Leptin levels in children with central precocious puberty

Several studies have suggested that sufficient serum leptin levels may be involved in the initiation of puberty. To assess further the relationship between leptin and the onset of puberty in humans, we measured the serum leptin concentration in children with central precocious puberty (CPP). We studied 65 children with either idiopathic (IPP; n = 50 girls and 3 boys) or neurogenic central precocious puberty (NPP; n = 5 girls and 7 boys). The serum leptin levels in these patients were compared with normative data from healthy children and adolescents using SD scores that adjust for body mass index (BMI) and Tanner stage. The mean SD scores of IPP and NPP girls were +0.4 +/- 0.1 and +1.0 +/- 0.5, respectively, compared with that of age-matched prepubertal girls and +0.7 +/- 0.2 and +1.6 +/- 0.6 compared with that of girls matched for pubertal stage. The CPP girls with lower BMIs contributed larger SD scores, such that the leptin SD score was negatively correlated with BMI. A similar, modest increase in leptin levels in the CPP girls was evident when additional normative data were considered. The mean leptin SD scores of IPP and NPP boys were -0.9 +/- 0.5 and +0.7 +/- 0.3, respectively, compared with that of normal boys at Tanner stage 3-4. Serum leptin levels in the boys with CPP were not different from those in healthy boys in any of the normative studies. These data should be interpreted cautiously, but they suggest that girls with CPP have modestly elevated serum leptin concentrations compared with those in healthy children and adolescents. In addition, the negative correlation between the leptin SD score and BMI suggests that sufficient leptin levels may be associated with initiation of puberty in girls.     

Leptin

Leptin (from the Greek leptos=thin) was identified only 3 years ago. It has attracted huge attention both scientifically, with more than 600 publications, and in the media, where this protein has been portrayed as the way to a cure for obesity. Indeed, leptin was first described as an adipocyte-derived signalling factor, which, after interaction with its receptors, induced a complex response including control of bodyweight and energy expenditure. Leptin seems in addition to its role in metabolic control to have important roles in reproduction and neuroendocrine signalling. Human obesity is a complex disorder, with many factors playing a part; the pathophysiology of leptin is not as simple as it seems to be in rodent models of obesity.     

Leptin

INTRODUCTION: The purpose of this study was to test whether radiofrequency (RF) energy could be used to fixate leads to the endocardium. METHODS AND RESULTS: In six dogs we measured the dislodgment force and pacing threshold before and after RF fixation in the coronary sinus (CS) and right ventricle (RV). RF fixation was achieved with a CardioRhythm Atakr ablation unit. The dislodgment force of CS leads fixed with RF energy was 1.63+/-0.65 oz, compared with < 0.1 oz for similar leads placed in the CS of six separate dogs. In the RV, leads fixed with RF energy had a dislodgment force of 1.29+/-0.27 oz, compared with 0.48+/-0.28 oz. for urethane (P < 0.01) and 1.01+/-0.21 oz for silicone (P = 0.41) tined leads. In the CS, the pacing threshold for RF fixed leads increased significantly from 2.2+/-1.1 V (0.5 msec) before fixation to 4.2+/-1.3 V after fixation (P < 0.01), while in the RV, the pacing threshold increased from 0.41+/-0.05 V (0.5 msec) before fixation to a mean of 2.03+/-0.44 V after fixation (P < 0.01). In another group of six dogs studied for 12 weeks, 5 of 6 RF fixed CS leads remained attached, as did 8 of 10 RF fixed RV leads. For the RV leads, the mean pacing threshold was 0.90+/-0.35 V, compared with 0.53+/-0.18 V (0.5 msec) for similar tined leads (P = 0.02) and 1.2+/-0.30 V (0.5 msec) for screw leads (P = 0.18) in the RV. CONCLUSION: We conclude that RF energy can be used to attach leads to the RV and CS endocardium. While the RV pacing thresholds increased acutely, the mean chronic thresholds were not significantly different for RF fixed leads and standard tined or screw leads.     

