During the past decade, possible advancement in timing of puberty has been reported in the United States. In addition, early pubertal development and an increased incidence of sexual precocity have been noticed in children, primarily girls, migrating for foreign adoption in several Western European countries. These observations are raising the issues of current differences and secular trends in timing of puberty in relation to ethnic, geographical, and socioeconomic background. None of these factors provide an unequivocal explanation for the earlier onset of puberty seen in the United States. In the formerly deprived migrating children, refeeding and catch-up growth may prime maturation. However, precocious puberty is seen also in some nondeprived migrating children. Attention has been paid to the changing milieu after migration, and recently, the possible role of endocrine- disrupting chemicals from the environment has been considered. These observations urge further study of the onset of puberty as a possible sensitive and early marker of the interactions between environmental conditions and genetic susceptibility that can influence physiological and pathological processes.

Puberty presents remarkable individual differences in timing reaching over 5 years in humans. We put emphasis on the two edges of the age distribution of pubertal signs in humans and point to an extended distribution towards earliness for initial pubertal stages and towards lateness for final pubertal stages. Such distortion of distribution is a recent phenomenon. This suggests changing environmental influences including the possible role of nutrition, stress and endocrine disruptors. Our ability to assess neuroendocrine effects and mechanisms is very limited in humans. Using the rodent as a model, we examine the impact of environmental factors on the individual variations in pubertal timing and the possible underlying mechanisms. The capacity of environmental factors to shape functioning of the neuroendocrine system is thought to be maximal during fetal and early postnatal life and possibly less important when approaching the time of onset of puberty.

Natural hormones and some synthetic chemicals spread into our surrounding environment share the capacity to interact with hormone action and metabolism. Exposure to such compounds can cause a variety of developmental and reproductive detrimental abnormalities in wildlife species and, potentially, in human. Many experimental and epidemiological data have reported that exposure of the developing fetus or neonate to environmentally relevant concentrations of some among these endocrine disrupters induces morphological, biochemical and/or physiological disorders in brain and reproductive organs, by interfering with the hormone actions. The impact of such exposures on the hypothalamic-pituitary-gonadal axis and subsequent sexual maturation is the subject of the present review. We will highlight epidemiological human studies and the effects of early exposure during gestational, perinatal or postnatal life in female rodents.

An increase in the frequency of pulsatile gonadotropin-releasing hormone (GnRH) secretion in vitro and a reduction in LH response to GnRH in vivo characterize hypothalamic-pituitary maturation before puberty in the female rat. In girls migrating for international adoption, sexual precocity is frequent and could implicate former exposure to the insecticide dichlorodiphenyltrichloroethane (DDT), since a long-lasting DDT derivative has been detected in the serum of such children. We aimed at studying the effects of early transient exposure to estradiol (E(2)) or DDT in vitro and in vivo in the infantile female rat. Using a static incubation system of hypothalamic explants from 15-day-old female rats, a concentration- and time-dependent reduction in GnRH interpulse interval (IPI) was seen during incubation with E(2) and DDT isomers. These effects were prevented by antagonists of alpha-amino-3-hydroxy-5-methylisoxazole-4 propionic acid (AMPA)/kainate receptors and estrogen receptor. Also, o,p'-DDT effects were prevented by an antagonist of the aryl hydrocarbon orphan dioxin receptor (AHR). After subcutaneous injections of E(2) or o,p'-DDT between Postnatal Days (PNDs) 6 and 10, a decreased GnRH IPI was observed on PND 15 as an ex vivo effect. After DDT administration, serum LH levels in response to GnRH were not different from controls on PND 15, whereas they tended to be lower on PND 22. Subsequently, early vaginal opening (VO) and first estrus were observed together with a premature age-related decrease in LH response to GnRH. After prolonged exposure to E(2) between PNDs 6 and 40, VO occurred at an earlier age, but first estrus was delayed. We conclude that a transient exposure to E(2) or o,p'-DDT in early postnatal life is followed by early maturation of pulsatile GnRH secretion and, subsequently, early developmental reduction of LH response to GnRH that are possible mechanisms of the subsequent sexual precocity. The early maturation of pulsatile GnRH secretion could involve effects mediated through estrogen receptor and/or AHR as well as AMPA/kainate subtype of glutamate receptors.

