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Original Studies |
Endocrine Sciences Research Group, Department of Medicine, University of Manchester, Manchester, United Kingdom M13 9PT; the Department of Endocrinology, Christie Hospital National Health Service Trust (A.A.T., S.M.S.), Withington, Manchester, United Kingdom M20 4BX; and the Department of Medicine, King’s College School of Medicine and Dentistry (J.J.), Denmark Hill, London, United Kingdom SE5 9PJ
Address all correspondence and requests for reprints to: Dr. Peter E. Clayton, Endocrine Sciences Research Group, Department of Medicine, University of Manchester, Oxford Road, Manchester, United Kingdom M13 9PT. E-mail: peter.clayton{at}man.ac.uk
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Abstract |
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In the acute study, patients received a single bolus dose of GH (0.1 mg/kg BW) at time zero, with blood samples drawn at 0, 12, 24, 48, and 72 h and 1 and 2 weeks. There was a significant rise in leptin, insulin, and IGF-I at a median time of 24 h, followed by a significant fall, and nadir concentrations were reached at a median time of 1.5 weeks (leptin) or 2 weeks (insulin and IGF-I). IGFBP-3 concentrations were also significantly increased, but peak concentrations were not achieved until 48 h. IGF-II, IGFBP-1, and IGFBP-2 exhibited transient decreases before returning to baseline levels. There was no relationship between increased leptin concentrations and either insulin or IGF-I concentrations.
In the chronic study, patients received daily GH treatment at doses of 0.17, 0.33, and 0.5 mg/day, each for 3 months (total time on GH, 9 months), and were then followed off GH for a further 3 months. Dual energy x-ray absortiometry was undertaken at 0, 3, 6, 9, and 12 months, and blood samples were drawn at these time points. Over 9 months on GH there was a significant fall in FM and a significant rise in LM, but no change in leptin. There were also significant increments in insulin, IGF-I, and IGFBP-3, whereas IGF-II, IGFBP-1, and IGFBP-2 did not change over 9 months of GH treatment. After 3 months off GH, there was a significant rise in FM and leptin.
High dose single bolus GH led to an increase in serum leptin within 24 h apparently independent of changes in insulin or IGF-I. Despite the changes in body composition during chronic GH treatment, there was no change in leptin. However, discontinuation of GH led to a rapid reversal of the favorable body composition and a rise in serum leptin.
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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The inverse relationship between body fatness and GH secretion, whereby increased adiposity is associated with decreased GH output, has been demonstrated in obese (10) and normal weight (11) individuals. The peripheral signal that mediates this reduction has not been identified, and although an inverse relationship between leptin and GH has been demonstrated (6, 12), there is no direct evidence of a role for leptin in inhibiting GH secretion. Another aspect of this reciprocal relationship is that GH has profound effects on body composition. GH deficiency (GHD) in adults is associated with increased body fat and decreased LM (13), and these changes are paralleled by increased serum leptin concentrations (6, 14), with a maintenance of the diurnal rhythm (15). The beneficial effects of GH replacement therapy in GHD adults are well recognized, with an increase in LM and a reduction in fat mass (FM) achieved after both short and long term treatment (13). However, the effect of exogenous GH on serum leptin concentrations is less well defined. Significant decreases in serum leptin have been described after 3 months (16) and 1 yr (17) of GH treatment. In contrast, a placebo-controlled study over 1 yr demonstrated no effect of GH on leptin despite a change in body composition (18).
In a previous cross-sectional study, we have demonstrated that serum leptin concentrations are significantly elevated in GH-deficient elderly subjects compared with those in healthy subjects (6). Furthermore, the difference in serum leptin could be attributed to the alterations in body composition associated with GHD. In the present study we have extended these observations to assess the impact of exogenous GH on serum leptin concentrations in GH-deficient adults both acutely, in response to a single GH dose, and chronically, in response to daily GH treatment over 9 months.
