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The Journal of Clinical Endocrinology & Metabolism Vol. 87, No. 2 540-545
Copyright © 2002 by The Endocrine Society

Endocrine Care

Leptin Concentrations in GH Deficiency: The Effect of GH Insensitivity

Paolo Marzullo, Caroline Buckway, Katherine L. Pratt, Annamaria Colao, Jaime Guevara-Aguirre and Ron G. Rosenfeld

Department of Pediatrics, Oregon Health and Science University (P.M., C.B., K.L.P., R.G.R.), Portland, Oregon 97201; Molecular/Clinical Endocrinology and Oncology, University Federico II (P.M., A.C.), 80131 Naples, Italy; and Instituto de Endocrinologia, Metabolismo y Reproduccion (J.G.A.), Quito, Ecuador

Address all correspondence and requests for reprints to: Paolo Marzullo, M.D., Department of Pediatrics NRC-5, Oregon Health Sciences University, 3181 SW Sam Jackson Park Road, Portland, Oregon 97201. E-mail: marzullo{at}ohsu.edu

Abstract

Disorders of GH secretion are known to impair the physiological lipostat and to affect the secretion of leptin, a sensitive marker of regional fat accumulation and total body composition. In both children and adults with GH deficiency (GHD), leptin levels are increased proportionately with enhanced adiposity. In GHI, mutations of the GH receptor gene result in a phenotype similar to GHD, with increased adiposity and unfavorable lipid profiles. To examine the impact of different forms of growth disorders on leptin production, we measured leptin levels in 22 GHI patients homozygous for the E180 splice mutation (15 females and 7 males, aged 8–37 yr) and compared results with those obtained in 20 subjects heterozygous for the mutation (11 females and 9 males, aged 7–54), 17 idiopathic GHD patients (6 females and 11 males, aged 3–34), and 44 normal subjects (25 females and 19 males, aged 7–45). After the baseline evaluation, all subjects received two 7-d GH treatments at doses of 0.025 and 0.050 mg/kg·d in random order. Leptin, IGF-I, and IGF-binding protein-3 (IGFBP-3) were assayed by specific immunoassays.

IGF-I and IGFBP-3 levels were significantly lower (P < 0.0001) in homozygous GHI and GHD patients compared with either controls or GHI heterozygotes. Circulating leptin levels were significantly higher in homozygous GHI patients than in normal controls (20.7 ± 4.2 vs. 8.7 ± 1.4 µg/liter) as well as when compared with heterozygous GHI subjects (14.4 ± 3.4 µg/liter) and GHD patients (9.8 ± 1.6 µg/liter; P < 0.01). Similar results were obtained when leptin was normalized for body mass index. When subjects were subgrouped by gender, leptin levels were significantly higher (P < 0.05) in GHI females than in females of all other groups and were significantly increased in GHD males (P < 0.01 vs. control males). Within the study groups, females had significantly higher leptin levels than males in controls (12.7 ± 2 vs. 3.3 ± 1 µg/liter; P < 0.001) and homozygous GHI patients (28.7 ± 5.3 vs. 6.9 ± 2.3 µg/liter; P < 0.05), but not in heterozygous GHI (20.1 ± 5.4 vs. 7.3 ± 2.4 µg/liter; P < 0.06) and GHD (10.9 ± 2.6 vs. 9.2 ± 2.1 µg/liter) patients. By multivariate analysis, log-normalized leptin levels were best predicted by gender and body mass index in homozygous GHI patients as well as in normal subjects. During the 1-wk courses of GH therapy, serum IGF-I and IGFBP-3 levels significantly increased (P < 0.0001) in GHD patients, heterozygous GHI patients, and control subjects at both GH doses. Inversely, leptin levels did not change significantly during either course of GH administration in the groups examined.

These data demonstrate that leptin is increased in patients affected with long-standing homozygous GHI, probably reflecting abnormalities of body composition and metabolism typical of this condition.

GH PLAYS A critical role in the regulation of body composition and energy balance. Both children and adults with GH deficiency (GHD) suffer from increased fat and decreased lean body mass, osteopenia, abnormalities of glucose and lipid homeostasis, and increased cardiovascular disorders (1, 2). The close relationship existing between GH status and adiposity is supported additionally by the evidence that GH secretion is decreased in obese individuals, whereas the rate of GH secretory bursts is apparently unaltered (3, 4).

