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GHRELIN LEVELS FROM FETAL LIFE THROUGH EARLY ADULTHOOD: RELATIONSHIP WITH ENDOCRINE AND METABOLIC AND ANTHROPOMETRIC MEASURES LEANDRO SORIANO-GUILLE´N, MD, VICENTE BARRIOS, PHD, JULIE A. CHOWEN, PHD, IGNACIO SA´NCHEZ, MD, SANTIAGO VILA, MD, JOSE´ QUERO, MD, PHD, AND JESU´S ARGENTE, MD, PHD
Objective To establish mean plasma ghrelin levels during fetal life and childhood. Study design Cord blood was obtained at birth from premature (n = 29) and full-term newborns (n = 124). Fasting blood samples were taken from 224 normal subjects divided according to Tanner stage and sex. Ponderal index or body mass index was determined. Ghrelin; insulin-like growth factor (IGF)-I; IGF-II; IGF binding proteins 1, 2, and 3; insulin; glucose; and leptin levels were measured.
Results Ghrelin levels did not differ between preterm and full-term newborns. Ghrelin increased significantly after birth, peaking during the first 2 years of life, then decreasing until the end of puberty. Ghrelin levels correlated negatively with anthropometric variables in full-term newborns and postnatally, but not in preterm newborns. A positive correlation between ghrelin and IGF binding protein 1 was found. Conclusions Ghrelin changes significantly throughout development, correlating with anthropometric and metabolic parameters during extrauterine life. The highest levels of ghrelin are found during early postnatal life, when growth hormone begins to exert its effects on growth and important changes in food intake occur, suggesting that this hormone may participate in these processes. (J Pediatr 2004;144:30-5)
he recent discovery of ghrelin, an acylated 28 amino acid peptide,1 has added new perspectives to our understanding of the control of food intake, energy balance, and growth. Ghrelin is primarily secreted by the stomach and duodenum, although a minor portion of ghrelin synthesis occurs in other sites such as the hypothalamus, pituitary, and lung. Ghrelin can bind to two different receptors2: growth hormone secretagogue receptor 1a, involved in the control of growth hormone (GH) secretion, and growth hormone secretagogue receptor 1b, whose function remains unknown. A new cell type in the human pancreas, lung, and stomach produces ghrelin in the fetus, suggesting an important role for this peptide in intrauterine life.3,4 In addition to its GH-releasing properties,5 ghrelin stimulates appetite, reduces fat utilization, produces adiposity,6-8 and induces hyperglycemia.9 Moreover, ghrelin is increased after fasting10 and decreased after feeding.11,12 These data suggest that ghrelin plays an important role in feeding and GH secretion and raises the question whether during gestation and in early extrauterine life, ghrelin is implicated in the control of growth and metabolism. It is well established that insulin, insulin-like growth factors (IGFs), and their binding proteins (IGFBPs) play an important role in the regulation of fetal growth.13,14 These factors are also good measures for the evaluation of growth during extrauterine life15 and are altered in nutritional disorders affecting systemic growth.16,17 Circulating levels of
T
AGA ANOVA BMI GH IGF
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Adequate for gestational age Analysis of variance Body mass index Growth hormone Insulin-like growth factor
IGFBP LGA PI SGA
Insulin-like growth factor binding protein Large for gestational age Ponderal index Small for gestational age
See related article, p 36.
From the Department of Pediatric Endocrinology and Research and the Department of Biochemistry, Universidad Auto´noma, Hospital Infantil Universitario Nin˜o Jesu´s; the Pediatric Intensive Care Unit. Universidad Complutense, Hospital Infantil Universitario 12 de Octubre; and the Department of Neonatology, Universidad Auto´noma, Hospital Infantil Universitario La Paz, Madrid, Spain. Submitted for publication Apr 25, 2003; revision received July 21, 2003; accepted Aug 29, 2003. Reprint requests: Jesu´s Argente, MD, PhD, Department of Pediatric Endocrinology and Research, Hospital Infantil Universitario Nin˜o Jesu´s, Avda Mene´ndez Pelayo 65, E-28009 Madrid, Spain. E-mail: [email protected] 0022-3476/$ - see front matter Copyright ª 2004 Elsevier Inc. All rights reserved. 10.1016/j.jpeds.2003.08.050
leptin, a hormone secreted by adipocytes and the placenta that acts as a hormonal feedback signal to regulate fat stores through a hypothalamic mechanism, are positively correlated with intrauterine growth18 and are also modulated in nutritional disorders.19 Although it is known that ghrelin has important metabolic effects postnatally, there are few data concerning cord plasma ghrelin levels in newborns20 and in normal controls21 and their relationship with anthropometric data and the previously mentioned endocrine factors implicated in growth and nutritional disorders. To investigate further the role of ghrelin in growth and the evolution of ghrelin levels from the fetus through puberty, we analyzed (1) the cord plasma ghrelin levels in term and preterm newborns, (2) the plasma ghrelin levels in normal controls, (3) the relationship between ghrelin and anthropometric data, (4) the relationships between ghrelin and leptin, insulin, IGF-I, IGF-II, and IGFBP-1 in newborns, and (5) the relationships between ghrelin and leptin, insulin, glucose, IGF-I, IGFBP-1, IGFBP-2, and IGFBP-3 in normal postnatal subjects.
