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The Journal of Clinical Endocrinology & Metabolism 86(11):5509 –5515
Copyright © 2001 by The Endocrine Society
Altered Neuroregulation of GH Secretion in Viscerally
Obese Premenopausal Women
HANNO PIJL, JANNEKE G. LANGENDONK, JACOBUS BURGGRAAF, MARIJKE FRÖLICH,
ADAM F. COHEN, JOHANNES D. VELDHUIS, AND A. EDO MEINDERS
Department of General Internal Medicine (H.P., J.G.L., M.F., A.E.M.), and Center for Human Drug Research (J.B., A.F.C.),
Leiden University Medical Center, 2300 RC Leiden, The Netherlands; and Division of Endocrinology (J.D.V.), Department of
Internal Medicine, General Clinical Research Center and Center for Biomathematical Technology, University of Virginia
Medical School, Charlottesville, Virginia 22908
We used deconvolution analysis of 24-h plasma GH concentration profiles (10- min sampling intervals) to appraise GH
secretion rates and elimination kinetics in obese (body mass
index, ⬃34 kg/m2) premenopausal women with large visceral
fat area (LVFA; n ⴝ 8) vs. small visceral fat area (SVFA; n ⴝ 8)
as determined by magnetic resonance imaging. The subjects
were matched for body mass index, body fat percentage, and
age. The impact of the loss of 50% of prestudy weight excess
induced by caloric restriction was assessed as well. The results were compared with those obtained in normal weight
control women (n ⴝ 8). LVFA subjects manifested markedly
(4-fold) reduced mean plasma GH levels, which was brought
about by jointly diminished basal and pulsatile GH secretion.
Moreover, visceral obesity was associated with loss of regularity of GH release, as established by the approximate entropy statistic. In contrast, SVFA subjects produced normal
daily amounts of GH and exhibited mean 24-h plasma GH
R
ELATIVE AND ABSOLUTE GH deficiency states are
associated with a marked increase in total body fat (1).
Excess body fat preferentially accumulates in visceral depots
in GH-deficient patients and GH replacement therapy reduces visceral adipose stores in particular (2, 3). Conversely,
fat mass is reduced in acromegalic patients with GH excess.
These data are consistent with the ability of GH to facilitate
lipolysis and impair triglyceride storage (4).
It has been firmly established that human obesity is
marked by a considerable reduction of the plasma GH concentration (5– 8). Body fat distribution may also be a determinant of plasma GH concentrations in obese subjects (5, 9).
A high waist-to-hip circumference ratio (WHR) reflects predominant storage of fat in upper (abdominal) vs. lower (gluteo-femoral) body compartments. An inverse correlation of
WHR with plasma GH levels was observed in mildly obese
men (9) and massively obese females (5). These data suggest
that hyposomatotropism in obese humans mainly occurs in
patients with a tendency to store fat in abdominal adipose
tissue. However, a high WHR often goes together with a
large total fat mass, which is a potential confounder in data
reading. To our knowledge, GH kinetics have not been ad-
Abbreviations: ApEn, Approximate entropy; LVFA, large visceral fat
area; MRI, magnetic resonance imaging; NW, normal weight; rhGH,
recombinant human GH; SVFA, small visceral fat area; WHR, waistto-hip circumference ratio.
concentrations that were similar to those in normal weight
controls. GH half-life and distribution volume were not different among the study groups. Importantly, weight loss did
not affect the daily GH secretion rate in LVFA women, so that
their mean plasma GH concentration remained considerably
reduced (⬃50%) compared with controls (despite the loss of
⬃40% of visceral fat). Normal GH kinetics in SVFA women
were not significantly influenced by weight reduction. Thus,
GH neuroregulation appears to be particularly altered in
obese women with a tendency to store fat in their visceral
adipose depot. Because weight loss did not reverse GH secretion rate in viscerally obese women, we speculate that relative
hyposomatotropism is a primary feature of these women,
which could be involved in their tendency to preferentially
store excess fat in visceral adipose tissue. (J Clin Endocrinol
Metab 86: 5509 –5515, 2001)
equately assessed in relation to differences in regional (visceral vs. sc) fat distribution in the obese human.
