help button home button Endocrine Society JCEM
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Submit a related Letter to the Editor
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Copyright Permission
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Palmert, M. R.
Right arrow Articles by Boepple, P. A.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Palmert, M. R.
Right arrow Articles by Boepple, P. A.
The Journal of Clinical Endocrinology & Metabolism Vol. 83, No. 4 1091-1096
Copyright © 1998 by The Endocrine Society

From the Clinical Research Centers

The Impact of Reversible Gonadal Sex Steroid Suppression on Serum Leptin Concentrations in Children with Central Precocious Puberty1

Mark R. Palmert, Sally Radovick and Paul A. Boepple

Division of Endocrinology, Department of Medicine, Children’s Hospital (M.R.P., S.R.), Boston, Massachusetts 02115; Clinical Investigator Training Program, Beth Israel Deaconess Medical Center, Harvard/Massachusetts Institute of Technology Health Sciences and Technology (in collaboration with Pfizer, Inc.) (M.R.P.), Boston, Massachusetts 02115; Pediatric and Reproductive Endocrine Units, Massachusetts General Hospital (P.A.B.), Boston, Massachusetts 02114

Address all correspondence and requests for reprints to: Paul A. Boepple, M.D., Reproductive Endocrine Unit, Bartlett Hall Extension 5, Massachusetts General Hospital, Fruit Street, Boston, Massachusetts 02114.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Serum leptin concentrations increase during childhood in both sexes. During sexual maturation, levels rise further in girls, but decrease in boys. These data suggest that testosterone either directly suppresses leptin levels or induces changes in body composition that result in lower leptin concentrations.

To examine further the relationship between sex steroids and leptin, we performed a longitudinal study in children with central precocious puberty (28 girls and 12 boys) before, during, and after discontinuation of GnRH agonist-induced pituitary-gonadal suppression. Nighttime and daytime leptin levels were measured to determine whether the activity of the pituitary-gonadal axis affects their diurnal variation.

In the boys, suppression of testosterone increased leptin levels, whereas resumption of puberty was associated with decreased leptin levels [3.5 ± 0.8 vs. 9.5 ± 3.1 ng/dL (P = 0.005) and 12.2 ± 4.5 vs. 7.0 ± 2.6 ng/dL (P = 0.012), respectively]. Serum leptin levels did not change in the girls with alteration of the pituitary-ovarian axis and consistently exceeded those in boys. Nighttime levels were consistently greater than daytime values by an average of 38.3% in the girls and 29.4% in the boys.

These serial observations during reversible pituitary-gonadal suppression suggest that testosterone decreases leptin concentrations, but that estrogen, at least in this childhood model, has no discernible effect. In addition, our data indicate that the presence of the diurnal rhythm in leptin concentrations is independent of the state of the reproductive axis.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
SINCE THE recent discovery of leptin, the product of the ob gene (1), a rapidly growing body of research has begun to elucidate the role of leptin and its receptor in the regulation of body composition (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13). Homozygous defects in the ob gene, as in the ob/ob mouse, result in genetic obesity and infertility, characterized by persistent immaturity of the hypothalamic-pituitary axis (14, 15, 16), both of which are corrected by exogenous leptin administration (15, 16). In addition, administration of leptin to normal female mice either accelerates (17, 18) or acts as a permissive factor in (19) the onset of puberty. Taken together, these findings indicate that leptin plays a vital role in the control of reproductive function in rodent models. Data from a longitudinal study of boys progressing through normal puberty suggest that leptin may also play a role in controlling reproductive function in humans (20, 21).

The corollary is that the reproductive endocrine axis may regulate leptin levels. A putative role for gonadal steroids in the modulation of leptin levels is supported by cross-sectional data in both children and adults (22, 23, 24, 25, 26, 27, 28, 29). Women have greater leptin concentrations than men (22, 23), and girls have greater concentrations than boys (24, 25, 26, 27, 28, 29). These sex differences persist after having corrected for body mass index (BMI) (28, 29) and body fat mass (28). Serum leptin levels increase with age in both boys and girls until early puberty (27, 28, 29). Thereafter, leptin concentrations continue to increase as girls proceed through puberty, but decrease during male pubertal development (27, 28, 29). Although these results are in agreement with the limited longitudinal data in boys progressing through puberty (20) and imply that increased testosterone secretion leads to decreased serum leptin concentrations, cross-sectional studies cannot dissect sex steroid modulation of leptin secretion from the sex differences that arise from variations in the amount and distribution (e.g. sc vs. intraabdominal) of body fat in males and females (30).

