Childhood obesity and the timing of puberty

Review

Childhood obesity and the timing of puberty M. Lynn Ahmed1,2, Ken K. Ong1,3 and David B. Dunger1 1

Department of Paediatrics, University of Cambridge, Addenbrooke’s Hospital, Box 116, Cambridge, CB2 0QQ, UK Department of Paediatrics, University of Oxford, Children’s Hospital, Oxford OX3 9DU, UK 3 MRC Epidemiology Unit, Institute of Metabolic Science, Addenbrooke’s Hospital Box 285, Cambridge, CB2 0QQ, UK 2

The potential relationship between childhood obesity and earlier puberty onset has major public health implications. Earlier menarche in girls is associated with increased risk of adult obesity, type 2 diabetes and breast cancer. Current methods for assessing puberty are unreliable, with a lack of consensus regarding the impact of childhood obesity on breast development and/ or age of menarche. Effects of obesity on early puberty in boys are more contentious, necessitating development of robust biomarkers. The possibility of the obesity epidemic lowering the age of puberty onset fuels concerns over the growing mismatch in age of sexual and social maturity. Here, we describe the biological basis linking childhood obesity to early puberty and consider evidence for a trend towards its earlier onset. Introduction Puberty is a period during which children attain adult secondary sexual characteristics and reproductive capability [1]. The onset of puberty is described as the first appearance of breast buds in girls (B2) and genital changes in boys (G2), as described by the Tanner definitions (Box 1). Marshall and Tanner reported the mean (SD) onset of puberty in girls to be 11.15 (1.10) years and that in boys to be 11.64 (1.07) years [2,3]. These original Tanner pubertal stages were based on photographic observation of genital development of a relatively small but longitudinal sample of 192 girls and 228 boys living in a children’s home, who were seen every three months throughout puberty. Despite the probably poor representative nature of this sample, comparable studies from Prader’s group in Switzerland [4,5], the ongoing longitudinal Fels study in the USA [6] and the Danish data of Juul et al. [7] suggest roughly similar mean ages of puberty onset. In contrast to these detailed assessments of pubertal development in longitudinal studies, much of the secular trend data on timing of puberty has relied on age at menarche in girls, which is relatively easy to ascertain and least affected by observational errors [8]. From the late 19th century, evidence from several European countries shows a decrease in the age of menarche – a decrease generally ascribed to better health, nutrition and sanitation [8]. However, in the last forty years, several investigators have noted a halt or even a reversal in this trend in countries where general levels of health and nutrition are optimal [9]. Corresponding author: Dunger, D.B. ([email protected]).

The concept of optimal nutrition has recently given way to a discussion of the effects of being overweight or obese. In most publications, obesity is defined as greater than or equal to the 95th percentile of body mass index (BMI) based on relevant national references and ‘overweight’ is considered greater than the 85th percentile, both increasingly prevalent conditions [10,11]. Cole et al. [12] documented changes in the prevalence of overweight children between 1970 and 2000 in ten countries; the USA and Canada showed the fastest rates of increase, and the rates of overweight children in Germany, Finland, Brazil, England, Scotland and Austria increased by approximately 4% every ten years. The striking data reported by Kaplowitz from white American children aged 6–11 years demonstrated an increase of rates of obesity from approximately 5% between 1963 and 1965 to 12% in 1999–2000 [13]. The possibility that these increasing rates of obesity encouraged the secular trend towards early puberty onset was highlighted in the report by Herman-Giddens et al. in 1997 [14]. This report suggested that some girls were entering puberty (defined as breast buds or pubic hair appearance) when starting school at approximately 6 years of age and that overall, in the USA, 6.7% of girls had clinical evidence of puberty at age 7 years and 14.7% by age 8 years. Indeed, that study described the youngest ever reported population age at puberty onset of 9.96 1.82 years (mean SD) [14]. This observation of earlier pubertal onset fuelled the debate of whether increasing rates of obesity in the population lead to earlier pubertal development, the result having profound social and health implications for the next generation. In this review, we discuss some of the biological arguments linking increased childhood BMI to risk for early puberty and the possible implications for future adult health. We conclude with an evaluation of the strength of the data linking obesity to earlier puberty and suggestions for future studies. Biological links between body weight and puberty There are clear associations between childhood adiposity, as reflected in BMI, and early pubertal development. In a Pediatric Research in Office Settings (PROS) study [13], 6to 9-year-old white girls with breast development were noted to have a larger BMI standard deviation score than prepubertal girls of the same age. Similarly, in the Bogalusa Heart study [15], there was a negative association between age at menarche and BMI, in that the incidence of

