USA . yeed@uthscsa.edu
".In 1992, a special issue of Breast Cancer Research
and Treatment was devoted to the insulin-like growth
factors and breast cancer. In that issue, identification
of the key components of the IGF system was reviewed
and their potential role in breast cancer growth was
described. In this issue, we revisit the IGF system
with particular attention to data that further supports
their role in the growth regulation of breast cancer.
Several new facets of the IGF system are described,
and several laboratories have more clearly defined how
each individual component of the IGF system may influence
breast cancer biology ."
Pollak M
Department of Medicine, McGill University , Montreal
, Quebec , Canada .
".Recent studies imply that IGF-I levels vary greatly
between normal women, and that premenopausal breast
cancer risk is increased among women with higher IGF-I
levels . It is known that tamoxifen lowers IGF-I levels,
but further research is needed to determine whether
antiestrogens will be of particular value in risk reduction
for women with high IGF-I levels, and also to determine
if IGF-I levels can indeed be used as an intermediate
endpoint in risk reduction interventions. With respect
to adjuvant therapy, we currently have convincing data
that antiestrogens have moderate IGF-I lowering actions,
but it remains unclear to what extent these contribute
to the therapeutic effect of these compounds. Ongoing
trials are addressing this question, as well as the
hypothesis that interventions that increase IGF-I suppression
will be associated with reduced relapse rates ."
Hankinson SE, Willett WC, Colditz GA , Hunter DJ, Michaud
DS, Deroo B, Rosner B, Speizer FE, Pollak M
Channing Laboratory, Brigham and Women's Hospital and
Harvard Medical School , Boston , MA 02115 , USA .
".BACKGROUND: Insulin-like growth factor (IGF)-I, a
mitogenic and antiapoptotic peptide, can affect the
proliferation of breast epithelial cells, and is thought
to have a role in breast cancer . We hypothesised that
high circulating IGF-I concentrations would be associated
with an increased risk of breast cancer . METHODS: We
carried out a nested case-control study within the prospective
Nurses' Health Study cohort. Plasma concentrations of
IGF-I and IGF binding protein 3 (IGFBP-3) were measured
in blood samples collected in 1989-90. We identified
397 women who had a diagnosis of breast cancer after
this date and 620 age-matched controls. IGF-I concentrations
were compared by logistic regression with adjustment
for other breast-cancer risk factors. FINDINGS: There
was no association between IGF-I concentrations and
breast-cancer risk among the whole study group. In postmenopausal
women there was no association between IGF-I concentrations
and breast-cancer risk (top vs bottom quintile of IGF-I,
relative risk 0.85 [95% CI 0.53-1.39]). The relative
risk of breast cancer among premenopausal women by IGF-I
concentration (top vs bottom tertile) was 2.33 (1.06-5.16;
p for trend 0.08). Among premenopausal women less than
50 years old at the time of blood collection, the relative
risk was 4.58 (1.75-12.0; p for trend 0.02). After further
adjustment for plasma IGFBP-3 concentrations these relative
risks were 2.88 and 7.28, respectively. INTERPRETATION:
A positive relation between circulating IGF-I concentration
and risk of breast cancer was found among premenopausal
but not postmenopausal women . Plasma IGF-I concentrations
may be useful in the identification of women at high
risk of breast cancer and in the development of risk
reduction strategies. Additional larger studies of this
association among premenopausal women are needed to
provide more precise estimates of effect."
Del Giudice ME, Fantus IG, Ezzat S, McKeown-Eyssen
G, Page D, Goodwin PJ
Mount Sinai Hospital , Division of Clinical Epidemiology
of the Samuel Lunenfeld Research Institute, Toronto
, Ontario , Canada .
".BACKGROUND: Insulin and insulin-like growth factor
I (IGF-I) are important mitogens in vitro and in vivo
. It has been hypothesized that these factors may play
an important role in the development of breast cancer.
METHODS: A case-control study comparing plasma insulin
levels in 99 premenopausal women with newly diagnosed
node-negative invasive carcinoma of the breast and 99
age-matched controls with incident biopsied non-proliferative
breast disease (NP) was conducted. Women with known
diabetes were excluded. RESULTS: For the entire study
group, mean age was 42.6 +/- 5.1 years and mean weight
was 62.9 +/- 10.3 kg. After adjustment for age and weight,
elevated insulin levels were significantly associated
with breast cancer, Odds Ratio (OR) for women in the
highest insulin quintile versus the lowest quintile
= 2.83 (95% Confidence Interval [CI] 1.22-6.58). There
were no statistically significant differences between
cases and controls for IGF-I and IGFBP-1 levels. However,
after adjustment for age, the association between plasma
levels of insulin-like growth factor binding protein
3 (IGFBP-3) and breast cancer approached statistical
significance; OR for highest quintile versus lowest
quintile of IGFBP-3 being 2.05 (95% CI, 0.93-4.53).
All results were independent of diet and other known
risk factors for breast cancer. CONCLUSION: Circulating
insulin levels and possibly IGFBP-3 levels are elevated
in women with premenopausal breast cancer . This association
may reflect an underlying syndrome of insulin tolerance
that is independent of obesity."
".In addition to the unusual growth patterns IGF-1
seems to promote, there is strong evidence of a cancer
risk from IGF-1. Science Magazine recently reported
that IGF-1 increases the malignancy of human breast
cancer cells, including their invasiveness and ability
to spread to distant organs. A study in the New England
Journal of Medicine confirmed that growth factors such
as IGF-1 are responsible for the promotion of breast
cancer cells. IGF-1 has been similarly linked with colon
cancer." "A leading British medical journal recently
reported that the breast cells of fetuses and infants
are particularly susceptible to hormonal influences.