Our study was designed to examine further the relationship between the reproductive endocrine axis and serum leptin concentrations. A longitudinal study in children with central precocious puberty (CPP) affords a unique opportunity to assess leptin levels in the same individual during controlled manipulations of the gonadal sex steroid milieus. We measured leptin concentrations 1) before the initiation of therapy, when the pubertal axis was fully active; 2) 6 months after pituitary-gonadal suppression had been induced by GnRH agonist (GnRHa) administration (31, 32); 3) immediately before discontinuation of GnRHa administration, when the reproductive endocrine axis was still suppressed; and 4) 6 months after discontinuation of GnRHa administration, when pubertal gonadotropin and gonadal sex steroid secretion had resumed (33, 34). Analysis of serial determinations of serum leptin levels within the same individual allowed us to minimize the effects of changes in body fat content and fat-free mass that occur during male and female puberty (35, 36) and focus on the impact of changing gonadal sex steroid milieus on leptin secretion in the human.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Patient population

The diagnosis of CPP was made based on the onset of breast development before 8 yr of age in girls or secondary sexual characteristics before 9 yr of age in boys associated with a pulsatile pattern of pituitary gonadotropin secretion and a pubertal response to exogenous GnRH in the absence of any identifiable adrenal or gonadal pathology, as detailed previously (37). GnRHa administration, as described below, was initiated after an initial evaluation. Subjects were included in this analysis if 1) suppression of pituitary gonadotropin and gonadal sex steroid secretion had been uniform throughout a period of GnRHa administration of 2 yr or more, 2) compliance with the regimen outlined below was deemed adequate as judged by parental report and record of medication administration, and 3) GnRHa had been discontinued for 6 months or more. Pituitary-gonadal suppression during GnRHa administration was judged to be adequate if 1) peak LH and FSH levels after challenge with natural sequence GnRH were below 5 mIU/mL Second International Reference Preparation of hMG, and 2) either serum estradiol values were below RIA sensitivity (<73 pmol/L or 20 pg/mL) in girls or serum testosterone values were less than 50 ng/dL in boys. Twenty-eight girls and 12 boys who met these criteria were selected for the present study. The girls were selected to be representative of a total of 111 girls with idiopathic CPP treated long term with GnRHa. CPP was idiopathic in 7 boys and was associated with neurofibromatosis type 1 (n = 1) or hypothalamic hamartoma (n = 4) in the rest. Patients were excluded from analysis if they had any additional conditions that might influence changes in body composition and/or serum leptin concentrations (e.g. GH deficiency, congenital adrenal hyperplasia, or primary hypothyroidism).

Sera were available for analysis for 10 boys and 22 girls for the paired comparison of pre-GnRHa vs. 3–6 months after beginning its administration and for 8 boys and 28 girls for comparison of immediately before discontinuation of GnRHa administration vs. 6 months later. With the exception of 2 boys, pretherapy characteristics were compared with those 6 months after initiation of GnRHa administration.

Protocol

Informed consent was obtained from parents before the enrollment of each patient in the study. The protocol had been approved by the human research committee of each of the three participating institutions [Massachusetts General Hospital (Boston, MA), Children’s Hospital (Boston MA), and Children’s Medical Center of the University of Virginia (Charlottesville, VA)]. Patients were evaluated at the General Clinical Research Centers of the three participating institutions before, at 3- to 6-month intervals during, and at 6- to 12-month intervals after GnRHa administration. Each patient received daily sc injections of GnRHa, using either deslorelin ([D-Trp6,Pro9-ethylamide]GnRH; 4–8 mg/kg·day) or histrelin ([imBzl-D-His6,Pro9-ethylamide]GnRH; 10 mg/kg·day). During each in-patient evaluation, confirmation of either active pubertal gonadotropin secretion (before and after discontinuation of GnRHa) or pituitary desensitization (during GnRHa administration) was based upon LH and FSH serum levels during frequent blood sampling (every 10–20 min) during the night (2200–0200 h) and day (1000–1400 h) and after the iv administration of 2.5 µg/kg natural sequence GnRH. Standing height was measured in the morning at least 30 min after the patient arose, using a wall-mounted stadiometer; the average of three replicates is reported. A left hand and wrist x-ray was obtained during each admission to monitor skeletal maturation.

Methods

Serum leptin concentrations were measured by RIA using a commercially available kit (Linco Research, St. Charles, MO) with sensitivity of 0.5 ng/mL. Based on replicate measurements of control sera in our laboratory, the intraassay coefficient of variation ranged from 4.5–6.0%, and the interassay coefficient of variation ranged from 6.1–8.5%. Serum leptin concentrations were measured in pools comprised of equal aliquots of every 20-min nighttime (2200–0200 h) and daytime (1000–1400 h) samples to investigate the diurnal variation in leptin levels (26, 38, 39, 40) across changing sex steroid milieus and to minimize the errors that arise when single measurements are employed to characterize a pulsatile pattern of secretion (40). LH, FSH, estradiol, and testosterone were measured using specific RIAs, as previously reported (41, 42). Bone age determinations were made using the Tanner-Whitehouse radius-ulnar-short (RUS) standards (43, 44, 45, 46).