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Subjects and Methods |
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Twelve subjects with organic GH deficiency were studied, nine men and three women (median age, 67.8 yr; range, 62.4–85.2 yr). All subjects had documented hypothalamic-pituitary disease that developed in adult life (nonfunctioning adenoma, n = 9; meningioma, n = 1; prolactinoma, n = 1; FSH-secreting adenoma, n = 1). None of the women had received sex steroid replacement therapy in the 5 yr preceding the study, whereas seven of the nine men with gonadotropin deficiency were receiving testosterone replacement. All subjects with ACTH deficiency were receiving replacement therapy at standard doses with hydrocortisone (n = 9), cortisone acetate (n = 1), or prednisolone (n = 1), and all subjects with TSH deficiency were receiving T4 (n = 8). GHD was defined by the peak response to arginine stimulation. Eleven patients had a peak GH less than 2 ng/mL, indicating severe GH deficiency, and one patient had a peak GH of 2.6 ng/mL and was defined as GH insufficient (19).
Study protocol
The protocol for this study was approved by the South Manchester Area Health Authority ethics committee. All subjects gave written consent before entering the study. In the acute study, patients were admitted to the hospital overnight on day 1, and a baseline fasted blood sample was taken. Patients then received a single bolus dose of GH as a sc injection (0.1 mg/kg BW; Genotropin, Pharmacia & Upjohn, Inc., Stockholm, Sweden) between 1000–1100 h, and blood was drawn at 12, 24, 48, and 72 h and 1 and 2 weeks after receiving GH. All blood samples were fasting samples with the exception of the 12-h sample. During admission, patients ate a normal hospital diet with no restriction on activity and were discharged after the 24-h sample was drawn. Subsequent samples were drawn at home after an overnight fast.
At 2 weeks, patients began GH treatment (Genotropin, Pharmacia & Upjohn, Inc.) at daily doses of 0.17, 0.33, and 0.5 mg/day, each for 3 months (total time on GH, 9 months). GH was administered as a sc injection at 2200 h using a pen device (KabiPen, Pharmacia & Upjohn, Inc.). GH was discontinued after 9 months of therapy, and patients were reassessed after 3 months off GH. Patients attended the ward for assessment at baseline and 3, 6, 9, and 12 months. After an overnight fast, a single blood sample was drawn, and patients underwent a total body dual energy x-ray absorptiometry (DEXA) scan for determination of body composition.
Body composition
Body composition was determined by DEXA at 0, 3, 6, 9, and 12 months, using a QDR4500A whole body scanner (Hologic, Waltham, MA). Subjects lay supine wearing a cotton gown. The coefficient of variation (CV) was 1.75% for FM and 0.56% for LM.
Assays
Serum leptin was measured by RIA (Linco Research, Inc., St. Charles, MO). The sensitivity of this assay was 0.5 ng/mL. The intraassay CVs for mean serum concentrations of 4.9, 10.4, and 25.6 ng/mL were 8.3%, 3.9%, and 3.4%, respectively.
Serum insulin was measured using an immunoradiometric assay (IRMA; Diagnostic Systems Laboratories, Inc., Webster, TX). The sensitivity of this assay was 0.05 ng/mL. The intraassay CVs for mean serum concentrations of 0.19, 0.70, and 2.18 ng/mL were 8.3%, 4.5%, and 6.4%, respectively.
Serum insulin-like growth factor I (IGF-I) was measured, after acid/alcohol extraction, using an in-house RIA. The reference preparation used was NIBSC 87/518. The intraassay CVs for mean IGF-I concentrations of 46, 246, and 706 ng/mL were 11.3%, 6.5%, and 4.7%, respectively. The sensitivity of this assay was 14 ng/mL.
Serum IGF-II was measured using an IRMA (Diagnostic Systems Laboratories, Inc.). The sensitivity of the assay was 15 ng/mL. The intraassay CVs for mean serum concentrations of 63, 416, and 1585 ng/mL were 4.8%, 7.2%, and 4.3%, respectively.