The present study aimed to investigate the effects of leptin and ghrelin on pulsatile pulsatile gonadotrophinreleasing hormone (GnRH) secretion in vitro with emphasis on neuropeptide mediators and changes between prepuberty (15 days) and sexual maturity (50 days) in the male rat. When hypothalamic expiants were studied 90 min after an intraperitoneal injection of leptin, ghrelin or agouti-related protein (AgRP) at 15 days, the GnRH interpulse interval (IPI) was significantly increased by ghrelin and AgRP and decreased by leptin. At 50 days, an increase in GnRH IPI was also caused by ghrelin and AgRP. When the peptides were directly incubated with the expiants, the effects of leptin and AgRP in vitro were consistent with those seen after in vivo administration. By contrast, ghrelin resulted in a reduction of GnRH IPI and this was observed at 15 days only. To delineate the neuropeptide mediators of leptin and the effects of ghrelin in the hypothalamus, various hypothalamic neuropeptides and antagonists were used in vitro. At 15 days, the GnRH IPI was significantly decreased after incubation with cocaine and amphetamine-regulated transcript (CART), α-melanocyte-stimulating hormone, corticotrophin-releasing factor (CRF) and neuropeptide Y (NPY). The reduction of GnRH IPI caused by leptin was partially prevented by either an anti-CART antiserum or SHU 9119, a melanocortin MC3/MC4 receptor antagonist or a CRF receptor antagonist. The NPY-Y5 receptor antagonist did not influence the effects of leptin whereas that antagonist totally prevented the decrease in GnRH IPI caused by ghrelin. The ghrelin-induced reduction of GnRH IPI was partially prevented by SHU 9119. When used alone, SHU 9119 or a CRF-receptor antagonist resulted in increased GnRH IPI at 50 days while they had no effects at 15 days. The NPY-Y5 receptor antagonist resulted in increased GnRH IPI at 15 and 50 days. In conclusion, leptin and ghrelin show opposing effects on pulsatile GnRH secretion after administration in vivo whereas they both have stimulatory effects in vitro. Such effects involve consistently the anorectic peptides CART and CRF for leptin that are mainly active at 15 days. The melanocortigenic system appears to mediate the effects of both leptin and ghrelin. The effects of ghrelin also involve NPY receptors and operate effectively before and at sexual maturity.Key words: gonadotrophin-releasing hormone, leptin, ghrelin, AgRP, α-MSH, CRF, rat.In the hypothalamus, the control of energy balance is tightly regulated through complex interactions between peripheral nutrition-related hormones and hypothalamic neuropeptides (1, 2). Several decades ago, a link between fat mass and menstrual cyclicity already suggested that nutrition-related hormones could influence the hypothalamic control of puberty and reproduction (3). Further insight came from isolation of leptin, an adipocyte-derived anorectic hormone involved in the regulation of body weight, as well as a facilitatory or permissive control of puberty and reproduction (4, 5). We have pre...

The frequency of infection at the time of admission with upper gastrointestinal haemorrhage has been determined in 149 successive cirrhotic patients admitted to an intensive care unit. Infection status was investigated by clinical examination, chest X-ray, and blood, urine and ascitic fluid culture. At initial examination infection was present in 32 patients (22 per cent) and was often in the form of septicaemia or spontaneous peritonitis; the bacteria responsible were frequently digestive in origin. At endoscopy, acute lesions of gastroduodenal mucosa were more frequent among infected patients, whereas gastro-oesophageal varices and chronic gastroduodenal ulcers were more frequent among the non-infected patients. Acute mucosal lesions were observed in 70 per cent of infected patients and in 19 per cent of non-infected patients. The mortality rate was higher in infected patients. Infection and the frequency of acute mucosal lesions were related to the severity of the cirrhosis. It is suggested that these lesions could be due to stress secondary to infection.

Leptin may act as a negative feedback signal to the hypothalamic control of appetite through suppression of neuropeptide Y (NPY) secretion and stimulation of cocaine and amphetamine regulated transcript (CART). We aimed at studying the effects of leptin, CART and NPY on the hypothalamic control of the pituitary-gonadal system. Pulsatile gonadotropin-releasing hormone (GnRH) secretion was studied in vitro using retrochiasmatic hypothalamic explants from adult rats. In the female, GnRH pulse amplitude was significantly 27 26increased by leptin (10 M) and CART (10 M) irrespective of the estrus cycle phase while no such effects were seen in the male. The GnRH interpulse interval was not affected in both sexes. Passive immunoneutralization against CART caused a reduction in GnRH pulse 27 amplitude in the female. A slight but significant increase in GnRH pulse amplitude was caused by NPY (10 M) in the female. However, 26GnRH pulse amplitude was not affected by a Y5-receptor antagonist (10 M) while the interpulse interval was significantly increased as shown previously in the male. The increase in GnRH pulse amplitude caused by leptin was totally prevented by coincubation with an 27 anti-CART antiserum whereas it was not affected by coincubation with the NPY Y5-receptor antagonist (10 M). In conclusion, leptin and NPY show separate permissive effects on GnRH secretion in the adult rat hypothalamus. In both sexes, NPY is prominently involved in the control of the frequency of pulsatile GnRH secretion through the Y5 receptor subtype. Leptin causes a female-specific facilitatory effect on GnRH pulse amplitude which is mediated by CART and which occurs irrespective of the estrus cycle phase.

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