Statistical analysis

The Wilcoxon matched pairs (sign and rank) test for nonparametric dependent variables was employed for the paired comparisons of nighttime and daytime leptin and for comparing the leptin concentrations 1) before the initiation of GnRHa therapy with those obtained 6 months after pituitary-gonadal suppression and 2) immediately before discontinuation of GnRHa administration with those obtained 6 months later. We performed the comparative analyses in both the daytime and nighttime samples and found similar results; the daytime leptin values are reported to permit comparison with most of the published literature. Linear regression (leptin vs. BMI) and the above statistical tests were performed using the Complete Statistical System: Statistica, from StatSoft, Tulsa, OK. All data are presented as the mean ± SEM; statistical significance was assigned a value of P < 0.05. Serum leptin concentrations were log transformed to generate a normal distribution before presentation in the figures.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Effect of reversible gonadal sex steroid suppression

The clinical characteristics of the boys and girls with CPP used in this analysis are summarized in Table 1Go. Serum leptin levels correlated positively with BMI throughout the study (daytime values: r = 0.58 for the boys and 0.79 for the girls; nighttime values: r = 0.68 for the boys and 0.92 for the girls; P < 0.001 for all).


View this table:
[in this window]
[in a new window]
  		Table 1. Characteristics of children with central precocious puberty before, during, and after discontinuation of GnRHa administration

 
In the boys, serum leptin levels rose in all 10 subjects after testosterone production had been suppressed by the pituitary desensitization induced by GnRHa administration (P = 0.005; Fig. 1Go), with daytime concentrations increasing from 3.5 ± 0.8 to 9.5 ± 3.1 ng/dL. Conversely, no effect of diminished estrogen production was observed in the girls. Leptin levels rose in 15 girls and decreased in 7, with daytime concentrations of 9.9 ± 1.6 and 10.3 ± 2.3 ng/dL before and during GnRHa administration (P = NS; Fig. 2Go).



View larger version (16K):
[in this window]
[in a new window]
  		Figure 1. Daytime leptin levels in boys with precocious puberty. Individual values for each subject and the group mean ± SEM are depicted at each time point: 1) before the initiation of GnRHa administration (PRE), 2) 6 months later (6 m ON), 3) immediately before discontinuation of GnRHa (Last ON), and 4) 6 months later (6 m OFF). Testosterone production is noted as either present (+) or absent (-). *, P <= 0.01 vs. preceding period.

 


View larger version (20K):
[in this window]
[in a new window]
  		Figure 2. Daytime leptin levels in girls with precocious puberty. Individual values for each subject and the group mean ± SEM are depicted at each time point: 1) before the initiation of GnRHa administration (PRE), 2) 6 months later (6 m ON), 3) immediately before discontinuation of GnRHa (Last ON), and 4) 6 months later (6 m OFF). Estrogen production is noted as either present (+) or absent (-). Differences were not significant.

 
In the second analysis, leptin levels obtained immediately before discontinuation of GnRHa administration were compared with those obtained 6 months later. In the boys, the leptin levels decreased in all 8 subjects with the resumption of pubertal testosterone production (12.2 ± 4.5 vs. 7.0 ± 2.6 ng/dL; P = 0.012; Fig. 1Go). In the girls, no significant effect of increased estrogen production was observed during the reactivation of puberty. Leptin levels rose in 18 girls, decreased in 9, and were unchanged in 1 (16.8 ± 2.0 vs. 18.9 ± 1.7 ng/dL; P = NS; Fig. 2Go).

Diurnal rhythm

In the girls, the nighttime leptin levels were greater than the daytime concentrations at each of the time points regardless of the status of the pituitary-ovarian axis (Fig. 3Go; all P < 0.001). Overall, the average nighttime level was 38.3% greater than the daytime measurement. In the boys, the nighttime leptin levels exceeded daytime concentrations by 29.4%, but these differences reached statistical significance at only two of the four time points, probably secondary to the small sample size (Fig. 4Go). The P values for the four comparisons were 0.06 for the pre-GnRHa measurements, 0.07 for the data obtained 6 months later, 0.02 for the values obtained immediately before discontinuation of GnRHa, and 0.01 for the levels obtained at the last time point. Together, the data from the girls and boys indicate that the diurnal pattern of serum leptin concentrations was present at each of the time points despite changes in the gonadal sex steroid milieu.



View larger version (26K):
[in this window]
[in a new window]
  		Figure 3. Nighttime vs. daytime leptin concentrations in girls with precocious puberty. Individual values for each subject and the group mean ± SEM are depicted at each time point: 1) before the initiation of GnRHa administration (PRE), 2) 6 months later (6 m ON), 3) immediately before discontinuation of GnRHa (Last ON), and 4) 6 months later (6 m OFF). *, P <= 0.001, day vs. night.

