1 Department of General
Internal Medicine, 3 Department of Clinical
Chemistry, and 2 Center for Human Drug Research, We studied the kinetics of exogenous recombinant
22-kDa human growth hormone (rhGH) in premenopausal women with upper
body obesity (UBO), lower body obesity (LBO), or normal body weight. A
bolus of 100 mU rhGH was administered during a continuous infusion of
somatostatin to suppress endogenous GH secretion. GH kinetics were
investigated with noncompartmental analysis of plasma GH curves. GH
peak values in response to GH infusion and plasma half-life of GH were
not significantly different between normal weight and obese subjects.
In contrast, GH clearance was 33% higher in LBO women and 51% higher
in UBO women compared with clearance in normal weight controls. The
difference in clearance between LBO and UBO was not statistically
significant. Altered GH clearance characteristics contribute to low
circulating GH levels in obese humans. Body fat distribution does not
appear to affect GH kinetics.
somatotropin; clearance; distribution volume; fat mass; fat
distribution
THE MEAN 24-H PLASMA GROWTH HORMONE (GH)
concentration and its level in response to virtually every known GH
secretagogue are considerably reduced in obese humans (25, 40, 41). The mechanisms underlying this phenomenon are unclear. The concentration of
GH (or any other hormone) in plasma is governed by its specific kinetic
features, i.e., distribution volume, clearance characteristics, and
production rate. A number of studies suggest that the metabolic clearance of GH is increased in obese humans (24, 38, 41). In mildly
obese men, body mass index (BMI) was shown to be a negative determinant
of plasma GH half-life, determined by deconvolution of spontaneous
plasma GH pulse patterns (24). In an elegant study using deconvolution
analysis of 24-h GH plasma concentration profiles, a dual defect in GH
secretion and half-life was suggested to subserve the hyposomatotropism
of massively obese men (41). Also, in an experiment in normal weight
men and women that employed continuous GH infusion, BMI was a positive
correlate of plasma GH clearance (38). However, BMI may not be a
completely accurate indicator of body fat mass (22, 33, 34). Body fat
mass was not measured in any of these studies.
The metabolic effects of excessive fat storage are dependent on its
location in various body fat stores. Visceral fat accumulation has far
more metabolic sequelae than subcutaneous fat storage (8). Thus it is
conceivable that body fat distribution affects GH metabolic clearance.
The waist-to-hip circumference ratio (WHR) is a measure of relative fat
storage in upper body (abdominal) vs. lower body (gluteal/femoral)
compartments. A high WHR reflects predominant storage in upper body
compartments. Two studies suggest that the WHR, in addition to BMI,
might be a determinant of plasma GH concentrations. An inverse
correlation of WHR with spontaneous and GH-releasing hormone-induced
plasma GH peak levels was observed in mildly obese older men (12).
Diminished GH secretion in upper body obesity might explain this
observation, because 24-h GH production rates were found to be
inversely correlated to WHR in severely obese humans (30). In addition,
increased GH clearance or distribution volume might contribute to low
circulating plasma GH concentrations in upper body obesity. However, it
is unknown to date whether fat storage in upper body compartments
affects GH clearance and/or distribution volume.
This study was conducted to examine whether an increased body fat mass
is associated with increased GH clearance and/or GH distribution
volume. Furthermore, we aimed to investigate whether body fat
distribution affects these kinetic parameters. To this end, a bolus
injection of recombinant human GH was administered in two groups of
obese women who were similar in BMI and body fat mass while exhibiting
a widely different distribution of their body fat as evidenced by their
WHR. The results were compared with those in a group of normal weight women.
Subjects.
Eight upper body obese (UBO) women (BMI >28
kg/m2, WHR >0.9), eight lower
body obese (LBO) women (BMI >28
kg/m2, WHR <0.8), and eight
normal weight women (NW) were enrolled. Waist circumference was
measured half-way between the lower costal margin and the iliac crest;
the hip circumference was measured at maximum circumference of the hip
while the subjects were standing (1). All subjects were healthy,
nonsmoking, premenopausal, and not taking any kind of medication
(including contraceptives). Their kidney function was normal as
indicated by plasma creatinine values within the normal range. They had
maintained a stable body weight for Study design.
All studies were performed in the follicular phase of the menstrual
cycle. The subjects were admitted to the research center at 8:00 AM
after an overnight (
ABSTRACT
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
INTRODUCTION
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
METHODS
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
3 mo before the study. The two
groups of obese women were similar in BMI, and all women were similar
in age. Written informed consent was obtained. The study was approved
by the Ethics Committee of Leiden University Medical Center.
