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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
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: h.pijl{at}lumc.nl
Abstract
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 = 8) vs. small visceral fat area (SVFA;
n = 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 = 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 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.
RELATIVE 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, 6, 7, 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 adequately 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, 6, 7, 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.
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.
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.
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 µg/min·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 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 µg/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
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).
Calculations and statistics
Percentage excess weight was calculated as: 100 x (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·day-1) = (pulsatile + basal) secretion/LVd (mU·L-1·day-1) x Vd (L).
Approximate entropy (ApEn) statistic. Normalized ApEn is a family of scale- and model-independent statistics for assessing regularity of time-series 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 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).
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 x 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.
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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
did not differ significantly among SVFA or LVFA subjects and NW
women.
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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
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 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).
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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 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, 6, 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 obesity-resistant 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 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 fat mass, and sc fat mass as other independent variables. Furthermore, multiple regression analysis did not reveal a significant relationship between mean plasma GH levels and IGF-I concentration. IGF-I levels have been found normal, reduced, or even increased in obese humans, despite considerably decreased circulating GH levels (26). This is probably because IGF-I levels are influenced by many other endocrine and metabolic factors than GH (26, 27). Thus, the plasma IGF-I concentration may not adequately reflect GH status in obese subjects. On these grounds, we believe that the reduced IGF-I level in viscerally obese women is not necessarily a reflection of true GH deficiency (which does not mean to say that these women are not GH-deficient).
In summary, obese women with topographically distinct distributions of total body fat differ vividly in GH secretory dynamics but not in GH elimination kinetics. In particular, visceral adiposity is associated with a 4-fold suppression of daily GH secretion, due to selective attenuation of GH secretory burst mass. The GH release process is also more irregular, consistent with altered neuroregulation of this axis. Substantial weight loss (50% of the prestudy excess weight) 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.
Footnotes
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, waist-to-hip circumference ratio.
Received December 22, 2000.
Accepted August 6, 2001.
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 P. Kok, M. M. Buijs, S. W. Kok, I. H. A. P. van Ierssel, M. Frolich, F. Roelfsema, P. J. Voshol, A. E. Meinders, and H. Pijl Acipimox enhances spontaneous growth hormone secretion in obese women Am J Physiol Regulatory Integrative Comp Physiol, April 1, 2004; 286(4): R693 - R698. [Abstract] [Full Text] [PDF]
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 Q. He, E. S. Engelson, J. B. Albu, S. B. Heymsfield, and D. P. Kotler Preferential loss of omental-mesenteric fat during growth hormone therapy of HIV-associated lipodystrophy J Appl Physiol, May 1, 2003; 94(5): 2051 - 2057. [Abstract] [Full Text] [PDF]
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 M. M Buijs, J. Burggraaf, C. Wijbrandts, M. L de Kam, M. Frolich, A. F Cohen, J. A Romijn, H. P Sauerwein, A E. Meinders, and H. Pijl Blunted lipolytic response to fasting in abdominally obese women: evidence for involvement of hyposomatotropism Am. J. Clinical Nutrition, March 1, 2003; 77(3): 544 - 550. [Abstract] [Full Text] [PDF]
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S. Overeem, S. W. Kok, G. J. Lammers, A. A. Vein, M. Frolich, A. E. Meinders, F. Roelfsema, and H. Pijl Somatotropic axis in hypocretin-deficient narcoleptic humans: altered circadian distribution of GH-secretory events Am J Physiol Endocrinol Metab, March 1, 2003; 284(3): E641 - E647. [Abstract] [Full Text] [PDF]
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M. M. Buijs, J. A. Romijn, J. Burggraaf, M. L. de Kam, A. F. Cohen, M. Frolich, F. Stellaard, A. E. Meinders, and H. Pijl Growth Hormone Blunts Protein Oxidation and Promotes Protein Turnover to a Similar Extent in Abdominally Obese and Normal-Weight Women J. Clin. Endocrinol. Metab., December 1, 2002; 87(12): 5668 - 5674. [Abstract] [Full Text] [PDF]
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E. W. C. M. van Dam, F. Roelfsema, F. H. Helmerhorst, M. Frolich, A. E. Meinders, J. D. Veldhuis, and H. Pijl Low Amplitude and Disorderly Spontaneous Growth Hormone Release in Obese Women with or without Polycystic Ovary Syndrome J. Clin. Endocrinol. Metab., September 1, 2002; 87(9): 4225 - 4230. [Abstract] [Full Text] [PDF]
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M. M. Buijs, J. Burggraaf, J. G. Langendonk, R. C. Schoemaker, M. Frolich, J.-W. Arndt, A. F. Cohen, J. A. Romijn, M. T. Ackermans, H. P. Sauerwein, et al. Hyposomatotropism Blunts Lipolysis in Abdominally Obese Women J. Clin. Endocrinol. Metab., August 1, 2002; 87(8): 3851 - 3858. [Abstract] [Full Text] [PDF]
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P < 0.01 vs. SVFA.