A wide number of studies have shown that the secretion of leptin, the product of the ob gene (5), constitutes a signaling peptide in the neuronal control of body fatness (6) and is a good indicator of fat accumulation and lean body mass in both animals and humans (7, 8, 9). Serum leptin levels progressively increase with fat accumulation and vary according to gender, being higher in females than in males, and reflecting substantial differences in fat accumulation/distribution, body composition, and gonadal steroid secretion (10, 11, 12, 13, 14, 15, 16). Although an inverse relationship exists between circulating leptin and GH concentrations, no direct evidence has been provided of a role for leptin in inhibiting GH secretion (14). Leptin levels may change, however, under certain endocrine conditions. In GHD, for example, the loss of lipolytic activity exerted normally by GH alters body composition and induces an increase in leptin levels (1, 2, 17, 18, 19, 20).

GH insensitivity (GHI) results in a phenotype similar to GHD and represents a unique metabolic model for understanding whether genetic resistance to GH may influence leptin secretion significantly more than in other causes of the GHD phenotype. Mutations of the GH receptor (GHR) gene, diagnosed in Ecuador kindred homozygous for an E180 splice mutation (21, 22, 23), are associated with statural and skeletal abnormalities, higher than expected postpubertal body weight, and an unfavorable lipid profile in adulthood (24, 25, 26, 27).

In this study we compared the circulating leptin levels measured in Ecuadorian individuals diagnosed with GHI or GHD with those obtained in a normal Ecuadorian population.

Subjects and Methods

Patients

Subjects enrolled in this study were selected cross-sectionally from Ecuador populations previously studied (21, 28, 29, 30). An effort was made to match age ranges and gender distribution among the subject groups. Of 198 subjects genotyped for the E180 splice mutation, 103 were selected and grouped as follows: 22 homozygous (15 females and 7 males; age range, 8–37 yr) and 20 heterozygous GHI subjects (11 females and 9 males; age range, 7–54 yr), 17 GHD patients (6 females and 11 males; age range, 3–34 yr), and 44 healthy subjects (25 females and 19 males; age range, 7–45 yr). All females had normal karyotypes. Diagnosis of homozygous GHI was based on phenotypical features, including a height at least 2 SD below the normal age-related values for the United States population, baseline serum GH concentrations above 10 µg/liter, serum IGF-I and IGF-binding protein-3 (IGFBP-3) concentrations more than 2 SD below age-matched control levels, and homozygosity for the E180 mutation of the GHR gene (22). The condition of heterozygosity for this mutation was confirmed by genotyping in relatives showing normal serum concentrations of GH, IGF-I, and IGFBP-3 for age and absence of statural and skeletal retardation/abnormalities (29). The diagnosis of GHD was based on multiple criteria, i.e. height greater than 2 SD below the mean for age, GH response below 10 µg/liter to insulin-induced hypoglycemia, and IGF-I concentrations greater than 2 SD below the age- and sex-matched normal mean. GHD was idiopathic in all but 1 patient suffering from craniopharyngioma. All GHD and control subjects were shown to be homozygous for the normal GHR allele.

Study design and clinical evaluation

The research protocol was approved by the ethics committee of the Institute of Endocrinology, Metabolism, and Reproduction (Quito, Ecuador). All parents of minors signed Spanish translations of the approved consent forms. Standing height was determined as the mean of three consecutive measurements obtained with a Harpenden stadiometer, and weight was determined after an overnight fast, after subjects had voided. Body mass index (BMI) was defined as weight in kilograms divided by the square of height in centimeters. To assess the effects of sexual development on leptin measurement, subjects in each groups were subdivided by Tanner stages; because of the modest number of subjects of each gender in each category, subjects were grouped as Tanner stage 1–4 or adult.

After a baseline evaluation, all subjects underwent two sequential 7-d treatments with recombinant human GH (Genentech, Inc., South San Francisco, CA), separated by a 2-wk washout period. Recombinant human GH was given as courses of either 0.025 (low dose test) or 0.050 (high dose test) mg/kg·d in random order, and then, after the washout period, the alternative dosage of GH was administered. Fasting blood samples were drawn under basal conditions and after 4 d (d 5) and 7 d (d 8). After centrifugation, serum samples were kept frozen at -80 C until assay.

Hormone assays

All measurements were performed using commercially available kits (Diagnostics Systems Laboratories, Inc., Webster, TX). IGF-I, IGFBP-3, and leptin levels were measured with noncompetitive sandwich-type assays. A total IGF-I immunoradiometric assay was performed after extraction. The assay sensitivity was 0.8 µg/liter, and intra- and interassay coefficients of variation (CVs) were 1.5–3.4% and 1.5–8.2%, respectively. The IGFBP-3 immunoradiometric assay had a sensitivity of 0.5 µg/liter; the intra- and interassay CVs were 1.8–3.9% and 0.5–1.6%, respectively. Leptin was measured by ELISA and had a sensitivity of 0.05 µg/liter; the intra- and interassay CVs were 1.5–6.2% and 3.3–5.3%, respectively.