Serum IGF-binding protein-1 (IGFBP-1) was measured using an IRMA (Diagnostic Systems Laboratories, Inc.). The sensitivity of this assay was 0.04 ng/mL. The intraassay CVs were 5.2%, 0.9%, and 5.2% for mean serum concentrations of 0.96, 4.49, and 9.52 ng/mL.
Serum IGFBP-2 was measured by RIA (Diagnostic Systems Laboratories, Inc.). The sensitivity of this assay was 0.5 ng/mL. The intraassay CVs for mean serum concentrations of 13.0, 32.2, and 94.4 ng/mL were 8.5%, 6.2%, and 4.7%, respectively.
Serum IGFBP-3 was measured using an IRMA (Diagnostic Systems Laboratories, Inc.). The sensitivity of this assay was 0.5 µg/mL. The intraassay CVs for mean serum concentrations of 1.0, 2.2, and 9.8 µg/mL were 6.1%, 4.1%, and 4.4%, respectively.
Statistical analysis
Leptin, insulin, and IGFBP-1 concentrations were log10 transformed before statistical analysis, and results are presented as the geometric mean (-1, +1 tolerance factor). All other data are presented as the mean ± 1 SD. ANOVA for repeated measures was used to examine changes in variables over time. Relationships between variables were assessed using Pearson’s correlation coefficient and stepwise multiple linear regression. P < 0.05 was considered statistically significant. For multiple pairwise comparisons over time, P < 0.01 was considered statistically significant.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Serum leptin concentrations were significantly elevated in
response to a single bolus injection of GH, from a baseline of 13.3
ng/mL to a peak of 20.3 ng/mL, which occurred within a median time of
24 h (range, 12–48 h). There followed a significant decrease in
leptin concentrations to a nadir of 9.0 ng/mL, at a median time of 1.5
weeks, with the nadir concentration significantly lower than both
baseline and peak concentrations (Fig. 1A
and Table 1). Serum insulin
concentrations showed a similar pattern, with a rapid increase from a
baseline level of 0.4 ng/mL to a peak of 6.4 ng/mL over a median period
of 24 h (range, 12–72). Concentrations then showed a significant
decline to reach a nadir of 0.3 ng/mL at 2 weeks (Fig. 1B and Table 1).
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). However, peak concentrations of IGF-I were
attained at a median time of 24 h, whereas IGFBP-3 concentrations
were maximal at 48 h (Table 1). In contrast, IGF-II and IGFBP-1
concentrations were significantly reduced 18 h after the
administration of GH. IGF-II concentrations recovered to become
significantly greater than both baseline and nadir levels by 72 h,
whereas IGFBP-1 concentrations returned to baseline levels within 2
weeks. IGFBP-2 concentrations were decreased in response to GH, but
nadir concentrations were not significantly lower than baseline levels.
After 2 weeks, IGFBP-2 concentrations were significantly higher than
nadir concentrations (Table 1). There was no association between leptin concentrations at any time point and either insulin or IGF-I concentrations. Similarly, there was no correlation between peak leptin concentrations and any other biochemical parameter. However, when expressed as the percent increase over baseline, there was a positive correlation between the percent change in leptin and the percent change in IGF-I at 48 h (r = 0.65; P < 0.05). The amount of leptin generated over the 2-week period, expressed as the area under the curve (AUC), was positively correlated with baseline body composition (vs. FM: r = 0.89, P < 0.001; vs. LM: r = -0.58; P < 0.05; vs. percent fat: r = 0.95; P < 0.001). The AUC for insulin was inversely correlated with the AUC for IGFBP-1 (r = -0.61; P < 0.05) and the AUC for IGFBP-2 (r = -0.68; P < 0.05). The AUC for IGFBP-3 was positively correlated with the AUC for both IGF-I (r = 0.80) and IGF-II (r = 0.88; both P < 0.01)
Chronic study
Over 9 months of GH treatment there was a significant reduction in
FM and a significant increase in LM, with a corresponding reduction in
the percent body fat (Table 2). The
reduction in FM was significant after 6 months of treatment, with a
mean change in FM of -1.3 ± 1.2 kg, falling further after 9
months to give a mean change of -1.8 ± 1.9 kg (Fig. 2 and Table 2). Similarly, the increase
in LM was significant after 6 months of treatment (mean change,
+2.1 ± 0.9 kg), with no further change over the subsequent 3
months (mean change after 9 months, +2.0 ± 1.4 kg; Fig. 2 and
Table 2). After cessation of GH treatment, there was rapid reversal of
the changes in body composition, with a significant increase in FM and
a decrease in LM (Fig. 2), such that after 12 months, percent body fat,
FM, and LM were not significantly different from baseline values (Table 2).