8-h) fast. After voiding, the subjects stayed
semirecumbent for the duration of the experiment. Body composition was
measured using bioelectrical impedance analysis (Bodystat, Douglas,
Isle of Man, UK), and electrodes were placed at the right hand and foot
(26). A cannula was placed in an antecubital vein for blood sampling. A
second cannula was placed in a contralateral antecubital vein for
infusions. One hour after insertion of both catheters, a continuous
infusion of somatostatin-14 (SMS, Ferring, Hoofddorp, The Netherlands)
was started (0.83 µg · min
1 · m
body surface area
2) and
continued for 150 min throughout the study. At 60 min, a single bolus
of 100 mU of 22-kDa GH (Eli Lilly, Nieuwegein, The Netherlands) was
administered intravenously at a constant infusion rate over 5 min by
means of a calibrated infusion pump (Harvard Apparatus, Edenbridge, UK).
Blood sampling and assays.
Blood samples were collected in heparinized tubes. All samples were
centrifuged within the hour of sampling, and plasma was stored at
40°C until assay.
Calculations.
GH kinetics was investigated with noncompartmental methods using
WinNonlin V1.1 (Scientific Consulting, Apex, NC). Noncompartmental methods were chosen because they require fewer assumptions. The area
under the curve (AUC) was calculated using the linear trapezoidal rule
and extrapolated to infinity using the terminal half-life estimated
with log-linear regression. Adequacy of the log-linear regression for
determination of the terminal half-life is the only assumption
necessary for noncompartmental modeling. The number of points to be
included for this estimate was automatically determined by the program
on the basis of the largest adjusted
r2. In three NW
subjects, the terminal part of the curve tended to flatten out,
resulting in unlikely half-life estimates. For these subjects, this
terminal part of the curve was disregarded in the calculations. The
part of the AUC attributable to nonzero prevalues
(AUCpre) was estimated by use of
the calculated terminal half-life and the prevalue
(AUCpre = prevalue/z). This part was subtracted from the initial AUC, resulting in the corrected AUC to be
used for clearance calculation [clearance = dose/(corrected AUC)]. Additionally, compartmental modeling was used to obtain two-compartment model parameter estimates. In this analysis, the flattened part of the curves were also disregarded.
Statistical analysis. GH kinetic parameters were compared between groups using unpaired Student's t-tests. Anthropometric descriptives were correlated with clearance by use of Pearson's correlation coefficients. All data are presented as means ± SD, unless otherwise specified. 95% Confidence intervals of the difference between means (95% CI) are given if indicated. Statistical calculations and data management were performed using SPSS for Windows V6.1.2 (SPSS, Chicago, IL).
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RESULTS |
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The characteristics of the subjects that were enrolled in the study are
shown in Table 1.
|
SMS infusion adequately suppressed endogenous GH secretion in all
groups. GH levels fell below 0.75 mU/ml in all participants except one
subject in the control group. The average GH profiles for each group
after intravenous injection of 100 mU of exogenous GH are given in Fig.
1.
|
The peak GH concentrations
(Cmax), although 40% lower in
the UBO group compared with the controls and the LBO subjects, were not
statistically significantly different between groups (95% CI:
0.1,+8.7 for UBO vs. NW and
2.6,+10.9 for LBO vs. UBO;
Table 2).
|
Inspection of the plasma GH disappearance curves reveals a
biexponential decline (Fig. 1). There were no indications for further phases. Noncompartmental analysis revealed that GH clearance was 33%
higher in LBO subjects compared with NW controls (603 vs. 803 ml/min;
95% CI: +4,+395). In UBO subjects, GH clearance was observed to be
51% higher than in NW controls (909 ml/min; 95% CI: +129,+482, Table
2). Significant positive correlations
(P < 0.01) existed between clearance
and weight (r = 0.63), BMI
(r = 0.51), waist circumference
(r = 0.52), hip circumference
(r = 0.52), and body fat mass
(r = 0.56, Fig.
2). The apparent volume of
distribution (Vd) of GH tended
to be larger in obese subjects, although the difference with NW
controls did not reach statistical significance (Table 2). As a result
of increased clearance and a larger
Vd, plasma GH terminal half-life
was not different between groups. Plasma GH terminal half-life was not
significantly different in obese and NW women (Table 2).
|
Compartmental analysis indicated clearance, volume, and terminal
half-life estimates comparable to the noncompartmental results (Table
3). Data are presented as medians and ranges because of outliers in the terminal half-life estimates for the NW group. Compartmental analysis resulted in parameter estimates that were similar to those obtained by noncompartmental analysis. Therefore, only
noncompartmental results are discussed.
|
GHBP concentration in plasma was measured in all subjects except three LBO women. The obese groups in which GHBP concentrations were compared were still similar in BMI and age (data not shown). Plasma GHBP concentrations tended to be higher in UBO women (compared with LBO and NW controls). The differences between groups did not reach statistical significance (Table 2).