 


View larger version (21K):
[in this window]
[in a new window]
  		Figure 4. Nighttime vs. daytime leptin concentrations in boys with precocious puberty. Individual values for each subject and the group mean ± SEM are depicted at each time point: 1) before the initiation of GnRHa administration (PRE), 2) 6 months later (6 m ON), 3) immediately before discontinuation of GnRHa (Last ON), and 4) 6 months later (6 m OFF). *, P <= 0.02, day vs. night.

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
We have serially measured serum leptin concentrations in a cohort of girls and boys with CPP before, during, and after GnRHa administration, allowing us to investigate the impact of changes in the activity of the pituitary-gonadal axis. Both sets of paired comparisons in the male patients suggested that pubertal levels of testosterone secretion suppressed serum leptin levels, whereas serial measurements in the girls did not reveal any modulation by changing ovarian estradiol production. It is possible, however, that our study lacked sufficient power to detect the small increases in serum leptin levels that have been variably attributed to estrogen in some (47), but not other (48), studies of adult women.

We employed a longitudinal study design to minimize the differences in body composition among individuals that could have confounded a cross-sectional comparison. The 6-month interval between the paired observations ensured that the pituitary-gonadal axis was completely suppressed after initiation of GnRHa administration and, similarly, that the axis was reactivated after discontinuation of therapy. Unfortunately, it also allowed for small changes in body composition to occur between the measurements. We cannot eliminate completely the possibility that such changes confounded our assessment of the modulation of serum leptin concentrations by gonadal steroids. However, only small differences were found among the BMIs of the subjects across the time points of the paired analyses. In addition, the data from the two comparisons were internally consistent; higher testosterone levels were associated with lower serum leptin concentrations, independent of the changes in BMI. Definitive proof that testosterone affects serum leptin levels in children, independent of the body composition changes induced by the hormone, awaits a future study in which leptin concentrations are followed serially at shorter intervals, as would be possible during initiation of testosterone therapy in boys with delayed puberty.

Such a study has been reported in hypogonadal men receiving testosterone replacement therapy (49). Jockenhovel et al. found that serum leptin levels decrease after the initiation of testosterone therapy, but leptin was first measured 50 days after testosterone administration, also leaving open the possibility that subtle, but significant, changes in body composition had occurred between the observations that influenced leptin production. A second study by Elbers et al. (50) demonstrated that administration of cross-sex hormones in male to female and female to male transsexuals induced a reversal of the sexual dimorphism in serum leptin levels over 4 months independent of the amount of body fat. Our data from children with precocious puberty studied during reversible gonadal sex steroid suppression are consistent with these two recent reports in adults. Although the data from these three human in vivo studies are consistent with the idea that testosterone induces a decrease in serum leptin levels, the mechanism of this effect was not addressed. In vitro studies using cultured human adipocytes provide evidence for a direct effect of testosterone on adipose tissue. In these experiments, the presence of testosterone in the culture medium reduced adipocyte leptin secretion by up to 62% and suppressed leptin messenger ribonucleic acid levels to a similar extent (51).

The differential effects of male and female gonadal sex steroids along with gender differences in body composition probably account for most of the sexual dimorphism observed in leptin concentrations (22, 23, 24, 25, 26, 27, 28, 29). However, gender differences have also been observed in prepubertal children (24, 25, 26, 27, 28, 29). Gonadal sex steroid production occurs in utero and during infancy, but is then largely quiescent until the hypothalamic-pituitary-gonadal axis becomes active again during puberty. Thus, it seems unlikely that the gender differences observed in prepubertal children are caused by ongoing sex hormone production. Further investigation is needed to determine whether these differences can be explained fully by variations in body composition (30) or whether they stem from sex differences unrelated to gonadal steroids and body fat distribution.

The measurement of leptin in pooled sera from nighttime and daytime periods allowed us to assess the diurnal pattern of serum leptin concentrations (26, 38, 39, 40) without our analyses being confounded by leptin’s pulsatile secretion (40). We found that the nighttime serum leptin levels exceeded the daytime concentrations in both girls and boys at each of the time points examined. Although a study of sedentary and athletic women found that hypothalamic amenorrhea was associated with loss of the diurnal rhythm in leptin levels (38), our data suggest that the diurnal pattern of leptin secretion is independent of the activity of the pituitary-gonadal axis. This finding is consistent with the report that the nocturnal rise in serum leptin concentrations is preserved in patients with perinatal stalk transection syndrome (26).