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and Table 3 illustrate the changes in leptin and
insulin concentrations over the period of GH treatment. Leptin
concentrations after 9 months of GH treatment were not significantly
different from baseline concentrations. However, when GH treatment was
discontinued, there was a significant increase in leptin, with
concentrations at 12 months significantly higher than those at 9 months
(Fig. 3A and Table 3). Leptin concentrations at 12 months were not
significantly different from baseline. In contrast, insulin
concentrations increased gradually with GH treatment, and
concentrations after 9 months were significantly higher than
baseline (Fig. 3B and Table 3). There followed a nonsignificant
decrease in insulin concentrations when GH treatment was stopped.
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). There was a significant decrease in IGF-I
and IGFBP-3 concentrations after cessation of GH treatment. IGF-II
tended to increase during treatment, although this was not
statistically significant. However, there was a significant drop in
IGF-II concentrations at 12 months. IGFBP-1 and IGFBP-2
concentrations were unchanged during GH treatment, and after 3 months
off GH, only IGFBP-2 showed a significant rise.
Stepwise multiple linear regression analysis was used to examine
determinants of leptin concentrations at each time point (Table 4). Log10(leptin) was entered
as the dependent variable, and FM, LM, log10(insulin), and
IGF-I were entered as explanatory variables. At baseline, 3 months, 6
months, and 12 months, FM and LM were the only
significant determinants of leptin concentrations, accounting for
85–95% of the variability in leptin concentrations (Table 4).
Similarly, at 9 months, FM and LM accounted for 86% of
the variability in leptin, but there was an additional positive
influence of insulin, accounting for a further 8% of the
variability (Table 4).
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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GH exerts potent effects on adipose tissue. At the preadipocyte level it stimulates proliferation, whereas in mature adipocytes lipolysis is increased, and lipogenesis is decreased (22). As mature, differentiated adipocytes express GH receptors (22) and are one of the major sites of ob gene expression (1), it has been postulated that GH may have direct effects on leptin production. To examine the acute effect of GH on serum leptin, patients received a single high dose bolus of GH, which induced rapid elevations of leptin, insulin, and IGF-I concentrations in all subjects, peaking at 24 h and declining thereafter to baseline levels by 2 weeks. There was, however, no significant association between the increase in leptin concentrations and the increase in either insulin or IGF-I concentrations. The only relationship that could be discerned was a positive correlation between leptin and IGF-I at 48 h, when expressed as a percentage of baseline levels. However, this occurred at a time when peak leptin and IGF-I levels had already been achieved. A possible influence of the diurnal rhythm on the observed increase in leptin can be ruled out, as all blood samples were drawn in the morning after an overnight fast, the time at which leptin concentrations are lowest (8, 15). In the absence of a correlation between leptin and insulin or IGF-I, these results imply that a direct effect of GH at the level of the adipocyte may be responsible for the acute elevation in leptin.