Data analysis

Results are presented as the mean ± SEM. Two-tailed unpaired t test and repeated measures ANOVA, followed by Newman-Keuls posttest, were used for comparison among groups. The effects of gender, age, and Tanner stages on serum leptin levels were analyzed by two-way ANOVA. When appropriate, leptin was log-transformed to correct unskewed distribution or expressed as the SD score over the gender-related mean. During GH administration, variations over time were examined with ANOVA for repeated measures and paired t test of areas under the curve (AUCs). Relationships between variables were analyzed using Pearson’s correlation coefficient and multiple linear regression analysis. Significance was set at P < 0.05. Analyses were performed using SPSS 10.0 (SPSS, Inc., Chicago, IL) and PRISM (GraphPad Software, Inc., San Diego, CA).

Results

IGF-I and IGFBP-3 concentrations

Anthropometric and endocrine characteristics are presented in Table 1Go. Ages were not significantly different among the GHI, GHD, and normal subject groups, whereas GHI heterozygotes were slightly, but significantly, older. The female to male ratio was similar in normal subjects and heterozygous GHI patients; females predominated in the homozygous GHI patients, while males predominated in the GHD group. The mean BMI in the normal control, GHI, and GHD groups were 20.4, 21.0, and 21.1 kg/m2, respectively, and were modestly higher in the GHI heterozygotes (23 kg/m2; P < 0.05 compared with controls). In control subjects, IGF-I and IGBFP-3 concentrations were inversely correlated with age (r = -0.48 and r = -0.57, respectively; P < 0.001 in both cases) and BMI values (r = -0.30 and r = -0.37, respectively; P < 0.05 in both cases). Conversely, in homozygous GHI patients both IGF-I (r = 0.52; P < 0.05) and IGFBP-3 (r = 0.57; P < 0.01) levels increased directly with BMI values. IGF-I and IGFBP-3 were positively correlated to each other in all groups (data not shown). As expected, IGF-I and IGFBP-3 levels were significantly lower in homozygous GHI and GHD patients when compared with either the control population or heterozygous GHI subjects (P < 0.0001 in both cases). No gender-related difference in IGF-I and IGFBP-3 levels existed in any of the groups tested.


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  		Table 1. Anthropometric and hormonal characteristics (mean ± SEM) of the study groups

 
Leptin concentrations

A great variability in leptin concentrations was observed in normal controls (range, 0.6–41 µg/liter), GHD patients (range, 1.6–24.2 µg/liter), GHI homozygotes (range, 1.5–66.4 µg/liter), and heterozygotes (range, 1–64.5 µg/liter). Despite the considerable overlap, mean circulating leptin levels were significantly higher (P < 0.01) in homozygous GHI patients than in all other groups studied when expressed as absolute concentrations or when normalized to individual BMI values, an indirect measure of body fat (Table 1Go and Fig. 1Go). When gender was introduced into the analysis, leptin levels showed a wide separation between adolescent and adult subjects, which was particularly pronounced in females (Table 2Go). In a gender-based comparison among groups, leptin levels were significantly increased in GHI females (P < 0.05), but not in males, compared with the other groups; a significant increase was also observed in GHD males (P < 0.01 vs. control males; Fig. 2Go). When expressed as the SD score, leptin levels were above +2 SD in eight homozygous GHI patients (36%; five females and three males), four heterozygous GHI subjects (20%; two females and two males), and four GHD males (23%).



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  		Figure 1. Individual leptin values in control subjects, GHD patients, homozygous GHI patients, and heterozygous GHI subjects at baseline.

 

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  		Table 2. Leptin levels (mean ± SEM) in groups divided by gender and subgrouped by sexual development

 


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  		Figure 2. Mean gender-related leptin concentrations in control subjects, homozygous GHI patients, heterozygous GHI subjects, and GHD patients, at baseline. *, P < 0.05 vs. remaining groups (by repeated measures ANOVA).

 
The relationship between leptin and BMI values reached statistical significance only in females of all groups (controls: r = 0.46; P < 0.05; homozygous GHI: r = 0.70; P < 0.004; heterozygous GHI: r = 0.704; P < 0.05; GHD: r = 0.896; P < 0.05). As expected, females showed significantly higher leptin levels than males in the group of normal subjects (12.7 ± 2 vs. 3.3 ± 1 µg/liter; P < 0.001), homozygous GHI (28.7 ± 5.3 vs. 6.9 ± 2.3 µg/liter; P < 0.05) and heterozygous GHI (20.1 ± 5.4 vs. 7.3 ± 2.4 µg/liter; P < 0.06), but not in the group of GHD patients (10.9 ± 2.6 vs. 9.2 ± 2.1 µg/liter; Fig. 2Go). Similar results were obtained by comparing leptin levels as a function of BMI values.