In summary, longitudinal studies in children with precocious puberty who have undergone reversible suppression of pubertal gonadotropin and gonadal sex steroid secretion indicate that testosterone suppresses serum leptin concentrations, but find no discernible effect of estrogen. We have also shown that the diurnal pattern of leptin concentrations is independent of the activity of the pituitary-gonadal axis. Several groups have demonstrated that leptin affects the function of the hypothalamic-pituitary-gonadal axis (15, 16, 17, 18, 19). It is now likely that, at least in males, communication between the hypothalamic-pituitary-gonadal axis and adipose tissue represents a complete, bidirectional feedback loop. It remains to be determined whether testosterone itself affects leptin production, perhaps through the androgen receptors that have been identified on adipocytes (52), or whether an intermediary system is involved.


   Acknowledgments
 
We gratefully acknowledge the nursing staff of the participating General Clinical Research Centers for their dedicated care of these young patients during these longitudinal studies. We also thank the personnel of the Radioimmunoassay Core Laboratory of the Reproductive Endocrine Sciences Center at Massachusetts General Hospital for their diligent efforts in coordinating and performing the leptin assays. We acknowledge Drs. John D. Crawford, John F. Crigler, Jr., Robert M. Blizzard, M. Joan Mansfield, and William F. Crowley, Jr., for their invaluable contributions to the studies of this patient group.


   Footnotes
 
1 This work was supported in part by NIH Grants HD-18169, RR-01066, RR-02172, RR-08847, and T32-DK-07699, and the Reproductive Endocrine Sciences Center (Grant P30-HD-23138). Back

Received October 29, 1997.

Revised December 10, 1997.