This issue seems all the more important because hyposomatotropism may underlie or exacerbate visceral fat storage
in obese individuals, considering the metabolic effects of GH
and the aforementioned clinical characteristics of GH deficiency. In apparent conflict with this notion, several studies
have shown that weight loss can at least partially overcome
the reduction in GH output in obese individuals (5– 8), which
suggests that hyposomatotropism is a sequel rather than a
cause of body fat accumulation. However, few if any of these
studies have documented full reversibility of the GH impoverishment. Moreover, none of them appraised the effects
of weight loss on GH kinetics in relation to body fat topography. Thus, it remains to be established whether weight
reduction affects GH kinetics equally in obese subjects with
distinct types of body fat distribution.
The present study was performed to assess the relationships between regional fat storage and specific quantitative
features of GH secretion and elimination in obese women.
We hypothesized that obese subjects with large visceral fat
stores would manifest more prominent hyposomatotropism
than those with predominantly sc adiposity. We further reasoned that if hyposomatotropism is a cause rather than a
sequel of visceral fat storage in (obese) humans, then viscerally obese women would maintain low GH secretion rates
even after the loss of significant amounts of visceral fat.
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J Clin Endocrinol Metab, November 2001, 86(11):5509 –5515
Materials and Methods
Subjects
Sixteen healthy obese and eight normal weight (NW) premenopausal
women were asked to participate through advertisements in local newspapers. The obese subjects were selected on the basis of their WHR; one
half had a WHR less than 0.80, and the other half had a WHR greater
than 0.95. Care was taken to ensure that body weight was similar groupwise. This was done to increase the a priori chance of selecting two
groups of obese subjects with small visceral fat areas (SVFAs) vs. large
visceral fat areas (LVFAs), respectively, and similar body weight. Subsequently, visceral fat area was measured by magnetic resonance imaging (MRI; see below), and the group of obese subjects was split in two
on the basis of the size of their visceral fat depot (SVFA or LVFA). All
women had a normal menstrual cycle and did not take any medications,
including oral contraceptives. A hemoglobin A1C value greater than
6.7% and smoking were exclusion criteria. All women had a stable body
weight for at least 3 months before the study. Written informed consent
was obtained from all subjects. The study was approved by the Ethics
Committee of Leiden University Medical Center.
Pijl et al. • Body Fat and GH Kinetics in Women
C until assay. Plasma human GH concentrations were determined with
an ultrasensitive 22 kDa specific immunofluorometric assay (Delfia hGH
kit, Wallac Oy, Turku, Finland). The detection limit was 0.03 mU/liter
(0.012 ␮g/liter). The intra-assay coefficients of variation ranged from 1.6
to 8.4% over the GH concentration range of 50 – 0.25 mU/liter and more
than 30% for GH concentrations of less than 0.1 mU/liter. Insulin was
measured by immunoradiometric assay (Biosource Technologies, Inc.,
Nivelles, Belgium). IGF-I and IGFBP-3 were measured by RIA (Serono,
Biomedica, Milan, Italy; and Nichols, San Juan Capristano, CA, respectively). Serum insulin was assayed by RIA (Medgenix, Fleurus, Belgium)
with a detection limit of 3.6 mU/liter. The interassay coefficient of
variation was 3.8 – 8.0% over the concentration range of 12.5–94.5
mU/liter.
Body composition
Body fat mass was measured by bioelectrical impedance analysis
(Bodystat 1500, Bodystat Ltd., Isle of Man, UK) in the morning after the
subjects had voided and while they were fasting and resting in bed (12).
MRI measurement
Study design
Twenty four-hour plasma GH concentration profiles (study 1) were
obtained within 7 d of menses onset. Subsequently, the GH distribution
volume (study 2) was measured within 7 d of study 1.