No significant relationship between leptin and IGF-I or IGFBP-3 was observed in any study group, except for homozygous GHI patients (IGF-I, r = 0.43; IGFBP-3, r = 0.48; P < 0.05 in both cases). By multivariate analysis, log- normalized leptin levels were best predicted by gender and BMI in GHI patients and normal subjects, whereas the other covariates included in the regression equation did not significantly affect leptin variability (Table 3Go).


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  		Table 3. Multiple regression analysis of the anthropometric and hormonal parameters influencing log normalized leptin levels in the study groups

 
GH administration

As previously reported (30), both low and high dose courses of GH administration induced a significant increase in IGF-I and IGFBP-3 levels (P < 0.0001) in GHD patients, heterozygous GHI patients, and control subjects (data not shown). In contrast, GH administration had no effect on leptin levels at either GH dosage, and there was no correlation between basal leptin concentrations and either IGF-I or IGFBP-3 response to GH treatments. A slightly positive correlation was otherwise noted between basal leptin levels and IGFBP-3 AUCs under high GH dose in controls (r = 0.31; P < 0.05) and GHD patients (r = 0.52; P < 0.05).

Discussion

GHI due to genetic mutations of the GHR is associated with changes in body composition, bone mineral density, muscular development, and glucose metabolism (25). Adult patients with homozygous GHI may develop an unfavorable lipid profile, characterized by an increase in total and low density lipoprotein cholesterol (26). Conversely, siblings or relatives of GHI patients, including heterozygous carriers of the GHR mutation, are reportedly phenotypically normal (29). The results of this study support the existing evidence of a relationship between GHI and metabolic disorders. We observed that leptin levels were increased in homozygous GHI, significantly more than in GHD and heterozygous GHI, compared with the healthy population. This result was most prominent in adult females, and remained unaltered when leptin levels were corrected for BMI values. As expected, short-term GH administration significantly increased IGF-I and IGFBP-3 generation in all GH-responsive groups, but did not affect leptin production.

Leptin constitutes a natural signal for the hypothalamus to regulate appetite and fuel homeostasis and is emerging as a sensitive marker of regional fat accumulation as well as total body composition (5, 6). Subcutaneous fat depots are major production sites for leptin (9, 13), which is well predicted by total or percent body fat (31, 32, 33). Given the evidence that leptin is negatively regulated by androgens and positively correlated with estrogens (9, 13, 34), both adiposity and gender have been indicated as main determinants of leptin secretion. The observed sexual dimorphism can be detected at the neonatal stage (35, 36), but it becomes more evident at puberty (10, 11, 12) and is enhanced in adulthood; at this stage, women may have 2- to 3-fold higher leptin levels and a greater amplitude of leptin pulses than men (37, 38, 39).

GH plays a pivotal role in the regulation of body composition and energy balance, and both children and adults with GHD present with increased adiposity and decreased lean mass. Thus, the increase in leptin concentrations in GHD patients appears to be due to fat accumulation and reduced lean body mass, whereas the opposite occurs in acromegaly (40, 41). Previous studies have also indicated that leptin levels are significantly higher in females than in males with GHD (17, 19, 20, 40, 41, 42, 43).

In this cross-sectional study we analyzed patients with mutations of the GHR to investigate the occurrence of metabolic abnormalities involving leptin synthesis in this disorder. GHI is characterized by the coexistence of normal to abnormally elevated GH levels with a clinical phenotype of GHD. Typically, patients with homozygous GHI have increased fat mass and percent body fat compared with the normal, age-matched population. As in the normal population, this occurrence is enhanced in women with GHI (26, 44). In a previous investigation by Laron et al. (45), leptin concentrations were reported to be substantially similar between nonobese GHI patients and normal subjects; leptin levels were significantly elevated only in three patients with BMI values above 30. In our study great variability in individual leptin concentrations was seen across all groups examined. Mean leptin levels in homozygous GHI patients were found, however, to be more than doubled compared with those in the age-, sex-, and BMI-matched healthy population. The unexpected finding that leptin in GHI homozygotes was also significantly higher than that in GHD patients may be due to differences in disease duration or in GH signaling between the two populations, but a significant effect may also be produced by the entity and chronicity of fat accumulation in GHI subjects. Due to the retrospective nature of this investigation, fat accumulation could only be estimated by calculation of the patients’ BMI values, which provide an indirect measure of the degree of adiposity. At variance with other results (45), however, leptin levels were significantly elevated, i.e. above +2 SD of the normal mean, in eight homozygous GHI patients, seven of whom had BMI values below 25.