Accepted December 17, 1997.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

  1. 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]
  2. Tartaglia LA, Dembski M, Weng X, et al. 1995 Identification and expression cloning of a leptin receptor, OB-R. Cell. 83:1263–1271.[CrossRef][Medline]
  3. Chua SC, Chung WK, Wu-Peng S, et al. Phenotypes of mouse diabetes and rat fatty due to mutations in the OB (leptin) receptor. Science. 271:994–996.
  4. Halaas JL, Gajiwala KS, Maffei M, et al. 1995 Weight-reducing effects of the plasma protein encoded by the obese gene. Science. 269:543–546.[Abstract/Free Full Text]
  5. Pelleymounter MA, Cullen MJ, Baker MB, et al. 1995 Effects of the obese gene product on body weight regulation in ob/ob mice. Science. 269:540–543.[Abstract/Free Full Text]
  6. Campfield LA, Smith FJ, Guisez Y, Devos R, Burn P. 1995 Recombinant mouse OB protein: evidence for a peripheral signal linking adiposity and central neural networks. Science. 269:546–549.[Abstract/Free Full Text]
  7. Considine RV, Sinha MK, Heiman ML, et al. 1996 Serum immunoreactive-leptin concentrations in normal-weight and obese humans. N Engl J Med. 334:292–295.[Abstract/Free Full Text]
  8. Maffei M, Halaas J, Ravussin E, et al. 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]
  9. Ahima RS, Prabakaran D, Mantzoros C, et al. 1996 Role of leptin in the neuroendocrine response to fasting. Nature. 382:250–252.[CrossRef][Medline]
  10. Boden G, Chen X, Mozzoli M, Ryan I. 1996 Effect of fasting on serum leptin in normal human subjects. J Clin Endocrinol Metab. 81:3419–3423.[Abstract]
  11. Grinspoon S, Gulick T, Askari H, et al. 1996 Serum leptin levels in women with anorexia nervosa. J Clin Endocrinol Metab. 81:3861–3863.[Abstract/Free Full Text]
  12. Caro JF, Sinha MK, Kolaczynski JW, Zhang PL, Considine RV. 1996 Leptin: the tale of the obesity gene. Diabetes. 45:1455–1462.[Medline]
  13. Montague CT, Farooqi IS, Whitehead JP, et al. 1997 Congenital leptin deficiency is associated with severe early-onset obesity in humans. Nature. 387:903–907.[CrossRef][Medline]
  14. Swerdloff RS, Batt RA, Bray GA. 1976 Reproductive hormonal function in the genetically obese (ob/ob) mouse. Endocrinology. 98:1359–1364.[Abstract/Free Full Text]
  15. Chehab FF, Lim ME, Lu R. 1996 Correction of the sterility defect in homozygous obese female mice treated with the human recombinant leptin. Nat Genet. 12:318–320.[CrossRef][Medline]
  16. Barash IA, Cheung CC, Weigle DS, et al. 1996 Leptin is a metabolic signal to the reproductive system. Endocrinology. 137:3144–3147.[Abstract]
  17. Chehab FF, Mounzih K, Lu R, Lim ME. 1997 Early onset of reproductive function in normal female mice treated with leptin. Science. 275:88–90.[Abstract/Free Full Text]
  18. Ahima RS, Dushay J, Flier SN, Prabakaran D, Flier JS. 1997 Leptin accelerates the onset of puberty in normal female mice. J Clin Invest. 99:391–395.[Medline]
  19. Cheung CC, Thronton JE, Kuijper JL, Weigle DS, Clifton DK, Steiner RA. 1997 Leptin is a metabolic gate for the onset of puberty in the female rat. Endocrinology. 138:855–858.[Abstract/Free Full Text]
  20. Mantzoros CS, Flier JS, Rogol AD. 1997 A longitudinal assessment of hormonal and physical alterations during normal puberty in boys. V. Rising leptin levels may signal the onset of puberty. J Clin Endocrinol Metab. 82:1066–1070.[Abstract/Free Full Text]
  21. Vogel G. 1996 Leptin: a trigger for puberty. Science. 274:1466–1467.[Free Full Text]
  22. Ostlund RE, Yang JW, Klein S, Gingerich R. 1996 Relation between plasma leptin concentration and body fat, gender, diet, age, and metabolic covariates. J Clin Endocrinol Metab. 81:3909–3913.[Abstract/Free Full Text]
  23. Rosenbaum M, Nicoloson M, Hirsch J, et al. 1996 Effects of gender, body composition, and menopause on plasma concentrations of leptin. J Clin Endocrinol Metab. 81:3424–3427.[Abstract]
  24. Hassink SG, Sheslow DV, de Lancey E, Opentanova I, Considine RV, Caro JF. 1996 Serum leptin in children with obesity: relationship to gender and development. Pediatrics. 98:201–203.[Abstract/Free Full Text]
  25. Lahlou N, Landais P, De Boissieu D, Bougneres P-F. 1997 Circulating leptin in normal children and during the dynamic phase of juvenile obesity. Diabetes. 46:989–993.[Abstract]
  26. Pombo M, Herrera-Justiniane E, Considine RV, et al. 1997 Nocturnal rise in leptin in normal prepubertal and pubertal children and in patients with perinatal stalk-transection syndrome. J Clin Endocrinol Metab. 82:2751–2754.[Abstract/Free Full Text]
  27. Clayton PE, Gill MS, Hall CM, Tillmann V, Whatmore AJ, Price DA. 1997 Serum leptin through childhood and adolescence. Clin Endocrinol (Oxf). 46:727–733.[CrossRef][Medline]
  28. Blum WF, Englaro P, Hanitsch S, et al. 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]
  29. Garcia-Mayor RV, Andrade MA, Rios M, Lage M, Dieguex 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]
  30. Nagy TR, Cower 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]
  31. Comite F, Cutler GB, Rivier J, Vale WW, Loriaux DL, Crowley WF. 1981 Short-term treatment of idiopathic precocious puberty with a long-acting analogue of luteinizing hormone-releasing hormone: A preliminary report. N Engl J Med. 305:1546–1550.[Abstract]
  32. Boepple PA, Mansfield MJ, Wierman, ME, et al. 1986 Use of a potent, long acting agonist gonadotropin-releasing hormone in the treatment of precocious puberty. Endocr Rev. 7:24–33.[Abstract/Free Full Text]
  33. Manasco PK, Pescovitz OH, Feuillan PP, et al. 1988 Resumption of puberty after long term luteinizing hormone-releasing hormone agonist treatment of central precocious puberty. J Clin Endocrinol Metab. 67:368–372.[Abstract/Free Full Text]
  34. Jay N, Mansfield MJ, Blizzard RM, et al. 1992 Ovulation and menstrual function of adolescent girls with central precocious puberty after therapy with gonadotropin-releasing hormone agonists. J Clin Endocrinol Metab. 75:890–894.[Abstract]
  35. Rico H, Revilla M, Villa LF, Hernandez ER, Alverez de Buergo M, Villa M. 1993 Body composition in children and Tanner’s stage: a study with dual-energy x-ray absorptiometry. Metabolism. 42:967–970.[CrossRef][Medline]
  36. Daniels SR, Khoury PR, Morrison JA. 1997 The utility of body mass index as a measure of body fatness in children and adolescents: differences by race and gender. Pediatrics. 99:804–807.[Abstract/Free Full Text]
  37. Mansfield MJ, Beardsworth DE, Loughlin JS, et al. 1983 Long-term treatment of central precocious puberty with a long-acting analogue of luteinizing hormone-releasing hormone. N Engl J Med. 309:1286–1290.[Abstract]
  38. Laughlin GA, Yen SSC. 1997 Hypoleptinemia in women athletes: absence of a diurnal rhythm with amenorrhea. J Clin Endocrinol Metab. 82:318–321.[Abstract/Free Full Text]
  39. Sinha MK, Ohannesian JP, Heiman ML, et al. 1996 Nocturnal rise in leptin in lean, obese, and non-insulin-dependent diabetes mellitus subjects. J Clin Invest. 97:1344–1347.[Medline]
  40. Licinio J, Mantzoros C, Negrao AB, et al. 1997 Human leptin levels are pulsatile and inversely related to pituitary-adrenal function. Nat Med. 3:575–579.[CrossRef][Medline]
  41. Filicori M, Butler JP, Crowley Jr WF. 1984 Neuroendocrine regulation of the corpus luteum in the human. Evidence for pulsatile progesterone secretion. J Clin Invest. 73:1638–1647.
  42. Finkelstein JS, Whitcomb RW, O’Dea LSL, Longcope C, Schoenfeld DA, Crowley WF. 1991 Sex steroid control of gonadotropin secretion in the human male. I. Effects of testosterone administration in normal and gonadotropin-releasing hormone-deficient men. J Clin Endocrinol Metab. 73:609–620.[Abstract/Free Full Text]
  43. Tanner JM, Whitehouse RH, Cameron N, Marshall WA, Healy MJR, Goldstein H. 1983 Assessment of skeletal maturity and prediction of adult height (TW2 method). London: Academic Press.
  44. Boepple PA, Mansfield MJ, Link K, et al. 1988 Impact of sex steroids and their suppression upon skeletal growth and maturation. Am J Physiol. 255:E559–E566.
  45. Boepple PA, Mansfield MJ, Crawford JD, Crigler JF, Blizzard RM, Crowley WF. 1990 Gonadotropin-releasing hormone agonist treatment of central precocious puberty: an analysis of growth data in a developmental context. Acta Paediatr Scand. 367(Suppl):38–43.
  46. Boepple PA, Mansfield MJ, Crawford JD, Crigler Jr JF, Blizzard RM, Crowley Jr WF. 1993 Analysis of growth data in children with central precocious puberty: The impact of long-term GnRH agonist therapy. In: Grave GD, Cutler Jr GB, eds. Sexual precocity: etiology, diagnosis, and management. New York: Raven Press; 69–83.
  47. Shimizu H, Shimomura Y, Nakanishi Y, et al. 1997 Estrogen increases in vivo leptin production in rats and human subjects. J Endocrinol. 154:285–292.[Abstract/Free Full Text]
  48. Kohrt WM, Landt M, Birge Jr SJ. 1996 Serum leptin levels are reduced in repsonse to exercise training, but not hormone replacement therapy, in older women. J Clin Endocrinol Metab. 81:3980–3985.[Abstract/Free Full Text]
  49. Jockenhovel F, Blum WF, Vogel E, et al. 1997 Testosterone substitution normalizes elevated serum leptin levels in hypogonadal men. J Clin Endocrinol Metab. 82:2510–2513.[Abstract/Free Full Text]
  50. Elbers JMH, Asscheman H, Seidell JC, Frolich M, Meinders AE, Gooren LJG. 1997 Reversal of the sex hormone difference in serum leptin levels upon cross-sex hormone administration in transsexuals. J Clin Endocrinol Metab. 82:3267–3270.[Abstract/Free Full Text]
  51. Wabitsch M, Blum WF, Muche R, et al. 1997 Contribution of androgens to the gender difference in leptin production in obese children and adolescents. J Clin Invest. 100:808–813.[Medline]
  52. Pedersen SB, Fuglsig S, Sjoren P, Richelsen B. 1996 Identification of steroid receptors in human adipose tissue. Eur J Clin Invest. 26:1051–1056.[CrossRef][Medline]