MRI scans were made using a multislice fast-spin echo sequence
(Gyroscan-T5 whole body scanner 0.5 Tesla, Phillips Medical Systems,
Best, The Netherlands). Visceral and sc adipose tissue areas (square
centimeters) were assessed in all groups before and after weight loss, as
previously described (13).
24-h plasma GH concentration time series (study 1)
The subjects were admitted to the research center at 0800 h after an
overnight fast. A 20-gauge cannula was placed in an antecubital vein for
blood sampling. Blood for measurement of plasma insulin, IGF-I, and
IGF binding protein (IGFBP)-3 was collected. One hour after the insertion of the cannula, blood was withdrawn through a nonthrombogenic
catheter connected to a constant withdrawal pump (Conflo, Carmeda
AB, Taeby, Sweden) (10). The withdrawal rate was 7.8 ml/h, and the
reservoir tubes were changed every 10 min for a 24-h period.
Volunteers were instructed to consume a standardized (liquid) diet
during 3 d before admission. The diet contained a total of 8.3 MJ/d, of
which 20% energy was protein, 34% energy was fat, and 46% energy was
carbohydrate (Modifast, Novartis, Veenendaal, The Netherlands; Nutridrink, Nutricia, Zoetermeer, The Netherlands). On study days, these
food products were served in equal portions as meals at 0930, 1300, and
1830 h. The subjects were allowed to walk around inside the research
center during the day, but not to climb stairs. Lights went off at 2330 h.
GH distribution volume (study 2)
One hour after insertion of bilateral iv catheters, a continuous infusion
of somatostatin-14 (SMS, Ferring Pharmaceuticals Ltd. BV, Hoofddorp,
The Netherlands) was started (0.83 ␮g/min䡠m2 body surface area) (11)
and continued for 240 min throughout the study. At 60 min., a single
bolus of 100 mU of 22 kDa recombinant human GH (rhGH) (Eli Lilly &
Co., Nieuwegein, The Netherlands) was administered iv at a constant
infusion rate over 5 min using a calibrated infusion pump (Harvard
Apparatus, Edenbridge, UK).
During the first 60 min of SMS infusion, blood samples were drawn
every 10 min. After rhGH administration, blood was sampled every 5
min during the first hour and thereafter every 10 min to monitor GH
kinetics.
Weight loss program
Obese women were prescribed a liquid hypocaloric diet (2 MJ/d; 43%
energy as protein, 15% energy as fat, and 42% energy as carbohydrate;
Modifast, Novartis, Veenendaal, The Netherlands) after the above two
studies were completed. Subjects were instructed not to increase their
physical activity level. When the subjects had lost 50% of their excess
weight, the sampling studies (see below) were repeated.
Blood sampling and assays
Blood samples were collected in heparinized tubes. Samples were
centrifuged within the hour of sampling, and plasma was stored at ⫺40
Calculations and statistics
Percentage excess weight was calculated as: 100 ⫻ (weight/ideal
body weight) ⫺ 100. Ideal body weight for height was determined
according to the Metropolitan Life Insurance tables (1983).
Deconvolution analysis of plasma GH time series. A multiparameter deconvolution technique was used, which assumes that GH release from the
pituitary gland takes place as a discrete finite series of bursts that can
be approximated algebraically by a Gaussian-shaped or minimally
skewed distribution of secretory rates of nonzero amplitude. The location, amplitude, and duration of each GH secretory burst acted upon
continuously by an endogenous subject-specific hormone half-life are
assumed to determine the plasma GH concentration at any given instant.
GH disappearance from plasma was modeled as a monocomponent
exponential decay function with a subject-specific rate constant. A convolution integral was used to relate the serum GH concentrations to the
foregoing specific measures of secretion and removal, which were quantified by iterative nonlinear least-squares parameter estimation. Thus,
any given GH pulse is described by its location in time, amplitude, and
half-duration, as superimposed upon a finite (zero or positive) basal
(time-invariant) GH secretory rate. The integral of each secretory burst
yields the pulse mass. A detailed mathematical description of the above
waveform-specific deconvolution method has been given elsewhere
(14).
