Early and late weight gain and the timing of puberty

Molecular and Cellular Endocrinology 254–255 (2006) 140–145 Early and late weight gain and the timing of puberty David B. Dunger ∗ , M. Lynn Ahmed, Ken K. Ong Department of Paediatrics, University of Cambridge, Addenbrooke’s Hospital, Box 116, Cambridge CB2 2QQ, UK Abstract Nutrition is an important regulator of the tempo of growth and obesity is usually associated with tall childhood stature and earlier pubertal development. Several longitudinal studies have demonstrated that timing of puberty is most closely linked to infancy weight gain: suggesting an early window for programming of growth and development. Earlier puberty in the UK MRC 1946 birth cohort was related to smaller size at birth and rapid growth between 0 and 2 years. Rapid early weight gain leads to taller childhood stature and higher insulin-like growth factor I (IGF-I) levels, possibly through early induction of growth hormone (GH) receptor numbers, and such children are also at risk of childhood obesity. In the Avon Longitudinal Study of Parents and Children, rapid infancy weight gain was associated with increased risk of obesity at 5 and 8 years, with evidence of insulin resistance, exaggerated adrenarche and reduced levels of sex hormone binding globulin (SHBG). Potentially the elevated IGF-I and adrenal androgen levels, increased aromatase activity and increased ‘free’ sex steroid levels consequent to lower SHBG levels could all promote activity of the GnRH pulse generator. In addition obese children have higher leptin levels, a proven permissive factor in initiating LH pulsatility. Obesity could also affect the rate of progression through puberty as nutrition and SHBG may act respectively as an accelerator and brake on peripheral sex steroid action. Early weight gain and early pubertal development might also be associated with loss of the pubertal growth spurt perhaps through obesity-related suppression of GH secretion. Trans-generational recurrence of low birth weight, early catch-up weight gain, earlier menarche, and shorter adult stature have been observed in women, and could contribute to the strong heritability in age at menarche. © 2006 Elsevier Ireland Ltd. All rights reserved. Keywords: Tempo of growth; Puberty; Catch-up growth; Fetal growth restraint 1. Introduction The relationship between increased childhood weight gain, fat acquisition and earlier pubertal maturation has been explored over many years (Garn and Haskell, 1959; Garn et al., 1983). Generally children who develop puberty earlier are more likely to be overweight during childhood, and over 50 years ago Tanner (1955) observed from the Harvard Growth Study that early maturation, based on age at peak height velocity, was associated with a higher weight/height ratio (Cameron and Demerath, 2002). Buckler’s longitudinal study of schoolchildren in Leeds, UK clearly demonstrated differences in body weight between the earliest 20% of developing children and the 20% developing latest (Buckler, 1990). In such studies the direction of association is unclear, and association between early pubertal development and greater childhood gains in fat mass may simply reflect the effects of early maturation on acquisition of fat and lean body mass. However, there is increasing evidence that rate of weight gain during very early childhood may be the more critical deter- ∗ Corresponding author. Tel.: +44 1223 762944; fax: +44 1223 336996. E-mail address: dbd25@cam.ac.uk (D.B. Dunger). 0303-7207/$ – see front matter © 2006 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.mce.2006.04.003 minant of the timing of puberty in both boys and girls (Mills et al., 1986; Cooper et al., 1996). In the UK MRC 1946 Birth Cohort, growth and weight gain during the first 2 years of life clearly predicted the subsequent timing of menarche in girls (dos Santos Silva et al., 2002). Other studies have identified association between the timing of puberty and weight gain as early as 6 months of life (Adair, 2001). It has been suggested that infancy may be an early “window” during which variations in nutrition may programme subsequent growth and development, and support for this hypothesis was first provided through early animal experimental studies carried out by McCance and Widdowson (1956). The mechanisms that underpin these observed links between early weight gain and timing of puberty are still largely unknown. There is, however, circumstantial evidence to support a central role for insulin resistance and obesity in triggering other hormonal changes that may affect the tempo of growth and the initiation of pubertal development. 