Leptin

Three strains of yellow fever virus (YFV) were isolated in 1982 in The Ivory Coast, one from a human case and two from Aedes luteocephalus, during and subsequent to an epidemic. The complete genomic sequence of the human strain was determined and compared to that of the 1927 Asibi strain of YFV. The divergence observed was on average of 8.3%, ranging from 5.5 to 11.7% in the coding region. The transitions to transversions ratio was 5.9. Most mutations (84.3%) occurred on the third position of the codons, with synonymous mutations representing 92.5%. However, when partial sequences representing 60% of each genome were compared, homology between the three Ivory Coast strains was greater than 99%. These results demonstrate the homogeneity of the virus strains circulating in different hosts and vectors in a limited geographical region and validate the concept of topotype in viral quasi-species.     

Leptin and human reproduction

Leptin is a secretory product of adipocytes. It has been suggested that leptin acts as an afferent satiety signal to the brain modulating the expression of the orexigenic hypothalamic peptide, neuropeptide Y (NPY). Therefore leptin can be regarded as a marker of the nutritional status of the body. It was proposed that human obesity may result from a central resistance to leptin due to different pathophysiological mechanisms: saturation of the leptin transport into the cerebrospinal fluid of the obese subjects, abnormalities in the hypothalamic receptor for leptin, or post-receptor transduction mechanisms. It was shown that circulating leptin levels in humans significantly correlate with the body mass index (BMI). Although most studies point to white adipose tissue as a primary source of leptin there is still some uncertainty towards the relative expression of leptin between various body fat compartments. LEPTIN AND ONSET OF PUBERTY: Studies on animal models recognized various metabolic candidates for modulation of GnRH neuronal activity. It was supposed that mild changes in the body's metabolic status can serve to regulate the central drive to the reproductive axis. It is likely that leptin can serve as a "metabolic cue" that transmits signals of those mild metabolic changes towards activation of the GnRH neuronal system at the end of the prepubertal period. On the other side there is a possibility of altered leptin pulsatility during prepubertal period that can consequently influence hypothalamus and GnRH neuronal system. LEPTIN AND SEXUAL DIMORPHISM: Leptin levels in humans are similar in both sexes during the prepubertal period. During puberty leptin has a tendency to decline in boys and to remain constant in girls. Puberty is also characterized with a similar circadian rhythm pattern between sexes whil girls express different pulse characteristics. It seems that sexual dimorphism is established in early phases of human development. There is a possibility of sex steroid influence on such sexual dimorphism. LEPTIN AND REPRODUCTIVE FUNCTION: It was shown that administration of recombinant leptin to ob ob mice could restore fertility in these infertile animals. There is certain difference in leptin levels according to the phase of the menstrual cycle. It was shown that leptin peak is in the luteal phase of the cycle and that correlates to the maximal progesterone level. It is possible that leptin could directly influence ovary and that disruption of such an effect could play a role in menstrual irregularities in both obese and mal nourished women. This could even become a pathophysiological mechanism in women with polycystic ovary syndrome (PCOS). It was supposed that leptin resistance could be involved in infertility impairment of the obese women with PCOS. Leptin increases during pregnancy. Appearance of placenta as a new, nonadipose source of leptin production, increases a possibility of different leptin mRNA expression through gestation.     

Leptin Receptor

Leptin is a fat cell-derived satiety factor that regulates food intake and energy expenditure. Its effects are mediated by interactions with the leptin receptor (Ob-R) that is alternatively spliced to encode at least five isoforms(a-e), which are distributed in a wide range of tissues including the hypothalamus. Ob-R is a member of cytokine receptors and involves the JAK-STAT signal transduction system. We found Ob-R mutations in Zucker fatty rats and obese Koletsky rats and demonstrated that Ob-R dysfunction brings around hyperphagia and obesity. However we and others have not found any Ob-R mutation in human obese subjects.     