Total daily secretion was calculated as follows: Total daily GH secretion
(mU䡠day⫺1) ⫽ (pulsatile ⫹ basal) secretion/LVd (mU䡠L⫺1䡠day⫺1) ⫻ Vd (L).
Approximate entropy (ApEn) statistic. Normalized ApEn is a family of
scale- and model-independent statistics for assessing regularity of timeseries data. ApEn assigns a nonnegative number to a time series, quantifying a serial orderliness or regularity of subpatterns in the data.
Smaller ApEn values indicate a greater likelihood of successive regularity comparisons remaining close and therefore imply greater orderliness. The calculation and biological significance of ApEn has been
described earlier (15). Two input parameters, m and r, must be fixed to
compute ApEn; m is the length of compared runs, and r is a tolerance
or threshold. In this study, m ⫽ 1 and r ⫽ 20% of the sd of each GH time
series, which provides a replicable statistic that is concentrationindependent.
GH distribution volume. GH distribution volume was estimated by nonlinear least-square fitting of the plasma GH decay curve following bolus
GH infusion, using a two-compartment open model with a constant
coefficient of variation residual error model. Individual parameter estimates were obtained in each subject using nonlinear mixed effect
Pijl et al. • Body Fat and GH Kinetics in Women
J Clin Endocrinol Metab, November 2001, 86(11):5509 –5515 5511
modeling (NONMEM) version IV software (NONMEM Project Group,
University of California, San Francisco, CA) (16). Prebolus-infusion values were accounted for by modeling a variable steady-state infusion
parameter ending at the time of rhGH administration.
Statistical analysis. Because derived data were not normally distributed,
the Kruskall-Wallis test for multiple comparisons was used to detect
differences within and between groups. Differences were corroborated
by the Mann-Whitney U test for unpaired samples. Correlations between
calculated parameters were computed using two-tailed Spearman’s rank
test. Predictors of outcome parameters were determined using stepwise
multiple regression analysis. Significance level was set at 5%. All results
are presented as the mean ⫾ sd. Calculations were performed using
SPSS/PC⫹ version 4.0.1 and SPSS for Windows version 6.1 (SPSS, Inc.,
Chicago, IL).
did not differ significantly among SVFA or LVFA subjects
and NW women.
GH kinetics in SVFA vs. LVFA women
The mean plasma GH concentration, pulsatile GH secretion rate, burst amplitude, and burst mass were significantly
reduced in LVFA women compared with SVFA subjects. In
addition, ApEn scores were significantly higher in LVFA
subjects. In contrast, basal GH secretion, burst frequency, GH
distribution volume, and GH half-life were not different
between LVFA and SVFA subjects.
Effects of weight loss
Results
Subject characteristics
Subject characteristics are shown in Table 1. One subject in
the SVFA group was excluded from all analyses, because
values of all her GH variables were elevated by more than 3 ⫻
sd of group average. Inclusion of the results of this subject
would not have changed any of our conclusions. One LVFA
subject did not complete the weight loss program. Another
LVFA subject could not complete the second 24-h plasma
sample collection for technical reasons. LVFA subjects were
slightly older than SVFA subjects, whereas the age of NW
subjects was not different from that of either group of obese
women. Total body weight and body fat percentage were
similar in the two obese groups, whereas visceral fat area was
approximately 2-fold greater in the LVFA group (Table 1).
Plasma IGF-I levels were significantly lower in SVFA vs.
LVFA, whereas IGFBP-3 and insulin concentrations were not
statistically different among groups.