This article has been cited by other articles:


Home page
 J. Clin. Endocrinol. Metab.Home page
G. Kilciler, M. Ozata, C. Oktenli, S.Y. Sanisoglu, E. Bolu, N. Bingol, M. Kilciler, I. C. Ozdemir, and M. Kutlu
Diurnal Leptin Secretion Is Intact in Male Hypogonadotropic Hypogonadism and Is Not Influenced by Exogenous Gonadotropins
J. Clin. Endocrinol. Metab., November 1, 2002; 87(11): 5023 - 5029.
[Abstract] [Full Text] [PDF]

Home page
 J. Clin. Endocrinol. Metab.Home page
E. Charmandari, M. Weise, S. R. Bornstein, G. Eisenhofer, M. F. Keil, G. P. Chrousos, and D. P. Merke
Children with Classic Congenital Adrenal Hyperplasia Have Elevated Serum Leptin Concentrations and Insulin Resistance: Potential Clinical Implications
J. Clin. Endocrinol. Metab., May 1, 2002; 87(5): 2114 - 2120.
[Abstract] [Full Text] [PDF]

Home page
 EndocrinologyHome page
K. Kawamura, N. Sato, J. Fukuda, H. Kodama, J. Kumagai, H. Tanikawa, A. Nakamura, and T. Tanaka
Leptin Promotes the Development of Mouse Preimplantation Embryos in Vitro
Endocrinology, May 1, 2002; 143(5): 1922 - 1931.
[Abstract] [Full Text] [PDF]