2. Peri-natal influences on early childhood weight gain Several epidemiological studies have indicated that size at birth may influence early postnatal weight gain, subsequent fat distribution and long-term risk for obesity. In a study of 300,000 D.B. Dunger et al. / Molecular and Cellular Endocrinology 254–255 (2006) 140–145 19-year-old male survivors from 1944/1945 Dutch famine, there was an almost twofold increase in obesity risk in men whose mothers were exposed to famine during the first trimester of pregnancy (Ravelli et al., 1976). Among 70–75-year-old men studied by Gale et al. (2001) using Dual Energy X-ray Absorptiometry (DXA), low birth weight was associated with reduced lean tissue mass and greater body fat relative to current weight. Such long-term associations between birth weight and obesity risk may reflect the prenatal programming of adipogenesis. However, fetal growth restraint is usually followed by compensatory rapid weight gain during infancy and it is perhaps this early postnatal period which may contribute most to the subsequent risk of obesity and adverse body fat distribution. Growth data from large contemporary birth cohorts such as the Avon Longitudinal Study of Parents and Children (ALSPAC) (Golding et al., 2001) have confirmed earlier observations (Tanner, 1986) that around 25% of all newborns show rapid or “catch-up” weight gain in the first one to two postnatal years (Ong et al., 2000). These early postnatal growth patterns can be predicted by maternal influences on fetal growth such as: mothers’ parity, smoking during pregnancy, mothers’ pregnancy weight gain and her own birth weight (Ong et al., 2000, 2002a). Correlations between offspring body size and midparental height centiles improves during infancy indicating that this rapid weight gain may indeed represent “catch-up” growth that follows earlier growth restraint during prenatal development and it is generally largely completed by 12 months. Infancy growth is largely regulated by nutrition and the rapid infancy weight gain may be driven by a larger appetite, as suggested by early infant feeding studies (Ounsted and Sleigh, 1975) and by the association between levels of the satiety hormone leptin in cord blood at birth with subsequent rate of weight gain (Ong et al., 1999). Formula milk is more energy dense than breast milk and this could explain the marked differences in rate of early weight gain between formula fed and breast fed infants (Ong et al., 2002a). Among formula fed infants recent data from the ALSPAC cohort confirmed that levels of dietary energy intake at four months correlate with rate of weight gain during infancy (Ong et al., 2006). These early postnatal patterns of weight gain appear to have long lasting effects and the ALSPAC cohort infants who are relatively thin at birth and showed postnatal catch-up became the heaviest children at age 5 years (Ong et al., 2000). Similar consequences of rapid weight gain in the first few months of life have been seen in two large studies from the USA and Seychelles (Stettler et al., 2002a, 2002b). We have also recently observed that a faster weight gain during the first six months of life predicted greater percentage body fat at age 17 years, independent of childhood weight gain, maternal size and social factors in the Stockholm weight development study (Ekelund et al., 2004). Infant catch-up weight gain also seems to influence the distribution of body fat. In ALSPAC, the children who showed early catch-up growth had the largest waist circumference at age 5 years (Ong et al., 2000). In other populations the transition from low birth weight to normal BMI during childhood has been associated with wide variations in body composition and increased central fat deposition in children and adults (Law 141 et al., 1992; Yajnik, 2000; Loos et al., 2001, 2002). In the third National Health and Nutritional Examination Survey (NHANES III) (1988–1994) children born small for gestational age showed reduced lean tissue and higher percentage of body fat (Hediger et al., 1998) and studies from Australia have reported a similar association between low birth weight, increased current weight and increased central fat deposition (Garnett et al., 2001). 