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DISCUSSION |
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We studied the kinetics of exogenous recombinant 22-kDa variant hGH by intravenous administration of a GH bolus while endogenous GH secretion was suppressed by somatostatin. 22-kDa hGH is the GH variant that prevails in human serum (3). The dose and type of administration were chosen to mimic a physiological GH pulse concentration, which is of importance in view of the fact that plasma GH levels affect GH clearance (18, 38).
The plasma clearance of 22-kDa rhGH was shown to be enhanced in obese women compared with NW control women. UBO, as indicated by a high WHR, was associated with GH clearance values that were similar to those in peripheral obesity in women who were similar with respect to their amount of adipose tissue. GH clearance was clearly correlated with various indicators of adipose tissue mass. In apparent contradiction with these findings, plasma GH half-life was not significantly different between obese and NW women. However, small concomitant differences in Vd of GH between obese and NW women may explain these data. Increased clearance in the presence of a larger Vd leads to a similar half-life. Vd indeed tended to be larger in obese subjects (Table 2).
Plasma GH half-life in NW subjects was in keeping with previously published data obtained by others (16, 18, 41). In contrast to the present results, one study, employing deconvolution analysis of 24-h GH plasma profiles, did report a small but significant reduction of GH half-life in obese men (41). The apparent discrepancy between these data might be explained by the fact that massively obese subjects (average BMI 46 kg/m2) were studied in the latter experiment. It is conceivable that GH clearance in massively obese people is enhanced to such an extent that terminal half-life is affected. The clear linear relation between body fat mass and GH metabolic clearance that we observed is in line with this notion.
Body fat distribution does not appear to affect GH kinetic parameters to a significant extent. Thus, despite the fact that visceral fat is clearly more active (in a metabolic sense) than subcutaneous (gluteofemoral) fat, GH clearance is not increased in UBO women compared with their LBO controls. Also, GH Vd was not different between these groups. The results of the study showing an inverse correlation between plasma GH levels and WHR (12) may be confounded by the percentage of body fat, which tends to be higher in unselected UBO people. Alternatively, UBO might be characterized by reduced endogenous GH secretion to explain for lower plasma GH concentrations (30). The latter explanation seems more likely, because the GH secretion rate is a major determinant of plasma GH concentrations.
It is unlikely that differences in peak GH response to bolus injection have brought about differences in clearance estimates between our study groups. GH clearance, calculated from the plasma GH decay curve after discontinuation of a continuous GH infusion, is dependent on initial plasma concentrations such that low plasma levels are associated with increased clearance (18). Therefore, we wondered whether the fact that the peak plasma GH concentration in our UBO subjects was slightly (but not significantly) lower than that in the other two groups would have contributed to their increased clearance. We do not believe so, because the difference in peak GH levels between UBO and NW subjects in our experiment was very small (11 vs. 7 mU/l). A sevenfold decrease of initial GH levels appears to be necessary to have clearance values (18). In LBO subjects, GH clearance was clearly increased compared with NW women, whereas peak GH concentrations were virtually the same in these groups (11.51 vs. 11.39 mU/l).
We think that it is unlikely as well that differences in persistent GH secretion have significantly affected the main outcome of this study. Persistent pulsatile and/or basal GH secretion during SMS infusion could affect the GH kinetics parameter calculations. However, we believe that it did not do so in this study for three reasons. First, although some GH peaks appear to occur during SMS infusion in healthy NW humans (11), we did not observe peaks in our individual GH decay curves (data not shown). Second, basal GH secretion during SMS infusion was shown to be negligible, leading to plasma GH levels of 0.065 mU/l (11), which is only 0.7% of the peak levels measured in this study. Finally, GH inhibits its own secretion. Thus, when exogenous GH is injected, endogenous GH secretion is expected to be even lower than during SMS infusion alone. Despite all this, it is difficult to completely exclude the possibility that persistent (basal) GH secretion has flattened out the last part of GH decay curves in some subjects. In addition, assay variability may have scattered the final part of the concentration profiles (>30% for GH concentrations <0.1 mU/l). Because this final part of the curve was extrapolated to infinity to determine AUC, this could affect clearance estimates. However, the part of the AUC that resulted from extrapolation did not exceed 16% of total curve area in any case (data not shown). Thus clearance estimates were never affected to a major extent. For all these reasons, we believe that persistent GH secretion was not a factor affecting the overall estimates in the present study.