A potential limitation of our study is the lack of data on glucose homeostasis, as both circulating insulin and glucose may have a stimulatory effect on leptin secretion. Leptin concentrations dose-dependently increase during euglycemic hyperinsulinemic clamp experiments and are attenuated during hypoglycemic clamps (16, 46, 47). Competitive inhibition of glucose transport has been shown similarly capable of decreasing leptin secretion and mRNA content in cultured rat adipocytes (48). Of note, approximately 45% of young GHI patients experience hypoglycemic events (49), and hyperinsulinism has been reported to be a consequence of GHI in probands from Israel (27). Based on our observations, we cannot exclude that leptin secretion in GHI patients reflected abnormalities in glucose homeostasis, but only longitudinal future studies encompassing IGF-I treatment of GHI patients will provide further proof of this hypothesis. It is interesting to note that although IGF-I and IGFBP-3 were inversely correlated with BMI in normal controls, they were positively correlated in homozygous GHI subjects. As the effect of BMI on GH secretion is irrelevant in the GHI state, we speculate that obesity, perhaps through hyperinsulinemia, might have a direct effect on IGF-I and IGFBP-3 production in GHI subjects, thereby escaping the influence of obesity on GH levels.

To examine the effect of short-term GH administration on leptin production, all subjects received consecutive courses of GH treatments at doses of 0.025 and 0.050 mg/kg·d (30). As expected, IGF-I and IGFBP-3 concentrations promptly increased in all GH-sensitive populations under GH stimulation, whereas no significant change in leptin levels occurred with either low or high dose GH. Starting leptin levels did not appear to predict the increases in IGF-I and IGFBP-3 during low and high dose GH treatments, although a slight, but significant, relationship between basal leptin concentrations and IGFBP-3 AUCs was observed during the high dose GH course in control and GHD subjects. To date, few reports have studied the effects of short-term GH treatment on leptin generation. Acute administration of 0.1 mg/kg GH in GHD adults was reported to increase leptin secretion 12–24 h postadministration (20). Similarly, leptin levels were acutely increased in GHD adults during GH treatment for 5 d as well as in critically ill patients (50, 51). Conversely, leptin secretion appears to be reportedly suppressed in GHD children during 1-month GH treatment (19) as well as in GHD adults treated with GH (43, 52).

In conclusion, we have found that leptin is increased in GHI women and, to a lesser extent, in GHI and GHD men. Increased body fat and impaired glucose homeostasis might account for the rise in leptin levels observed in this category of patients, but additional studies are necessary to further define the mechanism(s) involved.

Acknowledgments

We thank Diagnostics Systems Laboratories, Inc., for generously providing all immunoassays used in this study. This focused report necessarily omits many primary references because of editorial constraints. We, therefore, acknowledge numerous researchers who have reported earlier foundational observations.

Footnotes

This work was supported in part by NIH Grant CA-58110 (to R.G.R.) and an unrestricted grant from Genentech, Inc.

Abbreviations: AUC, Area under the curve; BMI, body mass index; CV, coefficient of variation; GHD, GH deficiency; GHI, GH insensitivity; GHR, GH receptor; IGFBP, IGF-binding protein.

Received July 9, 2001.

Accepted October 31, 2001.