3. Insulin resistance during childhood It could be predicted that rapid infancy weight gain and the development of central adiposity during childhood may be linked to the development of insulin resistance and this indeed appears to be the case. The transition from relatively low birth weight to larger childhood weight is associated with an increased risk of insulin resistance as demonstrated by fasting insulin levels in 8-year-old children from Pune, India (Bavdekar et al., 1999). Other studies have confirmed, in children and adults, that the combination of low birth weight and larger current weight is the prime determinant of insulin sensitivity (Leger et al., 1997; Jaquet et al., 2000). From the ALSPAC cohort we have reported that infant catch-up weight gain was associated with insulin resistance at age 8 years (Ong et al., 2004a). In that study, as in earlier studies in adults (McKeigue et al., 1998), the effects of low birth weight per se was only really seen in those subjects in the greatest tertile of current BMI and the degree to which low birth weight or rapid postnatal weight gain directly contributes to insulin resistance is still a little unclear (Lucas et al., 1999). Thus, although babies who are large at birth and remain overweight during childhood may contribute to subsequent overall obesity risk based on BMI, it is those babies who are relatively smaller at birth and who show rapid infancy weight gain who may be most at risk for the development of increased body fat, central adiposity and insulin resistance. In a recent case control study in Chile, infants who showed rapid catch-up growth had higher fasting insulin levels as early as 1 year of age indicative of insulin resistance, even though they may not have achieved the BMI of control infants (Soto et al., 2003). One could speculate that even at that early age there may be differences in body fat distribution and this has been supported by recent pilot data in 3-year-old children born small who show rapid postnatal catchup growth (de Zegher et al., 2005). These very early changes in fat distribution and insulin sensitivity could have important consequences on the subsequent tempo of growth and possibly on the initiation of earlier pubertal development. 4. Tempo of statural growth Tempo of statural growth can be defined as the rapidity of early height gain and bone maturation, and it is closely linked to the timing of puberty. Onset of puberty occurs at a mean bone age of 11.1 years in girls and 11.7 years in boys (Marshall, 1974). The tempo of growth may be largely established within the first 2 years of life, with greater weight gain being associated with a more rapid tempo of height gain. Poor weight gain is associated with a delayed growth and, if severe, with ultimate stunting of adult height (Crowne et al., 1990, 1991; Albanese 142 D.B. Dunger et al. / Molecular and Cellular Endocrinology 254–255 (2006) 140–145 and Stanhope, 1995). In the ALSPAC cohort, rapid infant weight gain was associated with taller stature at age 8 years than that predicted from mid parental target height, thus supporting the concept that height tempo may be established during the first 2 years of life. In an analysis of secular trends in Japanese growth data, Cole observed that mean birth length had not changed in 40 years (1950–1990), but by age 2 years there had been an increase of 10 mm per decade in length (Cole, 2003). This means that by the age of 2 years children of the 1990s were 4 cm taller than those of the 1950s. This amount is similar to the increase in adult height gained in that population and indicates that all of the long-term height gain was achieved by 2 years of age. Indeed Brook (1992) and others have shown that while infant weight gain is associated with alteration of the tempo of growth, later changes in weight gain during mid-childhood have very little long-term effect on height trajectory. The mechanism whereby changes in infant weight gain could not only establish the later tempo of growth but also the timing of pubertal development remains speculative. Growth during infancy is largely regulated by insulin and insulin-like growth factor I (IGF-I), and the effect of growth hormone (GH) deficiency becomes increasingly evident only after the age of 1 year (Hanew et al., 2005). This age coincides with the induction of GH regulated IGF-I production and is reflected in the gradual appearance in the circulation GH binding protein (the soluble extra cellular domain of the GH receptor) during the first years of life (Low et al., 2001). The majority of circulating IGF-I is derived from the liver and the hepatic GH receptor is insulin dependent (Massa et al., 1993). Rapid infancy weight gain and the development of insulin resistance and higher circulating insulin levels could therefore increase GH receptor numbers and IGF-I generation. In the ALSPAC cohort rapid infancy weight gain was associated with not only greater height gain during childhood but also higher IGF-I levels (Ong et al., 2002b). However, such a model may be too simplistic as there are many other hormones (such as leptin) that may be associated with rapid infant weight gain, and could contribute to putative effects on the GnRH pulse generator, and thus link early tempo of growth to age at initiation of puberty. 