A similar acute increase in leptin levels has been observed in GH-deficient adults during GH treatment for 5 days (23), as opposed to the single injection used in our study. These researchers suggested that the elevation in leptin was mediated by GH-induced hyperinsulinemia, as an increase in C peptide levels was observed before the increase in leptin (23). Furthermore, in the same study patients receiving a continuous infusion of IGF-I for 5 days, which significantly reduced C peptide levels, showed a significant decrease in leptin concentrations. More recently, administration of GH secretagogues has been shown to elicit an acute rise in leptin concentrations in critically ill patients (24). In these studies the rise in leptin was correlated with the rise in insulin 12 h after treatment, whereas at 48 h leptin was related to the increased levels of IGF-I (24). Although the latter observation is consistent with our finding of a correlation between leptin and IGF-I, we could find no evidence for a direct link between leptin and insulin in our study. Further evidence of a physiological role for insulin in regulating leptin concentrations remains equally inconclusive. In vitro, ob gene expression and leptin secretion from primary cultures of mature human adipocytes can be stimulated by chronic insulin treatment (25, 26). In vivo, leptin concentrations do not change postprandially (27), and short term euglycemic hyperinsulinemic clamp studies have shown both an increase (27) and no change in leptin (26) at insulin concentrations in excess of those encountered in our study. However, long term exposure to increasing degrees of hyperinsulinemia does appear to increase leptin (28, 29). Thus, it remains unclear whether the apparent association between leptin and insulin, in response to GH (23, 24), reflects an underlying causal relationship or is an epiphenomenon, arising from the fact that GH directly influences both over a similar time course. Although we have demonstrated an increase in both leptin and insulin in response to acute administration of GH in GH-deficient subjects, the mechanism underlying these changes remains to be determined.
In contrast to IGF-I, there was a small, but significant, decrease in serum IGF-II concentrations after GH administration, with nadir concentrations occurring between 12–24 h after GH. This reduction in IGF-II appeared to be a transient phenomenon, as there was a significant increase in IGF-II at a median time of 72 h. A similar transient decrease in IGFBP-2 was observed followed by a significant increase in IGFBP-2 compared with baseline levels. Most studies that have examined the acute effect of GH on the IGF axis have observed a gradual increase in IGF-II concentrations (30, 31). Lee et al. (31) found that IGF-II concentrations peaked at about 20 h postinjection in GHD subjects, both before and after 6 months of GH treatment. The transient decrease in IGF-II observed in our study is difficult to explain, but may result from increased clearance of IGF-II from the circulation. Both IGF-I and IGF-II circulate in the 150-kDa ternary complex, which has an estimated half-life of 15–20 h (32). The rapid increase in IGF-I concentrations combined with a slower increase in IGFBP-3 concentrations would be expected to displace IGF-II from the ternary complex. This would lead to an apparent decrease in IGF-II concentrations, which would be reversed when IGFBP-3 concentrations increased. The significant reduction in IGFBP-1 concentrations in all subjects is consistent with the close inverse relationship between insulin and IGFBP-1 (33).
Studies of the effect of chronic GH replacement on serum leptin in GH-deficient subjects are few. In children, a decrease in serum leptin concentrations has been observed after 1 month of GH, which is maintained over 6 months of subsequent treatment (34). In hypopituitary adults, Florkowski et al. reported a reduction in both plasma leptin and total body fat in response to short term, low dose GH replacement (16). A fall in plasma leptin was observed when concentrations were adjusted by baseline percent fat, yet there was no difference in actual leptin concentrations between placebo-treated and GH-treated subjects. Similarly, in a placebo-controlled trial of GH therapy for 1 yr in 27 GHD adults, leptin concentrations were significantly higher in GHD subjects than in normal control subjects at baseline, but were not different after 1 yr of GH (18). However, when GH-treated subjects were compared with those who received placebo, there was no difference in leptin levels despite significant differences in body composition (18). In contrast, Janssen et al. demonstrated a significant decrease in serum leptin after 1 yr of GH treatment, which paralleled the change in body composition (17). GH excess in the form of acromegaly also results in reduced serum leptin concentrations (35). However, the reduction in leptin in these subjects appears to be the result of significantly reduced percent body fat compared with that in normal subjects rather than being a direct consequence of GH excess.