GH kinetics in SVFA and LVFA vs. NW women
GH secretory and kinetic parameters are shown in Table
2. There were no significant differences between obese
women with a SVFA and NW women, except for a slightly
increased interburst interval in SVFA subjects. In contrast,
the mean plasma GH concentration, basal GH secretion rate,
pulsatile GH secretion rate, secretory burst amplitude, secretory burst mass, and total daily GH secretion were approximately 70% lower in LVFA subjects compared with NW
controls (Figs. 1 and 2). GH distribution volume and half-life
Loss of 50% of body weight was achieved in 3–5 months
of very low-calorie diet in all subjects included in the analysis. All anthropometric parameters were significantly reduced in response to caloric restriction (Table 1). Plasma
IGF-I, IGFBP-3, and insulin were not significantly affected by
weight loss. However, the loss of visceral fat tended to be
associated with the change in IGF-I levels in obese subjects
(r ⫽ ⫺0.48; P ⫽ 0.09).
In SVFA women, only basal GH secretion increased significantly in response to weight loss, whereas all other GH
secretion and kinetic parameters were not significantly
affected.
Although pulsatile GH secretion per liter Vd increased
slightly in response to weight loss in LVFA women, total
daily GH secretion, GH pulse frequency, ApEn, GH half-life,
and GH distribution volume were not significantly affected
(Table 2). Moreover, basal, pulsatile and total GH secretion,
and mean plasma GH concentrations remained approximately 50 –70% lower in LVFA subjects compared with NW
controls (Table 2; Figs. 1 and 2), despite an approximate 40%
decrease in visceral fat mass.
Correlation of GH secretion characteristics with the size of
adipose tissue depots
NW and obese subjects (before weight loss) were included
in correlation analyses. Total and pulsatile daily GH secretion, but not basal secretion, correlated inversely with the
size of both the sc and the visceral fat area, and with various
TABLE 1. Subject characteristics
NW
Number
Age (yr)
BMI (kg/m2)
Fat percentage
Total sc fat (cm2)
Visceral fat (cm2)
IGF-I (nmol/liter)
IGFBP-3 (mg/liter)
Insulin (mU/liter)
8
38 (8)
22.4 (2.1)
29 (4)
1190 (308)
143 (48)
13.3 (2.0)
2.5 (0.6)
4.6 (1.4)
Data are mean (SD). BMI, Body mass index.
a
P ⬍ 0.05 vs. SVFA.
b
P ⬍ 0.001 vs. NW.
c
P ⬍ 0.01 vs. before weight loss.
d
P ⬍ 0.05 vs. NW.
Before weight loss
SVFA
7
32 (5)
32.7 (3.9)b
42 (4)b
2813 (629)b
278 (68)b
16.3 (3.2)d
2.2 (0.3)
6.5 (4.8)
After weight loss
LVFA
8
41 (6)a
34.9 (3.2)b
44 (4)b
2801 (429)b
616 (175)a,b
12.2 (3.2)a
2.3 (0.4)
6.1 (3.2)
SVFA
LVFA
7
6
39 (5)
28.9 (2.1)c
37 (2)c
2076 (313)c
372 (101)c
16.2 (3.9)
2.7 (1.0)
6.3 (2.9)
27.5 (2.8)c
34 (3)c
1959 (472)c
163 (65)c
13.7 (3.9)
2.3 (0.5)
3.1 (2.9)
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Pijl et al. • Body Fat and GH Kinetics in Women
TABLE 2. GH kinetic parameters in obese and NW women
Before weight loss
NW
Number
Mean plasma GH concentration (mU/liter)
Basal GH secretion rate (mU/LVd/d)
Pulsatile GH secretion rate (mU/LVd/d)
Total daily secretion (mU/d)
ApEn
GH half-life (min)
Number of bursts
Burst amplitude (mU/LVd/min)
Burst mass (mU/LVd/burst)
Burst half-duration (min)
Interburst interval (min)
GH volume of distribution (liter)
8
3.6 (1.7)
13 (8)
204 (113)
2370 (1205)
0.55 (0.18)
15.6 (2.4)
18.1 (3.6)
0.37 (0.2)
11.7 (5.9)
30 (4)
79 (14)
10.8 (1.9)
After weight loss
SVFA
LVFA
SVFA
LVFA
7
2.5 (1.3)
8 (6)
133 (61)
1946 (1144)
0.42 (0.11)
16.1 (1.6)
14.0 (4.1)
0.39 (0.08)
10.3 (5.5)
27 (9)
105 (23)e
12.9 (3.3)
8
0.9 (0.4)a,b
6 (10)a
53 (21)a,b
712 (285)a,b
0.60 (0.14)b
14.3 (2.4)
14.3 (2.4)
0.10 (0.05)a,b
3.6 (1.8)a,b
31 (7)
97 (24)
12.2 (3.7)
7
4.7 (2.1)