5. Weight gain and initiation of pubertal development Frisch and Revelle (1970, 1971), in their study of early and late maturing girls suggested that there may be a critical amount of body fat required for normal development and in particular establishment of a normal menstrual cycle. Specifically they suggested a critical weight of 48 kg, or body fat level of 22%, had to be achieved to allow puberty to progress (Frisch and Revelle, 1971; Apter et al., 1978; Van der Spuy, 1985). This ‘critical weight’ hypothesis has been controversial (Ellison, 1982; Scott and Johnston, 1982; Crawford and Osler, 1975), but the discovery of leptin in 1994 (Zhang et al., 1994) provided a candidate hormone that might sense body fat levels and feedback to the brain to activate central gonadotrophin secretion. Higher leptin levels following rapid infancy weight gain could provide the trigger for early pubertal development. Leptin is secreted by the adipocytes and signals through its hypothalamic receptor to regulate appetite and metabolism (Zhang et al., 1994). Several observations in rodents (Ahima et al., 1997; Chehab et al., 1997) promoted the theory that leptin may be the major trigger for the timing of puberty and in humans a longitudinal study of children during adolescence reported a small peak in leptin levels just prior to the onset of puberty (Mantzoros et al., 1997). However, this finding in humans has not been replicated and subsequent longitudinal studies have instead observed a slow but steady prepubertal rise in leptin levels (Clayton et al., 1997; Ahmed et al., 1999). Thus it is likely that rather than being a trigger, leptin may have a permissive role for the onset of puberty (Clayton et al., 1997; Cheung et al., 1997). This permissive effect has been confirmed by observations that leptin receptor deficient subjects have hypogonadotrophic hypogonadism (Clement et al., 1998; Strobel et al., 1998), and recombinant leptin administration in older but not younger children with leptin deficiency results in increased gonadotrophin pulsatility (Farooqi, 2002). More recently leptin administration to women with secondary hypothalamic amenorrhoea has been shown to increase LH pulsatility as well as ovarian volume, again suggesting a permissive role for leptin in the development of puberty (Welt et al., 2004). An increase in adrenal androgen secretion usually precedes puberty by about 2 years. This process is independent of pituitary/hypothalamic activation, but is partly controlled by ACTH. Higher levels of the adrenal androgens, dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulphate (DHEAS) have been observed in 8-year-old children who display relative low birth weight and rapid infant weight gain (Ong et al., 2004b). Increased secretion of adrenal androgens, as seen in subjects with congenital adrenal hyperplasia, is associated with earlier pubertal development (Parker, 1991). Early exaggerated adrenal androgen secretion may become clinically manifest as premature pubarche, and in girls from Barcelona, Spain this condition has been associated with low birth weight and increased weight gain during childhood (Ibanez et al., 1998). A central role for early weight gain and insulin resistance in this condition and its association with earlier pubertal development has been confirmed by studies where insulin sensitisation using Metformin has led to significant reductions in circulating adrenal androgen levels, and a delay in progression towards menarche (Ibanez et al., 2004, 2005). Insulin resistance and the associated compensatory hyperinsulinaemia will also reduce levels of sex hormone binding globulin (SHBG) (Holly et al., 1989). SHBG is thought to regulate the bioavailability of sex steroids, and high insulin levels will potentially increase the bioavailability of sex steroids (Kalme et al., 2003). In obese children, increased bioavailability of sex steroids combined with putative increased adipocyte aromatase activity, which could increase the peripheral conversion of androgens to oestrogens. Consequent higher free sex hormone levels may feedback to the hypothalamus to activate gonadotrophin secretion (Nakai et al., 1978). Increased IGF-I generation, following rapid infant weight gain, could also be an important mediator of age at pubertal development. The role of IGF-I in the initiation of puberty has been proposed over many years, but the results of studies are inconclusive (d’Alleves et al., 2000; Wilson and Suter, 2000). D.B. Dunger et al. / Molecular and Cellular Endocrinology 254–255 (2006) 140–145 Although causality is not proven by these association studies, the proposed link between early weight gain, insulin sensitivity and subsequent hormonal