In our study, GH replacement for 9 months generated a significant increase in LM and a significant decrease in FM, as determined by DEXA. These changes in body composition would be expected to generate a net decrease in serum leptin concentrations, yet there was no change over the 9 months of treatment. During this time insulin, IGF-I and IGFBP-3 concentrations exhibited a dose-dependent increase. Using stepwise multiple linear regression analysis, 85% of the variability in serum leptin at baseline was explained by FM and LM, in accordance with our previous study (6). The relative influence of FM and LM on leptin concentrations remained unchanged at each time point thereafter. However, at 9 months we detected an additional positive influence of insulin on leptin concentrations. Thus, the decrease in leptin that might be expected, given the change in body composition, may have been countered by a GH-mediated increase in insulin. In this respect it is noteworthy that a similar association between leptin and insulin has been observed in GHD subjects after long term GH treatment (18).
An alternative explanation for the lack of change in leptin can be expressed in terms of energy balance. It has been proposed that leptin is not just a measure of adiposity, but is also a component of a homeostatic system concerned with the maintenance of usual body weight (1). Alterations in body weight above or below the normal level are associated with changes in leptin that act to return body weight and energy balance to an equilibrium (1). Thus, diet-induced weight loss is accompanied by decreased energy expenditure and a reduction in serum leptin concentrations. However, the fall in leptin exceeds that which would be predicted from the change in body composition and has led to the suggestion that this relative hypoleptinemia may contribute to the tendency of individuals to regain weight after successful dieting (36, 37, 38). Conversely, leptin levels increase during weight gain, but only to a level that is appropriate for the change in body fat (39). These results contrast with the changes in leptin that occur during GH-induced changes in body composition. In a recent study of GH treatment in men with abdominal obesity, body fat was significantly reduced after 6 weeks, accompanied by a decrease in serum leptin and an increase in the basal metabolic rate (40). After 9 months of GH treatment, despite maintaining reduced body fat, serum leptin concentrations and basal metabolic rate had returned to baseline values, indicating an alteration in the steady state energy balance. Applied to our GH-deficient subjects, these findings suggest that the maintenance of leptin concentrations at the same level throughout treatment with GH may be important in sustaining the changes in body composition.
After withdrawal of GH, there was a rapid reversal of the favorable changes in body composition in our GHD subjects, with an increase in FM and a decrease in LM. This change was such that the percent body fat at baseline and that at 12 months were identical. During this time there was a significant increase in leptin concentrations compared with 9 month values. Thus, the beneficial effects of GH, achieved over a total of 9 months of treatment, were completely reversed in just 3 months without GH. In the context of the energy homeostasis model, removal of GH treatment would disturb the energy balance, with a new steady state being achieved at body composition and leptin values similar to those present before treatment. These data indicate that to maintain the favorable changes in body composition that occur during GH treatment, withdrawal of therapy, even for a short time, would not be recommended.
In conclusion, we have characterized the effect of exogenous GH on serum leptin concentrations in GH-deficient elderly subjects over two different time courses. In response to a single high dose bolus of GH, leptin was significantly elevated within 24 h, and this increase did not correlate with any increase in insulin or IGF-I, suggesting a direct effect of GH. In contrast, chronic GH treatment failed to change leptin concentrations despite favorable changes in body composition. There was a minor influence of insulin on leptin concentrations after 9 months of GH treatment, but body composition remained the principal determinant of leptin at all time points. Thus, the chronic effect of GH on leptin is indirect and is mediated via changes in body composition.
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Acknowledgments |
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Footnotes |
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Received August 28, 1998.
Revised November 17, 1998.
Accepted November 30, 1998.
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References |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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, P < 0.01, basal
vs. nadir,