Such imprinting by IGF-1 may increase future breast
cancer risks, and may also increase the sensitivity
of the breast to subsequent unrelated risks such as
mammography and the carcinogenic and estrogen-like effects
of pesticide re sid ues in food, particularly in pre-menopausal
women." ".Excessive IGF-1 also wreaks havoc on the gastro-intestinal
tract. A recent study on acromegaliacs--individuals who suffer
from excessive growth of the their head, hands, face,
and feet--shows that they have a higher incidence of
tumors in the colon (a portion of the intestines). Acromegaly
is caused by an excessive amount of natural IGF-1 in
the human body. In another recent study, IGF-1 was exposed
to human cells taken from the human gut. The study reported
that IGF-1 promoted cell division." "Another recent
study published in Cancer Research shows clearly that
IGF-1 is required for the establishment and maintenance
of tumors. This study found that IGF-1 protects the
cells from programmed cell death. IGF-1 was shown to
accelerate tumor growth and effect the aggressiveness
of tumors. As IGF-1 levels were decreased, cell death
took place."
Bohlke K, Cramer DW, Trichopoulos D, Mantzoros CS
Department of Epidemiology, Harvard School of Public
Health , Boston , MA , USA .
".We evaluated the association of plasma insulin-like
growth factor-I (IGF-I) and IGF binding protein-3 (IGFBP-3)
with risk of breast cancer in a study of 94 cases of
premenopausal ductal carcinoma in situ and 76 controls.
Compared with women in the lowest tertile of IGF-I,
women in the upper two tertiles of IGF-I had an elevated
risk for ductal carcinoma in situ . Conversely, compared
with women in the lowest tertile of IGFBP-3, women in
the upper two tertiles of IGFBP-3 had a decreased risk
for ductal carcinoma in situ. After grouping women on
the basis of both IGF-I and IGFBP-3, women in the highest
two tertiles of IGF-I and the lowest tertile of IGFBP-3
were at notably higher risk than women in the lowest
tertile of IGF-I and the highest two tertiles of IGFBP-3
(odds ratio = 3.7; 95% confidence interval = 1.1-12.2).
We conclude that the combination of high IGF-I and low
IGFBP-3 may increase the risk of premenopausal ductal
carcinoma in situ."
Orally active growth hormone
secretagogues: state of the art and clinical perspectives.
Ghigo E, Arvat E, Camanni F
Department of Internal Medicine, University of Turin
, Italy .
".Growth hormone secretagogues (GHS) are synthetic,
non-natural peptidyl and nonpeptidyl molecules with
potent stimulatory effect on somatotrope secretion.
They have no structural homology with growth hormone-releasing
hormone (GHRH) and act via a specific receptor, which
has now been cloned and is present at both the pituitary
and hypothalamic level. This evidence strongly suggests
the existence of a still unknown natural GHS-like ligand.
Several data references favor the hypothesis that GHS
could counteract somatostatinergic activity at both
the pituitary and hypothalamic level and/or, at least
partially, via a GHRH-mediated mechanism. However, the
possibility that they act via an unknown hypothalamic
factor remains open. GH-releasing peptide-6 (GHRP-6)
is the first hexapeptide studied extensively in humans.
More recently, peptidyl superanalogues GHRP-1, GHRP-2
and hexarelin, and nonpeptidyl mimetics, such as the
spiroindoline derivative MK-677, have been synthesized
and their effects have been studied in humans. The GH-releasing
activity of GHS is marked, dose related and reproducible
after intravenous, subcutaneous, intranasal and even
oral administration. The effect of GHS is partially
desensitized but prolonged, intermittent oral administration
increases insulin-like growth factor I (IGF-I) levels.
The GH-releasing effect of GHS undergoes age-related
variations; it increases from birth to puberty, remains
similar in adulthood and decreases with ageing. The
effect of GHS on GH release is synergistic with that
of GHRH, while it is only partially refractory to inhibitory
influences, which nearly abolish the effect of GHRH.
GHS maintain their GH-releasing activity in some somatotrope
hypersecretory states such as acromegaly, anorexia nervosa,
hyperthyroidism and critical illness. The GH response
to GHS has been reported clear although reduced in GH
deficiency, obesity and hypothyroidism, while it is
strongly reduced in patients with pituitary stalk disconnection
or Cushing's syndrome. In short children, elderly subjects,
critically ill patients and even in adult patients with
GH deficiency an increase of IGF-I has been shown after
GHS treatment. These data indicate that treatment with
orally active GHS in humans enhances the activity of
the GH-IGF-I axis and could be clinically useful."
Hormonal Laboratory Tests Required for Growth Hormone
Protocols as required by the:
Corning Nichols Institute,
33608 Ortega Highway ,
San Juan Capistrano , California 92676
1-800-553-5445
D.H.E.A.-S (dehydroepiandrosterone sulfate) _________ug/ml
Pregnenolone_________
Thyroid Stimulating Hormone ______
.....Thyroid, free T3 ________
.....Thyroid, free T4_________
Testosterone (total) ______ug/dl
.....Testosterone (free)_________
Estradiol___________ug/dl (women;week before menstruation)
FSH______________
LH.. _______________
Somatomedin C (IGF-1) ( Corning Lab,CA.) ______
Osteoporosis Screen (Dual Photon Densitometry) (optional)
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