changes may explain the apparent gender difference in risk for early and late pubertal development. The risk for early pubertal development is more common in girls whereas the prevalence of delayed puberty is more common in boys. Girls tend to have higher insulin and IGF-I levels (Clayton and Hall, 2004; Murphy et al., 2004), greater levels of fat mass (Mast et al., 1998) and higher leptin levels during childhood (Demerath et al., 1999), and these could all contribute to the trigger for earlier pubertal development. This could reflect the evolutionary and biological importance for the development of early reproductive capacity particularly where the prenatal experience has been of poor nutrition but the postnatal experience is one of improved nutrition as reflected in rapid infancy weight gain. 6. Genetic and epigenetic determinants of postnatal weight gain and puberty The strong heritability of the timing of pubertal development has been largely studied using age of menarche in girls (Parent et al., 2003), as there are few robust markers of puberty in boys. Preliminary ALSPAC data suggest dramatic intergenerational effects with patterns of rapid infant weight gain and early pubertal development repeating in consecutive generations (Figs. 1 and 2). It has been proposed that both the prenatal and postnatal nutritional environments may programme subsequent tempo of growth and pubertal development. The relatively low birth weight newborn, who has experienced nutritional restraint in utero, will likely be followed by infancy catch-up weight gain if the postnatal nutritional environment is adequate. The rapid transition from one nutritional environment to the other may be the signal for acceleration of tempo of growth, and early induction of puberty to maximise the potential for reproduction. These transgenerational effects could be mediated through epigenetic effects of pregnancy or early postnatal nutrition on 143 Fig. 2. Childhood height relative to mid-parental height, by mother’s age at menarche. genes which regulate appetite and fat deposition, or alternatively through more Mendelian inheritance of a predisposition to rapid infancy weight gain. These early determinants of size at birth and rapid postnatal catch-up growth could be important determinants of the timing of puberty and long-term health. 7. Conclusions From the various studies reviewed above, we conclude that infancy is probably the most important age during which weight gain influences the tempo of growth and timing of puberty onset. Although we cannot infer causality from observational studies, it is reasonable to propose that the development of insulin resistance, following rapid infant weight gain, may programme the subsequent developmental outcomes with respect of growth and puberty. In contrast, larger size at birth and rapid weight gain later during childhood may have less effect on promoting the tempo of growth and puberty. While the mechanisms that link insulin resistance to tempo of growth and timing of puberty remain speculative, from an evolutionary perspective the ability of the infant to sense the change from a poor prenatal nutritional environment to a relatively improved postnatal nutrition may be advantageous in triggering a pathway of rapid growth and secondary sexual development. References Fig. 1. Childhood height relative to mid-parental height, by pattern of infant weight gain (delta weight S.D. score between birth and 2 years: catch-up > +0.67; catch-down < −0.67 S.D. scores; or no-change −0.67 to +0.67). Adair, L.S., 2001. Size at birth predicts age at menarche. Pediatrics 107 (4), E59. Ahima, R.S., Dushay, J., Flier, S.N., Prabakaran, D., Flier, J.S., 1997. Leptin accelerates the onset of puberty in normal female mice. J. Clin. Invest. 99 (3), 391–395. Ahmed, M.L., Ong, K.K., Morrell, D.J., Cox, L., Drayer, N., Perry, L., et al., 1999. Longitudinal study of leptin concentrations during puberty: sex differences and relationship to changes in body composition. J. Clin. Endocrinol. Metab. 84 (3), 899–905. Albanese, A., Stanhope, R., 1995. Predictive factors in the determination of final height in boys with constitutional delay of growth and puberty. J. Pediatr. 126 (4), 545–550. Apter, D., Viinikka, L., Vihko, R., 1978. Hormonal pattern of adolescent menstrual cycles. J. Clin. Endocrinol. Metab. 47 (5), 944–954. 144 D.B. Dunger et al. / Molecular and Cellular Endocrinology 254–255 (2006) 140–145 Bavdekar, A., Yajnik, C.S., Fall, C.H., Bapat, S., Pandit, A.N., Deshpande, V., et al., 1999. Insulin resistance syndrome in 8-year-old Indian children: small at birth, big at 8 years, or both? Diabetes 48 (12), 2422– 2429. Brook, C.G., 1992. Monitoring of growth. Lancet 340 (8819), 612. Buckler, J., 1990. A Longitudinal Study of Adolescent Growth. SpringerVerlag, London, UK. Cameron, N., Demerath, E.W., 2002. Critical periods in human growth and their relationship to diseases of aging. Am. J. Phys. Anthropol. (Suppl. 