SUBJECTS AND METHODS Subjects NEWBORNS. The study cohort included 29 premature newborns (13 male and 16 female patients), four <32 weeks’ gestational age with a mean gestational age of 31.1 ± 0.1, and 25 with a period of gestation ranging from 32 to 36 weeks with a mean gestational age of 35.1 ± 0.3 weeks. We also included 124 full-term newborns (60 male and 64 female patients) with a mean gestational age of 39.4 ± 0.02 weeks. Only neonates born by uncomplicated vaginal delivery and without hypoxia were included. Mothers with pre-eclampsia, hypertension, or diabetes or who smoked were excluded. Gestational age was determined from the date of the last menstrual period and was confirmed by early ultrasound scan. Cord blood samples were obtained at birth. Venous cord blood was collected in tubes containing EDTA plus aprotinin and centrifuged at 48C. Plasma was stored at 0001808C until assayed. To evaluate the intrauterine nutritional state, the ponderal index (PI: weight [g]/length3 [cm] 3 100) was calculated. The newborns were then divided into three groups according to Spanish PI tables22: >1 SD (high PI), between 00011 and 1 SD (medium PI), and <00011 SD (low PI). Birth weight was measured and the newborns were divided into adequate for gestational age (AGA: 10th to 90th percentile), small for gestational age (SGA: < 10th percentile), and large for gestational age (LGA: 90th percentile) according to Spanish standard curves.23 The weight was determined by using a platform scale with an accuracy of ±10 g, and the length was measured by using a Holtain infantometer (Crymych, Wales, UK). All mothers were informed of the purpose of the study and gave consent as required by the local human ethics committee. Ghrelin Levels from Fetal Life Through Early Adulthood: Relationship with Endocrine and Metabolic and Anthropometric Measures
Tanner Stages I-V We also included 224 normal Spanish children divided into five groups according to Tanner stage: I (n = 87), 45 male and 42 female patients; II (n = 55), 21 male and 34 female patients; III (n = 20), eight male and 12 female patients; IV (n = 22), 10 male and 12 female patients; and V (n = 40), 16 male and 24 female patients. Control subjects were referred to our division for suspected endocrine abnormalities and were found to be normal with height between p10 and p90, weight between p10 and p85, and body mass index (BMI) between 00012 and +2 SD according to Spanish standards.24 Blood samples were obtained in the morning from fasting subjects into chilled tubes containing EDTA (1 mg/mL) plus aprotinin (500 U/mL). The tubes were centrifuged and stored at 0001808C until assayed. The BMI was calculated as weight (kg)/height (m2). The BMI SD score was based on normative data from Spanish children.24 All subjects were informed of the purpose of the study and gave consent as required by the local human ethics committee.
Biochemical Measurements Plasma ghrelin levels were measured by a commercial radioimmunoassay (Phoenix Pharmaceutical, Belmont, Calif ) using a polyclonal antibody that recognizes octanoylated and nonoctanoylated ghrelin and 125I-ghrelin as a tracer molecule. The intra-assay and interassay coefficients of variation were 5.0% and 11.2%, respectively. Assay sensitivity was 12 pg/mL. Serum IGF-I, IGF-II, IGFBP-1, IGFBP-2, IGFBP-3, insulin, and leptin were measured as previously reported.3-5,7 Plasma glucose was measured by the glucose oxidase method on a Beckman Glucose Analyzer (Full

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