References

  1. de Boer H, Blok GJ, Van der Veen EA 1995 Clinical aspects of growth hormone deficiency in adults. Endocr Rev 16:63–86[CrossRef][Medline]
  2. Carroll PV, Christ ER, Bengtsson BA, Carlsson L, Christiansen JS, Clemmons D, Hintz R, Ho K, Laron Z, Sizonenko P, Sonksen PH, Tanaka T, Thorner M 1998 Growth hormone deficiency in adulthood and the effects of growth hormone replacement: a review. Growth Hormone Research Society Scientific Committee. J Clin Endocrinol Metab 83:382–395[Abstract/Free Full Text]
  3. Veldhuis JD, Iranmanesh A, Ho KK, Waters MJ, Johnson ML, Lizarralde G 1991 Dual defects in pulsatile growth hormone secretion and clearance subserve the hyposomatotropism of obesity in man. J Clin Endocrinol Metab 72:51–59[Abstract]
  4. Iranmanesh A, Lizarralde G, Veldhuis JD 1991 Age and relative adiposity are specific negative determinants of the frequency and amplitude of growth hormone (GH) secretory bursts and the half-life of endogenous GH in healthy men. J Clin Endocrinol Metab 73:1081–1088[Abstract]
  5. Zhang Y, Proenca R, Maffei M, Barone M, Leopold L, Friedman JM 1994 Positional cloning of the mouse obese gene and its human homologue. Nature 372:425–432[CrossRef][Medline]
  6. Yu WH, Kimura M, Walczewska A, Karanth S, McCann SM 1997 Role of leptin in hypothalamic-pituitary function. Proc Natl Acad Sci USA 94:1023–1028[Abstract/Free Full Text]
  7. Pelleymounter MA, Cullen MJ, Baker MB, Hecht R, Winters D, Boone T, Collins F 1995 Effects of the obese gene product on body weight regulation in ob/ob mice. Science 269:540–543[Abstract/Free Full Text]
  8. Halaas JL, Gajiwala KS, Maffei M, Cohen SL, Chait BT, Rabinowitz D, Lallone RL, Burley SK, Friedman JM 1995 Weight-reducing effects of the plasma protein encoded by the obese gene. Science 269:543–546[Abstract/Free Full Text]
  9. Montague CT, Prins JB, Sanders L, Digby JE, O’Rahilly S 1997 Depot- and sex-specific differences in human leptin mRNA expression: implications for the control of regional fat distribution. Diabetes 46:342–347[Abstract]
  10. Rosenbaum M, Nicolson M, Hirsch J, Heymsfield SB, Gallagher D, Chu F, Leibel RL 1996 Effects of gender, body composition, and menopause on plasma concentrations of leptin. J Clin Endocrinol Metab 81:3424–3427[Abstract]
  11. Blum WF, Englaro P, Hanitsch S, Juul A, Hertel NT, Muller J, Skakkebaek NE, Heiman ML, Birkett M, Attanasio AM, Kiess W, Rascher W 1997 Plasma leptin levels in healthy children and adolescents: dependence on body mass index, body fat mass, gender, pubertal stage, and testosterone. J Clin Endocrinol Metab 82:2904–2910[Abstract/Free Full Text]
  12. Garcia-Mayor RV, Andrade MA, Rios M, Lage M, Dieguez C, Casanueva FF 1997 Serum leptin levels in normal children: relationship to age, gender, body mass index, pituitary-gonadal hormones, and pubertal stage. J Clin Endocrinol Metab 82:2849–2855[Abstract/Free Full Text]
  13. Nagy TR, Gower BA, Trowbridge CA, Dezenberg C, Shewchuk RM, Goran MI 1997 Effects of gender, ethnicity, body composition, and fat distribution on serum leptin concentrations in children. J Clin Endocrinol Metab 82:2148–2152[Abstract/Free Full Text]
  14. Casanueva FF, Dieguez C 1999 Neuroendocrine regulation and actions of leptin. Front Neuroendocrinol 20:317–363[CrossRef][Medline]
  15. Horlick MB, Rosenbaum M, Nicolson M, Levine LS, Fedun B, Wang J, Pierson Jr RN, Leibel RL 2000 Effect of puberty on the relationship between circulating leptin and body composition. J Clin Endocrinol Metab 85:2509–2518[Abstract/Free Full Text]
  16. Wellhoener P, Fruehwald-Schultes B, Kern W, Dantz D, Kerner W, Born J, Fehm HL, Peters A 2000 Glucose metabolism rather than insulin is a main determinant of leptin secretion in humans. J Clin Endocrinol Metab 85:1267–1271[Abstract/Free Full Text]
  17. al-Shoumer KA, Anyaoku V, Richmond W, Johnston DG 1997 Elevated leptin concentrations in growth hormone-deficient hypopituitary adults. Clin Endocrinol (Oxf) 47:169–171[CrossRef][Medline]