35), 159–184. Chehab, F.F., Mounzih, K., Lu, R., Lim, M.E., 1997. Early onset of reproductive function in normal female mice treated with leptin. Science 275 (5296), 88–90. Cheung, C.C., Thornton, J.E., Kuijper, J.L., Weigle, D.S., Clifton, D.K., Steiner, R.A., 1997. Leptin is a metabolic gate for the onset of puberty in the female rat. Endocrinology 138 (2), 855–858. Clayton, P.E., Hall, C.M., 2004. Insulin-like growth factor I levels in healthy children. Horm. Res. 62 (Suppl. 1), 2–7. Clayton, P.E., Gill, M.S., Hall, C.M., Tillmann, V., Whatmore, A.J., Price, D.A., 1997. Serum leptin through childhood and adolescence. Clin. Endocrinol. (Oxf.) 46 (6), 727–733. Clement, K., Vaisse, C., Lahlou, N., Cabrol, S., Pelloux, V., Cassuto, D., et al., 1998. A mutation in the human leptin receptor gene causes obesity and pituitary dysfunction. Nature 392 (6674), 398–401. Cole, T.J., 2003. The secular trend in human physical growth: a biological view. Econ. Hum. Biol. 1 (2), 161–168. Cooper, C., Kuh, D., Egger, P., Wadsworth, M., Barker, D., 1996. Childhood growth and age at menarche. Br. J. Obstet. Gynaecol. 103 (8), 814–817. Crawford, J.D., Osler, D.C., 1975. Body composition at menarche: the FrischRevelle hypothesis revisited. Pediatrics 56 (3), 449–458. Crowne, E.C., Shalet, S.M., Wallace, W.H., Eminson, D.M., Price, D.A., 1990. Final height in boys with untreated constitutional delay in growth and puberty. Arch. Dis. Child 65 (10), 1109–1112. Crowne, E.C., Shalet, S.M., Wallace, W.H., Eminson, D.M., Price, D.A., 1991. Final height in girls with untreated constitutional delay in growth and puberty. Eur. J. Pediatr. 150 (10), 708–712. d’Alleves, V., Gruaz-Gumowski, N.M., Aubert, M.L., 2000. The GH-IGF-I axis in sexual maturation: the rat paradigm. In: Bourguignon, J.P., Plant, T.M. (Eds.), The Onset of Puberty in Perspective. Elsevier Science B.V, Amsterdam, pp. 59–69. de Zegher, F.E., Dunger, D.D., Ibanez, L., 2005. The path from early growth restraint to later diabetes: body adiposity emerges between age 2 and 3 year in non-obese, low-birthweight girls. Abstract at the Endocrine Society’s 87th Annual Meeting, vol. OR34-4, p. 124. Demerath, E.W., Towne, B., Wisemandle, W., Blangero, J., Chumlea, W.C., Siervogel, R.M., 1999. Serum leptin concentration, body composition, and gonadal hormones during puberty. Int. J. Obes. Relat. Metab. Disord. 23 (7), 678–685. dos Santos Silva, I., De Stavola, B.L., Mann, V., Kuh, D., Hardy, R., Wadsworth, M.E., 2002. Prenatal factors, childhood growth trajectories and age at menarche. Int. J. Epidemiol. 31 (2), 405–412. Ekelund, U., Ong, K., Linne, Y., 2004. Both infancy and childhood weight gain predict obesity risk at age 17 years; prospective birth cohort study (SWEDES). Obes. Res. 12, A186. Ellison, P.T., 1982. Skeletal growth, fatness and menarcheal age: a comparison of two hypotheses. Hum. Biol. 54 (2), 269–281. Farooqi, I.S., 2002. Leptin and the onset of puberty: insights from rodent and human genetics. Semin. Reprod. Med. 20 (2), 139–144. Frisch, R.E., Revelle, R., 1970. Height and weight at menarche and a hypothesis of critical body weights and adolescent events. Science 169 (943), 397–399. Frisch, R.E., Revelle, R., 1971. Height and weight at menarche and a hypothesis of menarche. Arch. Dis. Child 46 (249), 695–701. Gale, C.R., Martyn, C.N., Kellingray, S., Eastell, R., Cooper, C., 2001. Intrauterine programming of adult body composition. J. Clin. Endocrinol. Metab. 86 (1), 267–272. Garn, S.M., Haskell, J.A., 1959. Fat and growth during childhood. Science 130, 1711–1712. Garn, S.M., LaVelle, M., Pilkington, J.J., 1983. Comparisons of fatness in premenarcheal and postmenarcheal girls of the same age. J. Pediatr. 103 (2), 328–331. Garnett, S.P., Cowell, C.T., Baur, L.A., Fay, R.A., Lee, J., Coakley, J., et al., 2001. Abdominal fat and birth size in healthy prepubertal children. Int. J. Obes. Relat. Metab. Disord. 25 (11), 1667–1673. Golding, J., Pembrey, M., Jones, R., 2001. ALSPAC—the Avon Longitudinal Study of Parents and Children. I. Study methodology. Paediatr. Perinat. Epidemiol. 