20 (7)c
259 (121)
3585 (2666)
0.53 (0.13)
15.4 (1.4)
14.3 (3.5)
0.57 (0.29)
18.9 (10.4)
31 (7)
98 (20)
11.9 (5.2)
6
2.1 (0.8)c,d
4 (3)e
106 (43)c,d
1050 (310)e
0.55 (0.18)
17.5 (0.9)c
16.5 (3.3)
0.27 (0.14)c
6.9 (3.8)c
24 (3)
87 (23)
10.2 (3.3)
Data are mean (SD).
a
P ⬍ 0.01 vs. NW.
b
P ⬍ 0.01 vs. SVFA.
c
P ⬍ 0.01 before vs. after weight loss.
d
P ⬍ 0.05 vs. NW.
e
P ⬍ 0.05 vs. NW.
more general measures of body fat storage (Table 3). Stepwise multiple regression analysis, including age, IGF-I, mean
plasma GH concentration, total daily GH production, basal
daily GH production, and pulsatile daily GH production as
independent variables, revealed that the mean plasma GH
level was the strongest single negative predictor of visceral
fat area. Quadratic regression provided the best fit of the
relation between visceral fat area and the time-integrated
plasma GH concentration (r2 ⫽ 0.58; P ⬍ 0.001) (Fig. 3). This
negative association remained significant when data from
weight-reduced obese subjects were included in the analysis
(r2 ⫽ 0.58; P ⬍ 0.001).
Simple regression analysis revealed a significant inverse
relationship between the plasma total IGF-I concentration
and the size of the visceral fat area (r ⫽ ⫺0.52; P ⫽ 0.03).
However, the relation lacked significance in a multiple regression model, including age, body weight, total fat mass,
and sc fat mass as other independent variables.
Age was not significantly associated with GH secretion
(r ⫽ ⫺0.09; P ⫽ 0.75) or mean GH concentration (r ⫽ ⫺0.3;
P ⫽ 0.26) in our study population, which is of importance in
view of the fact that age was slightly different among groups
(Table 1).
Discussion
The present study contrasts GH secretion and elimination
in obese premenopausal women with two distinct types of
body fat distribution and appraises the effects of weight loss
on these measures. The endpoint of caloric restriction was a
50% reduction in the prestudy weight excess. We employed
deconvolution analysis to distinguish between alterations in
GH secretion and half-life. GH distribution volume was estimated on the basis of the plasma GH decay curve after GH
bolus injection. Collectively, these analyses established that
the subset of obese premenopausal women with large visceral fat stores sustains markedly (4-fold) reduced mean
daily plasma GH levels. Mechanistically, this is brought
about by jointly diminished basal (2-fold) and pulsatile (4-
fold) GH secretion. Pulsatile GH secretion in viscerally obese
women is blunted by reduced secretory burst amplitude and
mass, whereas burst number and duration are similar compared with NW women. Moreover, visceral obesity in premenopausal women is associated with loss of regularity of
the GH release process. Although the 24-h mean plasma GH
concentration increased slightly in response to weight loss in
visceral obese women, total daily GH secretion was not affected. In fact, the daily GH secretion rate and mean plasma
GH concentration remained considerably (50%) reduced in
viscerally obese women after weight loss compared with
values in NW women. In contrast, equally obese women with
smaller visceral fat stores produced measurably normal daily
amounts of GH that weight loss did not affect further. Comparisons among the obese and NW cohorts further established that the half-life and distribution volume of (exogenous) GH are independent of body fat distribution in
premenopausal women. Regression analysis demonstrated
that the mean plasma GH concentration strongly predicts the
size of the visceral fat area in this study population. Finally,
plasma IGF-I levels were significantly reduced in viscerally
obese women vs. women with small visceral fat stores.