  18. Fisker S, Vahl N, Hansen TB, Jorgensen JO, Hagen C, Orskov H, Christiansen JS 1997 Serum leptin is increased in growth hormone-deficient adults: relationship to body composition and effects of placebo-controlled growth hormone therapy for 1 year. Metabolism 46:812–817[CrossRef][Medline]
  19. Rauch F, Westermann F, Englaro P, Blum WF, Schonau E 1998 Serum leptin is suppressed by growth hormone therapy in growth hormone-deficient children. Horm Res 50:18–21[CrossRef][Medline]
  20. Gill MS, Toogood AA, Jones J, Clayton PE, Shalet SM 1999 Serum leptin response to the acute and chronic administration of growth hormone (GH) to elderly subjects with GH deficiency. J Clin Endocrinol Metab 84:1288–1295[Abstract/Free Full Text]
  21. Rosenbloom AL, Guevara Aguirre J, Rosenfeld RG, Fielder PJ 1990 The little women of Loja-growth hormone-receptor deficiency in an inbred population of southern Ecuador. N Engl J Med 323:1367–1374[Abstract]
  22. Berg MA, Guevara-Aguirre J, Rosenbloom AL, Rosenfeld RG, Francke U 1992 Mutation creating a new splice site in the growth hormone receptor genes of 37 Ecuadorean patients with Laron syndrome. Hum Mutat 1:24–32[CrossRef][Medline]
  23. Lopez-Bermejo A, Buckway CK, Rosenfeld RG 2000 Genetic defects of the growth hormone-insulin-like growth factor axis. Trends Endocrinol Metab 11:39–49[CrossRef][Medline]
  24. Laron Z, Klinger B 1993 Body fat in Laron syndrome patients: effect of insulin-like growth factor I treatment. Horm Res 40:16–22[Medline]
  25. Rosenfeld RG, Rosenbloom AL, Guevara-Aguirre J 1994 Growth hormone (GH) insensitivity due to primary GH receptor deficiency. Endocr Rev 15:369–390[Abstract]
  26. Rosenbloom AL, Guevara-Aguirre J, Rosenfeld RG, Francke U 1999 Growth hormone receptor deficiency in Ecuador. J Clin Endocrinol Metab 84:4436–4443[Free Full Text]
  27. Laron Z 1999 The essential role of IGF-I: lessons from the long-term study and treatment of children and adults with Laron syndrome. J Clin Endocrinol Metab 84:4397–4404[Abstract/Free Full Text]
  28. Guevara-Aguirre J, Rosenbloom AL, Fielder PJ, Diamond Jr FB, Rosenfeld RG 1993 Growth hormone receptor deficiency in Ecuador: clinical and biochemical phenotype in two populations. J Clin Endocrinol Metab 76:417–423[Abstract]
  29. Rosenbloom AL, Guevara-Aguirre J, Berg MA, Francke U 1998 Stature in Ecuadorians heterozygous for growth hormone receptor gene E180 splice mutation does not differ from that of homozygous normal relatives. J Clin Endocrinol Metab 83:2373–2375[Abstract/Free Full Text]
  30. Buckway C, Guevara-Aguirre J, Pratt KL, Burren CP, Rosenfeld RG 2001 The insulin-like growth factor-I generation test revisited: a marker of growth hormone sensitivity. J Clin Endocrinol Metab 86:5176–5183[Abstract/Free Full Text]
  31. Maffei M, Halaas J, Ravussin E, Pratley RE, Lee GH, Zhang Y, Fei H, Kim S, Lallone R, Ranganathan S, Kern PA, Friedman JM 1995 Leptin levels in human and rodent: measurement of plasma leptin and ob RNA in obese and weight-reduced subjects. Nat Med 1:1155–1161[CrossRef][Medline]
  32. Considine RV, Sinha MK, Heiman ML, Kriauciunas A, Stephens TW, Nyce MR, Ohannesian JP, Marco CC, McKee LJ, Bauer TL, Caro JF 1996 Serum immunoreactive-leptin concentrations in normal-weight and obese humans. N Engl J Med 334:292–295[Abstract/Free Full Text]
  33. Fors H, Matsuoka H, Bosaeus I, Rosberg S, Wikland KA, Bjarnason R 1999 Serum leptin levels correlate with growth hormone secretion and body fat in children. J Clin Endocrinol Metab 84:3586–3590[Abstract/Free Full Text]
  34. Behre HM, Simoni M, Nieschlag E 1997 Strong association between serum levels of leptin and testosterone in men. Clin Endocrinol (Oxf) 47:237–240[CrossRef][Medline]
  35. Matsuda J, Yokota I, Iida M, Murakami T, Naito E, Ito M, Shima K, Kuroda Y 1997 Serum leptin concentration in cord blood: relationship to birth weight and gender. J Clin Endocrinol Metab 82:1642–1644[Abstract/Free Full Text]