15 (1), 74–87. Hanew, K., Tachibana, K., Yokoya, S., Fujieda, K., Tanaka, T., Igarashi, Y., et al., 2005. Studies of very severe short stature with severe GH deficiency: from the data registered with the foundation for growth science. Endocr. J. 52 (1), 37–43. Hediger, M.L., Overpeck, M.D., Maurer, K.R., Kuczmarski, R.J., McGlynn, A., Davis, W.W., 1998. Growth of infants and young children born small or large for gestational age: findings from the Third National Health and Nutrition Examination Survey. Arch. Pediatr. Adolesc. Med. 152 (12), 1225–1231. Holly, J.M., Smith, C.P., Dunger, D.B., Howell, R.J., Chard, T., Perry, L.A., et al., 1989. Relationship between the pubertal fall in sex hormone binding globulin and insulin-like growth factor binding protein-I. A synchronized approach to pubertal development? Clin. Endocrinol. (Oxf.) 31 (3), 277–284. Ibanez, L., Potau, N., Francois, I., de Zegher, F., 1998. Precocious pubarche, hyperinsulinism, and ovarian hyperandrogenism in girls: relation to reduced fetal growth. J. Clin. Endocrinol. Metab. 83 (10), 3558– 3562. Ibanez, L., Valls, C., Marcos, M.V., Ong, K., Dunger, D.B., De Zegher, F., 2004. Insulin sensitization for girls with precocious pubarche and with risk for polycystic ovary syndrome: effects of prepubertal initiation and postpubertal discontinuation of metformin treatment. J. Clin. Endocrinol. Metab. 89 (9), 4331–4337. Ibanez, L., Ong, K., Dunger, D.B., deZegher, F. Insulin Sensitization to Delay Pubertal Progression in Girls. In: European Society of Pediatric Endocrinology, poster 10–18; 2005; Lyon, France; 2005. Jaquet, D., Gaboriau, A., Czernichow, P., Levy-Marchal, C., 2000. Insulin resistance early in adulthood in subjects born with intrauterine growth retardation. J. Clin. Endocrinol. Metab. 85 (4), 1401–1406. Kalme, T., Koistinen, H., Loukovaara, M., Koistinen, R., Leinonen, P., Angervo, M., et al., 2003. Comparative studies on the regulation of insulin-like growth factor-binding protein-1 (IGFBP-1) and sex hormonebinding globulin (SHBG) production by insulin and insulin-like growth factors in human hepatoma cells. Estradiol increases the production of sex hormone-binding globulin but not insulin-like growth factor binding protein-1 in cultured human hepatoma cells. J. Steroid Biochem. Mol. Biol. 86 (2), 197–200. Law, C.M., Barker, D.J., Osmond, C., Fall, C.H., Simmonds, S.J., 1992. Early growth and abdominal fatness in adult life. J. Epidemiol. Community Health 46 (3), 184–186. Leger, J., Levy-Marchal, C., Bloch, J., Pinet, A., Chevenne, D., Porquet, D., et al., 1997. Reduced final height and indications for insulin resistance in 20 year olds born small for gestational age: regional cohort study. BMJ 315 (7104), 341–347. Loos, R.J., Beunen, G., Fagard, R., Derom, C., Vlietinck, R., 2001. Birth weight and body composition in young adult men–a prospective twin study. Int. J. Obes. Relat. Metab. Disord. 25 (10), 1537–1545. Loos, R.J., Beunen, G., Fagard, R., Derom, C., Vlietinck, R., 2002. Birth weight and body composition in young women: a prospective twin study. Am. J. Clin. Nutr. 75 (4), 676–682. Low, L.C., Tam, S.Y., Kwan, E.Y., Tsang, A.M., Karlberg, J., 2001. Onset of significant GH dependence of serum IGF-I and IGF-binding protein 3 concentrations in early life. Pediatr. Res. 50 (6), 737–742. Lucas, A., Fewtrell, M.S., Cole, T.J., 1999. Fetal origins of adult disease-the hypothesis revisited. BMJ 319 (7204), 245–249. Mantzoros, C.S., Flier, J.S., Rogol, A.D., 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 (4), 1066–1070. D.B. Dunger et al. / Molecular and Cellular Endocrinology 254–255 (2006) 140–145 Marshall, W.A., 1974. Interrelationships of skeletal maturation, sexual development and somatic growth in man. Ann. Hum. Biol. 1 (1), 29–40. Massa, G., Dooms, L., Bouillon, R., Vanderschueren-Lodeweyckx, M., 1993. Serum levels of growth hormone-binding protein and insulin-like growth factor I in children and adolescents with type 1 (insulin-dependent) diabetes mellitus. Diabetologia 36 (3), 239–243. Mast, M., Kortzinger, I., Konig, E., Muller, M.J., 1998. Gender differences in fat mass of 5–7-year old children. Int. J. Obes. Relat. Metab. Disord. 22 (9), 878–884. McCance, R.A., Widdowson, E.M., 1956. The effects of chronic undernutrition and of total starvation on growing and adult rats. Br. J. Nutr. 10 (4), 363–373. McKeigue, P.M., Lithell, H.O., Leon, D.A., 1998. Glucose tolerance and resistance to insulin-stimulated glucose uptake in men aged 70 years in relation to size at birth. Diabetologia 41 (10), 1133– 1138. Mills, J.L., Shiono, P.H., Shapiro, L.R., Crawford, P.B., Rhoads, G.G., 1986. Early growth predicts timing of puberty in boys: results of a 14-year nutrition and growth study. J. Pediatr. 