A major finding of this study is the prominent difference
in GH secretion between obese women who store fat in
visceral vs. sc depots. Visceral fat storage was associated with
profoundly reduced plasma GH concentrations, attributable
in large measure to reduced GH burst mass as inferred earlier
in total body obese men and middle-aged adults who tend
to store fat in visceral adipose tissue (17, 18). This finding
may be explained in two ways: 1) hyposomatotropism promotes the storage of excess body fat in visceral adipose tissue,
or 2) visceral fat storage reduces GH production.
Several observations favor the first explanation. First, daily
GH secretion remained significantly diminished in viscerally
obese women even after the loss of a substantial amount of
body fat. Indeed, reduction of approximately 40% of their
visceral fat area did not affect total daily GH secretion in
these women (Fig. 2). Secondly, the mean 24-h plasma GH
Pijl et al. • Body Fat and GH Kinetics in Women
J Clin Endocrinol Metab, November 2001, 86(11):5509 –5515 5513
FIG. 2. Total daily GH secretion rate in NW and obese women before
and after the loss of approximately 50% of overweight. *, P ⬍ 0.01 vs.
NW; **, P ⬍ 0.05 vs. NW; †, P ⬍ 0.01 vs. SVFA.
FIG. 1. Twenty four-hour plasma GH concentration profile in an
obese premenopausal woman with a SVFA (A), an obese woman with
a LVFA (B), and a NW control (C). A and B had a similar body mass
index (31.3 and 31.4 kg/m2, respectively), total body fat percentage
(39.6 and 41.0%, respectively) and age (38 and 45 yr, respectively), but
different visceral fat area (213 and 827 cm2, respectively). The control
subject was 45-yr old and had a body mass index of 20 kg/m2. Note
different y-axis scale in C.
concentration appears to be the strongest (negative) predictor of visceral fat area, explaining approximately 58% of the
variability of this parameter in our study population (Fig. 3).
In contrast, GH secretion was not diminished in LVFA subjects and weight loss did not significantly affect the mean GH
plasma concentration or GH kinetics in these women any
further. Partial reversal of plasma GH concentrations has
been inferred by some investigators in other weight loss
contexts (5–7, 19). However, none of the earlier studies evaluated the impact of weight loss in obese subjects with large
vs. small visceral fat stores. Our data indicate that this distinction is critical for adequate appraisal of the effects of
weight loss on GH kinetics in humans. Indeed, although
weight loss restored the mean plasma GH level to normal in
the obese group as a whole (data not shown), subgroup
analysis indicates that it remains below normal in visceral
obese subjects.
Although weight loss did not affect the GH secretion rate,
it did induce a slight but significant increase of the mean
plasma GH concentration in viscerally obese women. This
apparent paradox can be explained by the lengthening of GH
half-life that was observed in these women in response to
weight loss. A (nonsignificant) reduction of GH distribution
volume may have played an additional role. This finding
underscores the fact that, although GH secretion rate appears
to be of major importance, other kinetic features of GH subserve hyposomatotropism in obesity (17, 20).