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Review Box 1. Tanner puberty stages Girls Stage 1: Preadolescent; elevation of papilla only. Stage 2: Breast bud stage; elevation of breast and papilla as a small mound, enlargement of areola diameter. Stage 3: Further enlargement of breast and areola, with no separation of their contours. (Note that menarche occurs mainly in stages 3 and 4.) Stage 4: Projection of areola and papilla to form a secondary mound above the level of the breast. Stage 5: Mature stage; projection of papilla only, owing to recession of the areola to the general contour of the breast. Boys Stage 1: Preadolescent; testes, scrotum and penis are of approximately the same size and proportion as in early childhood. Stage 2: The scrotum and testes have enlarged, and there is a change in the texture of the scrotal skin. There is also some reddening of the scrotal skin. Stage 3: Growth of the penis has occurred, at first mainly in length but with some increase in breadth. There has been further growth of testes and scrotum. Stage 4: Penis further enlarged in length and breadth with development of glans. Testes and scrotum further enlarged. There is also further darkening of the scrotal skin. Stage 5: Genitalia adult in size and shape. No further enlargement takes place after stage 5 is reached.

menarche before the age of 11 years was 1.79 times greater for girls at the 75th percentile for BMI than for those at the 25th percentile. However, although apparent associations between greater adiposity and earlier pubertal development have been demonstrated, this does not necessarily prove causality. Nearly 40 years ago, Frisch and Revelle [16] proposed their critical weight hypothesis, suggesting that a weight of 48 kg was required to achieve menarche (based on 181 girls examined between 1929 and 1950); their observations were roundly criticized [17]. Yet in recent years, the discovery of leptin, a hormone secreted by adipocytes that signals through its hypothalamic receptor to report on fat stores and to regulate appetite and metabolism [18], has indicated that there might indeed be a ‘permissive’ fat mass for the initiation of pubertal development. For example, observations in rodents and, subsequently, in humans have suggested that feedback from fat mass might stimulate central pulsatile gonadotrophin secretion and trigger the timing of puberty [19,20]. In fact, rare human individuals with leptin deficiency or leptin receptor mutations have hypogonadotrophic hypogonadism [21,22], and leptin administration to women with either leptin deficiency or hypothalamic amenorrhea secondary to exercise-related low fat mass increases luteinizing hormone pulsatility and ovarian volume [23]. These data indicate that leptin, as a marker of fat mass, might be an important permissive factor in the initiation of puberty. However, although leptindeficient mice treated with leptin develop puberty earlier than control mice, leptin alone cannot induce precocious puberty in young mice [24] or leptin-deficient children [25]. Similarly, studies in human populations indicate that leptin has a permissive role in puberty onset but is not the crucial element or ‘trigger’ in the timing of puberty. This was demonstrated in longitudinal studies showing that there was a gradual rise in leptin levels from the peripu238