Home page
 J. Clin. Endocrinol. Metab.Home page
J. D. Veldhuis, S. M. Pincus, M. C. Garcia-Rudaz, M. G. Ropelato, M. E. Escobar, and M. Barontini
Disruption of the Synchronous Secretion of Leptin, LH, and Ovarian Androgens in Nonobese Adolescents with the Polycystic Ovarian Syndrome
J. Clin. Endocrinol. Metab., August 1, 2001; 86(8): 3772 - 3778.
[Abstract] [Full Text] [PDF]

Home page
 J. Clin. Endocrinol. Metab.Home page
M. L. Ahmed, K. K. L. Ong, A. P. Watts, D. J. Morrell, M. A. Preece, and D. B. Dunger
Elevated Leptin Levels Are Associated with Excess Gains in Fat Mass in Girls, But Not Boys, with Type 1 Diabetes: Longitudinal Study during Adolescence
J. Clin. Endocrinol. Metab., March 1, 2001; 86(3): 1188 - 1193.
[Abstract] [Full Text]

Home page
 J. Clin. Endocrinol. Metab.Home page
F. Andreelli, H. Hanaire-Broutin, M. Laville, J. P. Tauber, J. P. Riou, and C. Thivolet
Normal Reproductive Function in Leptin-Deficient Patients with Lipoatropic Diabetes
J. Clin. Endocrinol. Metab., February 1, 2000; 85(2): 715 - 719.
[Abstract] [Full Text]

Home page
 J. Clin. Endocrinol. Metab.Home page
K. J. Suter, C. R. Pohl, and M. E. Wilson
Circulating Concentrations of Nocturnal Leptin, Growth Hormone, and Insulin-Like Growth Factor-I Increase before the Onset of Puberty in Agonadal Male Monkeys: Potential Signals for the Initiation of Puberty
J. Clin. Endocrinol. Metab., February 1, 2000; 85(2): 808 - 814.
[Abstract] [Full Text]

Home page
 J. Clin. Endocrinol. Metab.Home page
Is Obesity an Outcome of Gonadotropin-Releasing Hormone Agonist Administration? Analysis of Growth and Body Composition in 110 Patients with Central Precocious Puberty
J. Clin. Endocrinol. Metab., December 1, 1999; 84(12): 4480 - 4488.
[Abstract] [Full Text]

Home page
 Hum ReprodHome page
T. Sir-Petermann, M. Maliqueo, A. Palomino, D. Vantman, S.E. Recabarren, and L. Wildt
Episodic leptin release is independent of luteinizing hormone secretion
Hum. Reprod., November 1, 1999; 14(11): 2695 - 2699.
[Abstract] [Full Text] [PDF]

Home page
 J. Clin. Endocrinol. Metab.Home page
G. Wiesner, M. Vaz, G. Collier, D. Seals, D. Kaye, G. Jennings, G. Lambert, D. Wilkinson, and M. Esler
Leptin Is Released from the Human Brain: Influence of Adiposity and Gender
J. Clin. Endocrinol. Metab., July 1, 1999; 84(7): 2270 - 2274.
[Abstract] [Full Text]

Home page
 Hum ReprodHome page
T. Sir-Petermann, V. Piwonka, F. Perez, M. Maliqueo, S.E. Recabarren, and L. Wildt
Are circulating leptin and luteinizing hormone synchronized in patients with polycystic ovary syndrome?
Hum. Reprod., June 1, 1999; 14(6): 1435 - 1439.
[Abstract] [Full Text] [PDF]

Home page
 J. Clin. Endocrinol. Metab.Home page
M. L. Ahmed, K. K. L. Ong, D. J. Morrell, L. Cox, N. Drayer, L. Perry, M. A. Preece, and D. B. Dunger
Longitudinal Study of Leptin Concentrations during Puberty: Sex Differences and Relationship to Changes in Body Composition
J. Clin. Endocrinol. Metab., March 1, 1999; 84(3): 899 - 905.
[Abstract] [Full Text]

Home page
 J. Clin. Endocrinol. Metab.Home page
M. R. Palmert, S. Radovick, and P. A. Boepple
Leptin Levels in Children with Central Precocious Puberty
J. Clin. Endocrinol. Metab., July 1, 1998; 83(7): 2260 - 2265.
[Abstract] [Full Text]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Submit a related Letter to the Editor
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Copyright Permission
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Palmert, M. R.
Right arrow Articles by Boepple, P. A.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Palmert, M. R.
Right arrow Articles by Boepple, P. A.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Endocrinology Endocrine Reviews J. Clin. End. & Metab.
Molecular Endocrinology Recent Prog. Horm. Res. All Endocrine Journals