Our results are in line with studies that revealed an increased GH clearance in obese monkeys (15). They suggest that low circulating GH levels in obese women are partly due to increased GH clearance rates. An increased GH Vd may contribute as well. However, it needs to be kept in mind that GH secretion, which was not measured in this study, is a major determinant of plasma GH concentrations. Thus, in addition to increased clearance, diminished GH secretion is likely to contribute to low circulating GH levels in obese humans (41). There is no way to deduce from our data whether the changed GH kinetics are a primary defect, preceding the development of obesity, or a secondary sequela of increased adipose tissue mass. In any case, low circulating GH levels may have profound metabolic effects that predispose to obesity and/or contribute to the maintenance of large fat stores. GH increases basal metabolic rate (37), facilitates catecholamine-induced lipolysis (7), promotes protein synthesis (13), and stimulates cholesterol removal from the circulation by activating low-cholesterol lipoprotein receptors (36). GH-deficient adults are characterized by obesity, decreased lean body mass, and dyslipidemia (14). Many obese patients (in particular those with UBO) exhibit the same features (except for a decreased lean body mass). It is conceivable that reduced circulating GH concentrations play a role in the pathogenesis of obesity itself and/or its adverse metabolic sequelae.
Increased glomerular filtration of GH may play a role in the enhanced plasma GH clearance in obese subjects. About 50% of GH clearance from the circulation takes place in the kidney (18). Studies in rats have shown that glomerular filtration, tubular reabsorption, and peritubular breakdown are together the main route for GH removal by the kidney (28). A linear relationship between the glomerular filtration rate (GFR) and GH clearance was observed in healthy humans (18). There are many data indicating that GFR is increased in obese subjects (19). Thus increased glomerular filtration of GH might play a role in its enhanced plasma clearance in obese subjects. However, it should be kept in mind that renal clearance of GH is dependent on both GFR and its glomerular sieving coefficient, reflecting fractional GH extraction by the glomerulotubular system. It is unknown whether the GH sieving coefficient is altered in obese people.
Changes in liver metabolism may play a role in the pathogenesis of increased GH clearance in obese individuals. Studies in patients with chronic renal failure reveal that ~50% of GH is cleared by extrarenal tissues, i.e., the liver (18). Hepatic GH metabolism takes place through receptor-ligand internalization and lysosomal degradation (10, 23). Because obesity is characterized by changes in hepatic drug disposition (9), it is conceivable that hepatic hormone clearance is also altered in obese people. Thus changes in liver metabolism may contribute to increased GH clearance in obese individuals. Within this framework, it seems important to note that the dose of SMS we employed in this study was shown to leave liver blood flow unaffected (39).
It is conceivable that GH processing by excessive body fat stores contributes significantly to enhanced GH clearance in obese people. Adipocytes are classic target cells for GH. Studies in isolated rat adipocytes have revealed typical hormone-receptor internalization and subsequent processing of GH by these cells. Seventy-five percent of internalized GH is degraded while the remaining 25% reenters the circulation through receptor-ligand cycling (35). The strong correlation that we observed between body fat mass and clearance (r = 0.56) is in keeping with the notion that adipose tissue takes part in GH metabolism.
The increased metabolic clearance of GH that we observed in obese women cannot be due to an increase of binding capacity in their serum. Two GHBPs that circulate in blood have been identified (5, 6, 20). A large part of a single, symmetric GH pulse is bound to GHBP soon after its distribution in serum (42). Binding of GH profoundly affects its biological behavior. Complexed GH is cleared at a much slower rate than free GH, probably because the GH/GHBP complex is largely confined to the circulation, whereas free GH is distributed into the intercellular space (2). Thus increased serum GH binding capacity (i.e., GHBP concentration) would lead to prolonged GH half-life and decreased metabolic clearance rate (42). We found GHBP to be slightly (but not significantly) increased in obese compared with NW women, which is in accordance with some (21, 41) but not all studies on GHBP in obesity (17, 27, 29, 32). It follows from previously discussed data that the increased metabolic clearance of GH we observed in obese women cannot be due to an increase of binding capacity in their serum. Moreover, obesity does not appear to be associated with changes in affinity of GHBP that could account for increased metabolic clearance rates (4, 21).
This study shows that exogenous 22-kDa hGH is cleared from the circulation at a higher rate in obese than in normal weight humans. Despite the fact that the distribution of excess body fat has profound effects on metabolism in general, it does not appear to affect GH clearance.
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ACKNOWLEDGEMENTS |
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We thank Annette van der Jagt, Toos Beekman, Anja van Vliet, Ria Kroon, and Eric Gribnau for excellent technical assistance. We also thank Eli Lilly Co., Nieuwegein, The Netherlands, for the generous gift of 22-kDa human growth hormone for these studies.
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FOOTNOTES |
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The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.
Address for correspondence and reprint requests: H. Pijl, Leiden Univ. Medical Center, Dept. of General Internal Medicine, Bldg. 1, C1-R39, PO Box 9600, 2300 RC Leiden, The Netherlands (E-mail: hpijl{at}aig.azl.nl).
Received 30 November 1998; accepted in final form 18 June 1999.
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