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bertal period into early puberty, rather than a sudden increase or pulse of leptin, and that there was a wide range in leptin levels at the onset of puberty, rather than a single general threshold [26,27]. Recently identified novel regulators of gonadotrophin-releasing hormone secretion – such as GPR54, a G-protein-coupled receptor gene [28]; the kisspeptins, a family of neuropeptides encoded by the Kiss1 gene [29,30]; and the ‘enhanced at puberty 1’ gene, EAP1 [31] – have been found to be essential for normal pubertal development; however, their relationship with weight gain has not yet been determined and they might not necessarily provide the signal that initiates puberty. The relationship between age of puberty onset and BMI might actually relate to changes much earlier in human development; it has been suggested that the rate of weight gain during early childhood is a crucial determinant in the timing of puberty in both boys and girls [32–36]. For example, in population cohort studies, rapid early postnatal weight gain predicts a faster tempo of childhood maturation and early puberty onset [37,38]. Earlier birth order and formula milk feeding are also associated with both rapid weight gain and early menarche [39,40]. Infancy, therefore, might be an early window during which variations in nutrition program subsequent growth and development [41]. Early nutrition within that window then might be an important determinant of both age of puberty onset and childhood adiposity risk. Rapid weight gain during early infancy and childhood could alter the early hormonal milieu and program the age of onset and rate of progression through puberty. Rapid infancy weight gain has been shown to be a risk factor for later obesity [42] and increased levels of adrenal steroids at 8 years of age [43]. Such changes in adrenal androgens could precipitate early pubertal development, as seen in patients with congenital adrenal hyperplasia [44], but might also be associated with the development of insulin resistance [45]. Insulin resistance in obese subjects is associated with compensatory hyperinsulinaemia and decreased levels of sex-hormone-binding globulin (SHBG) [46]. In prepubertal children, low circulating levels of sex steroids are detectable using highly sensitive assays, and a decrease in levels of the regulatory binding protein SHBG could result in increased sex steroid bioavailability [47]. Similarly, in theory, increased adiposity in prepubertal children could lead to increased aromatase activity resulting in increased conversion of androgens to estrogens [48], thereby overexposing tissues to oestrogen during prepubertal years. Thus, there are several putative mechanisms whereby the increased prevalence of overweight and obesity could trigger early pubertal development by increased exposure to sex steroids in prepubertal subjects (Figure 1). This hypothesis is further fuelled by the possibility that such endogenous sex steroid exposure might be further aggravated by phytoestrogens and other potential environmental agents (known collectively as endocrinedisrupting chemicals), which might also affect rates of early pubertal development and menarcheal age [49]. Implications of weight-related early puberty In addition to the obvious sociological and psychological impact of early puberty, there might also be important

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Box 2. Adverse outcomes of early puberty:     

Increased adolescent risk-taking behaviour Shorter adult stature Increased adult BMI, waist circumference and adiposity Increased risk of adult-onset diabetes (owing to elevated BMI) Increased cardiovascular disease risk markers (including insulin resistance, blood pressure and metabolic syndrome)  Increased risk of premenopausal breast cancer  Increased all-cause mortality

Figure 1. Proposed endocrine pathways linking childhood obesity and insulin resistance to early pubertal onset and maturation. Childhood obesity (and, in particular, the predisposition to visceral adiposity after intrauterine growth restraint) leads to insulin resistance and peripheral hyperinsulinaemia. In turn, insulin acts on various organs – including the adrenals, liver, ovary and fat cells – to increase sex steroid bioavailability. Finally, elevated circulating and tissue sex steroid levels in obese prepubertal children could either have only mild local effects or also activate early hypothalamic–pituitary puberty and early reproductive maturation.

medical implications. Women with a history of earlier menarche are at a fivefold higher risk of obesity than those with a later menarche [50], although it is unclear whether this risk is entirely because of their prepubertal weight status or is directly exacerbated by earlier pubertal development. An early menarche might also translate into increased risk for adult-onset diabetes [51], shorter adult height [50], increased adolescent risk-taking behaviour [52], increased breast cancer risk [53] and all-cause mortality [54] (Box 2). The Fels Longitudinal Study is an intergenerational study from birth to old age, and the serial nature of the data enables changes with time and interrelationships to be observed. Using data from the Fels Longitudinal Study, Remsberg et al. [55] investigated the effects of menarcheal timing on cardiovascular risk factors. They studied a subset of 391 Fels girls and observed an increase in cardiovascular risk factors (e.g. elevated blood pressure and glucose intolerance) independent of body composition and age in girls with an early menarche ( 11.9 years) [55]. With rising trends in obesity, therefore, early puberty might represent a robust marker to identify those obese adolescents who could be at a high risk for adverse long-term cardiovascular outcomes. Thus, reports of early pubertal development associated with increased weight gain need to be taken very seriously.