Gonadotrophin and prolactin secretory dynamics in girls with normal puberty, idiopathic precocious puberty and precocious puberty due to hypothalamic hamartoma

OBJECTIVE: This study was designed to test the hypothesis that hypothalamic hamartoma causes precocious puberty through a different neuroendocrine mechanism than that of normal puberty or of idiopathic precocious puberty. DESIGN AND PATIENTS: We compared the pattern of gonadotrophin secretion among 4 girls with precocious puberty due to hypothalamic hamartoma, 27 girls with idiopathic precocious puberty, and 14 girls with normal puberty. All subjects were breast stage 3 or 4. Blood samples were obtained every 20 min for 4 h during the day (1.000 hours to 1400 h) and night (22.00 hours to 0200 h). MEASUREMENTS: LH, FSH, and prolactin were measured in each blood sample. Girls also underwent LHRH-stimulation with measurement of LH and FSH before and after stimulation. RESULTS: There were no significant differences in mean LH level, LH peak amplitude, or LH or FSH peak frequency during either the day or the night among the three diagnostic groups. However, the mean +/- SD LHRH-stimulated peak LH levels were greater in girls with hypothalamic hamartoma than in girls with normal puberty or with idiopathic precocious puberty (194 +/- 142 vs 85 +/- 60 or 66 +/- 54 IU/l, respectively, P < 0.05). The LHRH-stimulated peak FSH level in girls with hypothalamic hamartoma exceeded the level for the normal pubertal girls (31 +/- 19 vs 17 +/- 7 IU/l, P < 0.05), but not the level for the girls with idiopathic precocious puberty (25 + 12 IU/l). The peak LH to peak FSH ratio in the girls with hypothalamic hamartoma exceeded the ratio for the girls with idiopathic precocious puberty (7.3 +/- 3.9 vs 2.6 +/- 3.0 IU/l, P < 0.05), but not the ratio for the normal pubertal girls (5.0 + 2.9). There were no significant differences in mean prolactin level, peak amplitude or frequency, or in the ratio of mean night to mean day prolactin, among the 3 diagnostic groups. CONCLUSIONS: We conclude that spontaneous gonadotrophin and prolactin secretion are similar among girls with hypothalamic hamartoma, idiopathic precocious puberty, or normal puberty. However, the increased LHRH-stimulated peak LH in the girls with hypothalamic hamartoma suggests subtle differences in neuroendocrine regulation that may underlie their more rapid pubertal maturation.     

Excitatory amino acid receptors and puberty

Glutamate is an important excitatory signal in the hypothalamus for the steroid-mediated preovulatory gonadotropin surge. Steroids may exert this action by regulating glutamate receptor levels or glutamate release, or both. Work in our laboratory found no changes in NMDA and kainate receptor binding in the hypothalamus of castrated or castrated plus steroid-replaced male and female rats. Likewise, we found that NMDA and kainate binding did not change over the onset of puberty in the female rat. A competitive quantitative RT-PCR assay using exogenous internal standards was used to measure NMDAR1, GluR1, and beta-actin mRNAs levels. NMDAR1 and GluR1 expression was examined in the preoptic hypothalamic area and in the medial basal hypothalamus at Postnatal Days 10, 15, 20, 25, 30, 32, 34, 36, 40, and 63. A transient increase in GluR1 mRNA levels in the preoptic hypothalamic area was observed on Day 20, with all other time points showing comparable levels. NMDAR1 levels in the POA and medial basal hypothalamus did not change significantly at any of the time points; in contrast, however, AMPA receptor binding levels were increased in the hypothalamus at the time of puberty in the female rat. Thus, in addition to the previously reported elevation of glutamate release rates in the hypothalamus at the time of puberty, AMPA receptors may also be elevated and play a role in mediating glutamate regulatory effects on the timing of puberty in the female rat.     