  36. Ertl T, Funke S, Sarkany I, Szabo I, Rascher W, Blum WF, Sulyok E 1999 Postnatal changes of leptin levels in full-term and preterm neonates: their relation to intrauterine growth, gender and testosterone. Biol Neonate 75: 167–176
  37. Rosenbaum M, Nicolson M, Hirsch J, Murphy E, Chu F, Leibel RL 1997 Effects of weight change on plasma leptin concentrations and energy expenditure. J Clin Endocrinol Metab 82:3647–3654[Abstract/Free Full Text]
  38. Licinio J, Negrao AB, Mantzoros C, Kaklamani V, Wong ML, Bongiorno PB, Negro PP, Mulla A, Veldhuis JD, Cearnal L, Flier JS, Gold PW 1998 Sex differences in circulating human leptin pulse amplitude: clinical implications. J Clin Endocrinol Metab 83:4140–4147[Abstract/Free Full Text]
  39. Heptulla R, Smitten A, Teague B, Tamborlane WV, Ma YZ, Caprio S 2001 Temporal patterns of circulating leptin levels in lean and obese adolescents: relationships to insulin, growth hormone, and free fatty acids rhythmicity. J Clin Endocrinol Metab 86:90–96[Abstract/Free Full Text]
  40. Miyakawa M, Tsushima T, Murakami H, Isozaki O, Demura H, Tanaka T 1998 Effect of growth hormone (GH) on serum concentrations of leptin: study in patients with acromegaly and GH deficiency. J Clin Endocrinol Metab 83:3476–3479[Abstract/Free Full Text]
  41. Damjanovic SS, Petakov MS, Raicevic S, Micic D, Marinkovic J, Dieguez C, Casanueva FF, Popovic V 2000 Serum leptin levels in patients with acromegaly before and after correction of hypersomatotropism by trans-sphenoidal surgery. J Clin Endocrinol Metab 85:147–154[Abstract/Free Full Text]
  42. Wabitsch M, Hauner H, Heinze E, Teller WM 1995 The role of growth hormone/insulin-like growth factors in adipocyte differentiation. Metabolism 44:45–49[CrossRef][Medline]
  43. Kristensen K, Pedersen SB, Fisker S, Norrelund H, Rosenfalck AM, Jorgensen JO, Richelsen B 1998 Serum leptin levels and leptin expression in growth hormone (GH)-deficient and healthy adults: influence of GH treatment, gender, and fasting. Metabolism 47:1514–1519[CrossRef][Medline]
  44. Bachrach LK, Marcus R, Ott SM, Rosenbloom AL, Vasconez O, Martinez V, Martinez AL, Rosenfeld RG, Guevara-Aguirre J 1998 Bone mineral, histomorphometry, and body composition in adults with growth hormone receptor deficiency. J Bone Miner Res 13:415–421[CrossRef][Medline]
  45. Laron Z, Silbergeld A, Lilos P, Blum FW 1998 Serum leptin in obese patients with Laron syndrome before and during IGF-I treatment. J Pediatr Endocrinol Metab 11:653–656[Medline]
  46. Boden G, Chen X, Kolaczynski JW, Polansky M 1997 Effects of prolonged hyperinsulinemia on serum leptin in normal human subjects. J Clin Invest 100:1107–1113[Medline]
  47. Saad MF, Khan A, Sharma A, Michael R, Riad-Gabriel MG, Boyadjian R, Jinagouda SD, Steil GM, Kamdar V 1998 Physiological insulinemia acutely modulates plasma leptin. Diabetes 47:544–549[Abstract]
  48. Mueller WM, Gregoire FM, Stanhope KL, Mobbs CV, Mizuno TM, Warden CH, Stern JS, Havel PJ 1998 Evidence that glucose metabolism regulates leptin secretion from cultured rat adipocytes. Endocrinology 139:551–558[Abstract/Free Full Text]
  49. Rosenbloom AL, Savage MO, Blum WF, Guevara-Aguirre J, Rosenfeld RG 1992 Clinical and biochemical characteristics of growth hormone receptor deficiency (Laron syndrome). Acta. Paediatr 383(Suppl):121–124
  50. Bianda TL, Glatz Y, Boeni-Schnetzler M, Froesch ER, Schmid C 1997 Effects of growth hormone (GH) and insulin-like growth factor-I on serum leptin in GH-deficient adults. Diabetologia 40:363–364[Medline]
  51. Van den Berghe G, Wouters P, Carlsson L, Baxter RC, Bouillon R, Bowers CY 1998 Leptin levels in protracted critical illness: effects of growth hormone-secretagogues and thyrotropin-releasing hormone. J Clin Endocrinol Metab 83:3062–3070[Abstract/Free Full Text]
  52. Ahmad AM, Guzder R, Wallac AM, Thomas J, Fraser WD, Vora JP 2001 Circadian and ultradian rhythm and leptin pulsatility in adult GH deficiency: effects of GH replacement. J Clin Endocrinol Metab 86:3499–3506[Abstract/Free Full Text]



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