109 (3), 543–547. Murphy, M.J., Metcalf, B.S., Voss, L.D., Jeffery, A.N., Kirkby, J., Mallam, K.M., et al., 2004. Girls at five are intrinsically more insulin resistant than boys: The Programming Hypotheses Revisited—The EarlyBird Study (EarlyBird 6). Pediatrics 113 (1 Pt. 1), 82–86. Nakai, Y., Plant, T.M., Hess, D.L., Keogh, E.J., Knobil, E., 1978. On the sites of the negative and positive feedback actions of estradiol in the control of gonadotropin secretion in the rhesus monkey. Endocrinology 102 (4), 1008–1014. Ong, K.K., Ahmed, M.L., Sherriff, A., Woods, K.A., Watts, A., Golding, J., et al., 1999. Cord blood leptin is associated with size at birth and predicts infancy weight gain in humans. ALSPAC Study Team. Avon Longitudinal Study of Pregnancy and Childhood. J. Clin. Endocrinol. Metab. 84 (3), 1145–1148. Ong, K.K., Ahmed, M.L., Emmett, P.M., Preece, M.A., Dunger, D.B., 2000. Association between postnatal catch-up growth and obesity in childhood: prospective cohort study. BMJ 320 (7240), 967–971. Ong, K.K., Preece, M.A., Emmett, P.M., Ahmed, M.L., Dunger, D.B., 2002a. Size at birth and early childhood growth in relation to maternal smoking, parity and infant breast-feeding: longitudinal birth cohort study and analysis. Pediatr. Res. 52 (6), 863–867. Ong, K., Kratzsch, J., Kiess, W., Dunger, D., 2002b. Circulating IGF-I levels in childhood are related to both current body composition and early postnatal growth rate. J. Clin. Endocrinol. Metab. 87 (3), 1041– 1044. Ong, K.K., Petry, C.J., Emmett, P.M., Sandhu, M.S., Kiess, W., Hales, C.N., et al., 2004a. Insulin sensitivity and secretion in normal children related to size at birth, postnatal growth, and plasma insulin-like growth factor-I levels. Diabetologia 47 (6), 1064–1070. Ong, K.K., Potau, N., Petry, C.J., Jones, R., Ness, A.R., Honour, J.W., et al., 2004b. Opposing influences of prenatal and postnatal weight gain on adrenarche in normal boys and girls. J. Clin. Endocrinol. Metab. 89 (6), 2647–2651. 145 Ong, K., Emmett, P., Noble, S., Ness, A., Dunger, D., 2006. Dietary energy intake at age 4-months predicts postnatal weight gain and childhood body mass index. Pediatrics 117 (3), e503–e508. Ounsted, M., Sleigh, G., 1975. The infant’s self-regulation of food intake and weight gain. Difference in metabolic balance after growth constraint or acceleration in utero. Lancet 1 (7922), 1393–1397. Parent, A.S., Teilmann, G., Juul, A., Skakkebaek, N.E., Toppari, J., Bourguignon, J.P., 2003. The timing of normal puberty and the age limits of sexual precocity: variations around the world, secular trends, and changes after migration. Endocr. Rev. 24 (5), 668–693. Parker, L.N., 1991. Adrenarche. Endocrinol. Metab. Clin. North Am. 20 (1), 71–83. Ravelli, G.P., Stein, Z.A., Susser, M.W., 1976. Obesity in young men after famine exposure in utero and early infancy. N. Engl. J. Med. 295 (7), 349–353. Scott, E.C., Johnston, F.E., 1982. Critical fat, menarche, and the maintenance of menstrual cycles: a critical review. J. Adolesc. Health Care 2 (4), 249–260. Soto, N., Bazaes, R.A., Pena, V., Salazar, T., Avila, A., Iniguez, G., et al., 2003. Insulin sensitivity and secretion are related to catch-up growth in small-for-gestational-age infants at age 1 year: results from a prospective cohort. J. Clin. Endocrinol. Metab. 88 (8), 3645–3650. Stettler, N., Bovet, P., Shamlaye, H., Zemel, B.S., Stallings, V.A., Paccaud, F., 2002a. Prevalence and risk factors for overweight and obesity in children from Seychelles, a country in rapid transition: the importance of early growth. Int. J. Obes. Relat. Metab. Disord. 26 (2), 214–219. Stettler, N., Zemel, B.S., Kumanyika, S., Stallings, V.A., 2002b. Infant weight gain and childhood overweight status in a multicenter, cohort study. Pediatrics 109 (2), 194–199. Strobel, A., Issad, T., Camoin, L., Ozata, M., Strosberg, A.D., 1998. A leptin missense mutation associated with hypogonadism and morbid obesity. Nat. Genet. 18 (3), 213–215. Tanner, J.M., 1955. Growth at Adolescence, first ed. Blackwell Scientific Publications, Oxford. Tanner, J.M., 1986. Growth as a target-seeking function: catch-up and catch-down growth in man. In: Falkner, F., Tanner, J.M. (Eds.), Human Growth; a Comprehensive Treatise. Plenum Press, New York, London, pp. 167–179. Van der Spuy, Z.M., 1985. Nutrition and reproduction. Clin. Obstet. Gynaecol. 12 (3), 579–604. Welt, C.K., Chan, J.L., Bullen, J., Murphy, R., Smith, P., DePaoli, A.M., et al., 2004. Recombinant human leptin in women with hypothalamic amenorrhea. N. Engl. J. Med. 351 (10), 987–997. Wilson, M.E., Suter, K.J., 2000. The GH-IGF-I axis in sexual maturation: the monkey paradigm. In: Bourguignon, J.P., Plant, T.M. (Eds.), The Onset of Puberty in Perspective. Elsevier Science B.V, Amsterdam, pp. 71–83. Yajnik, C., 2000. Interactions of perturbations in intrauterine growth and growth during childhood on the risk of adult-onset disease. Proc. Nutr. Soc. 59 (2), 257–265. Zhang, Y., Proenca, R., Maffei, M., Barone, M., Leopold, L., Friedman, J.M., 1994. Positional cloning of the mouse obese gene and its human homologue. Nature 372 (6505), 425–432.