We infer that our data support, albeit not prove, a primary
GH secretory defect in premenopausal women who tend to
store excess fat in visceral adipose tissue. However, we cannot rule out the possibility that further weight reduction
would have restored daily GH secretion in viscerally obese
women. Reduced GH output may be brought about by genes
that control pituitary GH synthesis and/or secretion. GH
secretion varies considerably even among subjects of similar
age, sex, and body composition, whereas GH burst mass and
secretion rate are highly conserved in individuals across
repeated measurement sessions (21), which suggests that
genetic factors play an important role in the regulation of the
GH secretion rate (22). Thus, genetically induced relative
hyposomatotropism may promote accumulation of adipose
tissue in visceral stores in patients who have other genes that
predispose them to develop obesity. This notion accords with
observations in GH-deficient adults who manifest visceral
obesity, whereas GH replacement specifically reduces visceral adipose tissue (2, 3). It is also in keeping with numerous
observations in animals: obesity-prone rats exhibit reduced
plasma GH levels before weight gain (as opposed to obesityresistant rats) (23); GH-deficient dwarf rats fed a high-fat diet
grow obese and insulin-resistant compared with wild-type
controls (24); and transgenic rats exhibiting low levels of
serum hGH develop obesity and insulin resistance (25).
IGF-I levels were significantly reduced in viscerally obese
women, although IGFBP-3 concentrations were similar to
those in equally obese women with small visceral fat stores.
This finding suggests, that visceral obesity is characterized
by true GH deficiency. However, although simple linear
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Pijl et al. • Body Fat and GH Kinetics in Women
TABLE 3. Spearman’s rank correlation coefficients between GH kinetic features and body fat
Mean plasma GH concentration (mU/liter)
Total GH secretion (mU/d)
Basal GH secretion rate (mU/LVd/d)
Pulsatile GH secretion rate (mU/LVd/d)
Average burst amplitude (mU/LVd)
Average burst mass (mU/LVd/burst)
Number of bursts
GH half-life (min)
Age (yr)
Visceral fat (cm2)
Total sc fat (cm2)
Fat percentage
BMI (kg/m2)
⫺0.13
⫺0.08
⫺0.13
⫺0.08
⫺0.25
⫺0.12
⫺0.007
⫺0.24
⫺0.76
⫺0.60a
⫺0.44b
⫺0.71a
⫺0.62a
⫺0.65a
⫺0.25
⫺0.41
⫺0.57
⫺0.42b
⫺0.22
⫺0.58a
⫺0.37
⫺0.47b
⫺0.24
⫺0.15
⫺0.65
⫺0.57b
⫺0.29
⫺0.73a
⫺0.51b
⫺0.60a
⫺0.31
⫺0.30
⫺0.65a
⫺0.52b
⫺0.28
⫺0.68a
⫺0.50b
⫺0.54a
⫺0.32
⫺0.23
a
a
a
Total sc fat, Total sc fat area (abdominal ⫹ femoral); BMI, body mass index.
P ⬍ 0.01.
b
P ⬍ 0.05.
a
does not augment total GH secretion rate in viscerally obese
premenopausal women. This finding suggests, albeit not
proves, that hyposomatotropism is a primary feature of visceral obesity in premenopausal women. Whether analogous
abnormalities occur and persist in viscerally obese men and
postmenopausal women is not known. Thus, the present
data establish an important linkage between factor(s) that
control regional fat distribution and activity of the GH axis
in the young obese female, which is not evidently remediable
to significant weight loss.
Acknowledgments
Received December 22, 2000. Accepted August 6, 2001.
Address all correspondence and requests for reprints to: H. Pijl, M.D.,
Ph.D., Department of General Internal Medicine, Leiden University
Medical Center, C1-R39, P.O. Box 9600, 2300 RC Leiden, The Netherlands. E-mail: [email protected].
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FIG. 3. Relationship between mean plasma GH concentration and
visceral fat area.
regression of our data revealed an inverse association between visceral fat area and total IGF-I concentration (r ⫽
⫺0.52; P ⫽ 0.03), the correlation lacked significance in a
multiple regression model, including age, body weight, total
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Furthermore, multiple regression analysis did not reveal a
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irregular, consistent with altered neuroregulation of this axis.
Substantial weight loss (50% of the prestudy excess weight)
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