Leptin and interleukin-6 in sepsis

Adenomyosis is a common pathologic finding significantly related to the menstrual and reproductive characteristics of women. Although noted during younger reproductive years, it usually presents in women over 35 years of age. For those with a strong desire to preserve fertility, there is presently no uniform agreement on the most appropriate therapeutic methods to manage the condition. Herein, we present a case of long-term secondary infertility with successful pregnancy after treatment of deep adenomyosis with cytoreductive surgery and a subsequent six-month course of gonadotropin-releasing hormone agonist (GnRHa) therapy. For those who want to conceive, early combined GnRHa therapy immediately following cytoreductive surgery and a delay of four to six months before attempting to fall pregnant is advisable. This is because adenomyosis tends to recur rapidly and the myometrium can be significantly disrupted during surgery. The major obstetric complications, such as uterine atony, rupture or placenta accreta, do not increase with adenomyosis during pregnancy. Although two events of threatened abortion and one of preterm labor were encountered during the pregnancy course, a healthy 2,900-g female was delivered by low transverse cesarean section at term. A cesarean section was performed because of previous large cytoreductive surgery. In contrast to GnRHa therapy alone, we report an effective alternative to hysterectomy in order to maintain fertility and achieve successful pregnancy.     

Endocrine biochemistry of puberty

Puberty corresponds to the development of gonads and secondary sexual characteristics, and on a biological point of view, to the functional maturation of the gonadal axis. Puberty begins at the age of 11.5 to 12 years in males and 10.5 to 11 years in females. Depending on secondary sexual characteristics, particularly pubic pilosity, puberty is classified in five stages (Tanner's stages). During puberty growth velocity increases in response to gonadal steroid secretion. From a biochemical point of view, three steps are involved in the development of the hypothalamo-hypophysogonadal axis: 1. nocturnal hypothalamic GnRH secretion increases and becomes pulsatile (a peak every 60 to 90 min); 2. the pituitary gonadotrophins FSH and LH follow the same pattern of secretion as GnRH; increase of GnRH and FSH/LH secretion is due to a decrease in hypothalamo-hypophysal sensitivity to the negative feed back exerted by circulating gonadal steroids; 3. secretion of estradiol in females and testosterone in males increases, as a consequence of pituitary stimulation. Hormonal exploration of puberty is mainly based on the measurement of FSH-LH and testosterone or estradiol. SDHA is also measured to investigate adrenal androgen secretion, which increases three or four years before puberty; this is related to the maturation of adrenal androgenic function (adrenarche). Dynamic tests are used to evaluate the biological stage of puberty (LH-RH test) and to measure the functional capacity of the testes. Pubertal abnormalities can theoretically be divided into precocious and delayed puberty. In the former, clinical and biological characteristics are used to define: dissociated puberties, central precocious puberty and peripheral precocious puberty. In the latter, hypogonadism has either a central origin (hypogonadotropic hypogonadism) or peripheral origin (hypergonadotropic hypogonadism).     

Delayed puberty in obese boys: comparison with constitutional delayed puberty and response to testosterone therapy

OBJECTIVE: To evaluate the results of a brief course of testosterone therapy in boys with delayed puberty and to compare the responses seen in boys with constitutional delayed puberty (CDP), boys with obesity, and boys with possible gonadotropin deficiency. Design and setting: A retrospective chart review was done for 36 boys aged 14 years or older, seen between 1983 and 1996 because of delayed puberty, who were given 4 monthly injections of testosterone, 100 mg/mo, and had adequate follow-up. RESULTS: There were 23 boys whose findings before and after treatment were consistent with a diagnosis of CDP. Testosterone treatment increased the growth rate from 4.3 cm/y to 11.2 cm/y (P <.00001), and mean testis length increased 0.6 to 0.8 cm in all (from a mean of 2.9 to 3.6 cm, P <.00001) in the 4 months after testosterone treatment. Serum testosterone 4 months after therapy was higher than that before therapy (P =.00003). Of 5 boys with growth hormone deficiency but unknown gonadotropin status, 2 had lack of progression after testosterone therapy and were believed to have permanent gonadotropin deficiency. Seven of the 36 boys were obese (body mass index, >25), and 6 had a response to testosterone similar to boys with CDP with clear pubertal progression. One obese boy and one nonobese boy were diagnosed as having isolated gonadotropin deficiency. CONCLUSIONS: Monitoring the growth and genital responses to a 4-month course of testosterone injections helps to differentiate CDP from gonadotropin deficiency in boys with delayed puberty. Obese boys constitute a distinct category of boys with pubertal delay in terms of their growth, but their response to testosterone is similar to that observed in boys with classic CDP.     

Prevalence and incidence of enuresis before puberty

The effects of hypochlorite (HOCl/OCl-) on the content of carotenoids (trans-lycopene, 5-cis-lycopene, alpha- and beta-carotene) and oxycarotenoids (lutein, zeaxanthin, trans- and cis-2',3'-anhydrolutein, alpha-and beta-cryptoxanthin) in human blood low-density lipoproteins (LDL) were compared using HPLC. Hypochlorite decreased the content of all the above-mentioned pigments in LDL. However, it was more reactive towards carotenoids rather than to their oxy derivatives. The ability of carotenoids and oxycarotenoids to scavenge HOCl/OCl- decreases in the series: trans-lycopene approximately 5-lycopene > alpha-carotene > beta-carotene > zeaxanthin > alpha-cryptoxanthin > cis-2',3'-anhydrolutein > beta-cryptoxanthin > trans-2',3'-anhydrolutein > lutein. Preincubation of LDL with hypochlorite decreased their resistance to CU(2+)-induced accumulation of dienic conjugates that are produced in the course of lipid peroxidation. The data suggest that hypochlorite-induced destruction of carotenoids in LDL decreases their resistance to oxidative modification, thus promoting the development of early stages of atherosclerosis.     

Integrated concentrations of luteinizing hormone and puberty

Integrated serum concentrations of luteinizing hormone have been compared among 30-minute collections from 10 boys (6-18 years old) and 5 girls (5-11 years old). This study suggests that perpubertal as well as pubertal boys have greater mean integrated concentrations of LH during sleep than during waking. One of two pubertal girls had greater concentrations of LH during sleep, while three prepubertal girls did not.     

Leptin: its pharmacokinetics and tissue distribution

OBJECTIVE: The pharmacokinetics and tissue distribution of leptin in rats was investigated. DESIGN: A catheter was inserted in the right jugular vein of rats on the day prior to experiment. The next day, blood was sampled and then a tracer dose of radioiodinated hormone was administered via the catheter. Thereafter, small (200 microl) samples of blood were taken at regular intervals. Two experiments were conducted over different sampling times. TCA precipitated radioactivity was counted in samples of plasma and tissues. Pharmacokinetic parameters were calculated after fitting a bi-exponential equation describing a two-pool model of plasma leptin distribution. Selected time-point plasma samples were fractioned using size exclusion chromatography and the leptin distribution determined. RESULTS: The two pool model described the pharmacokinetics of leptin in two forms: an initial fast decaying pool (t(1/2) = 3.4 min) and a slower decaying pool (t(1/2) = 71 min) with an overall clearance rate of 6.16 ml/min/kg. Size exclusion chromatography showed a persistent peak (all time-points tested) of 125I-leptin corresponding to the plasma albumin peak. The size of the free 125I-leptin peak became diminished or absent in later time-point plasma samples. Tissue distribution of leptin at 60 min and 180 min time-points showed that the small intestine contained the highest concentration of leptin, almost four times the level found in kidneys, liver, stomach and lungs. 125I-leptin was least abundant in skin, muscle, heart, caecum and brain. CONCLUSION: The pharmacokinetics of leptin are affected by three important factors: 1) its ability to bind to a plasma carrier molecule which increases its half-life; 2) its association with abundant peripheral tissue binding sites which creates an additional pool of leptin and 3) the rate of synthesis of leptin which may be less important than originally believed as the prolonged half-life and the additional pool of tissue binding sites are important factors in determining its plasma concentration.