Does the age of puberty onset change with the prevalence of overweight and obese patients? The data reported by Herman-Giddens et al. remain controversial. The PROS study was cross-sectional and although based on a large number of girls (more than 17 000), it was not necessarily nationally representative. Furthermore, the reports of early breast development were based on routine visual assessments by a wide range of clinicians with only a subset assessed by palpation. It has long been recognised that truncal obesity could falsely suggest the presence of breast development when assessed by visual inspection. In a personal communication reported by Kaplowitz [56], Herman-Giddens et al. provided data from 39% of their sample who had undergone both visual inspection and palpation and found that 15% of the most obese were classified as stage 2 when there was no palpable breast tissue. This highlights the problem of defining pubertal onset by breast development alone and does not provide any information as to whether such observations might be related to increased peripheral estrogen levels rather than the onset of true central precocious puberty. Early puberty in girls A recent international expert panel convened to evaluate whether sufficient data exist to suggest a continued secular trend in puberty timing in the USA from 1940 to 1994 [57]. The panel acknowledged the difficulty in comparing studies because different designs (e.g. cross-sectional versus longitudinal) were used, age ranges might have been censored, population characteristics (ethnicity and/or geography) varied and/or different measures of puberty (onset of puberty versus age at menarche) were used. Differences in analyses and data presentation between studies were also common; for example, age at menarche might have been reported as the mean or median, rounded down, or taken as the middle of the whole year. Even when authors examined the same datasets, they employed dissimilar criteria and analytical methods, often reaching opposing conclusions. The aforementioned panel reviewed data concerning age at menarche from a number of studies, including that of Wyshak et al. [58], which showed (in several northern European countries) that age at menarche decreased from 16–17 years of age in the 19th century to 13 years in the mid20th century. The large US study reported by HermanGiddens et al. [14] observed that the average age at menarche in white girls was 12.88 years, which was unchanged compared to US data from the previous 30 years. The Bogalusa Heart Study carried out seven cross-sectional 239

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Table 1. Selected studies of age of pubertal onset and age of menarche in white girls Menarche Mean SD 12.9 1.4

Caveats and comments

49

Age range (Y) Study type Breast stage 2 Mean SD 8–18 Long 10.8 1.1

192

8+

13.47

67

9.5–17.0

Photographs, not representative sample Self-examination; youngest 9.5 years Examination; large numbers but not population based Survival analysis Examination; no inter-rater reliability

Studies

N

Reynolds and Wines (1948), Amer. J. Dis. Child. 75, 329–350 Marshall and Tanner (1969), Arch. Dis. Child. 44, 291–303 Roche et al. (1995), J. Pediatr. Endocrinol. Metab. 8, 11–18 Herman-Giddens (1997), Pediatrics 99, 505–512 Whincup (2001), BMJ 322, 1095–96 Sun et al. (2002), Pediatrics 110, 911–19. NHANES III Median age at entry into stage 2 a Mean age for being in stage 2 b Freedman et al. (2002), Pediatrics 110, e43. Bogalusa Heart Study 1973–1974 1992–1994 Chumlea et al. (2003), Pediatrics 111, 110–13. NHANES III Anderson et al. (2003), Pediatrics 111, 844–850 1963–70, NHES II & III 1988–1994, NHANES III

Mixed

15 439 3–12

X-sec

1068 594

X-sec X-sec

12–16 8–19

11.15

1.10

11.2

0.7

9.96

1.82

10.38 11.05

1398 1230

1454 452

7–17 7–17 8–20

Mixed Mixed X-sec

10–15 10–15

X-sec X-sec

1.20

12.9

12.8–13.1

12.7 12.5 12.55

12.6–12.9 Reported menarcheal ages. Not nationally representative 12.4–12.8 12.31–12.79 Reported menarcheal ages

12.8 12.6

12.73–12.87 Reported menarcheal ages 12.48–12.71 Reported menarcheal ages

10.1–10.65 0.18 (SE)

10.4 10.4

12.88

10.1–10.7

Although some of these studies included girls of different ethnic backgrounds, these results are all on white girls. Data are expressed as mean and standard deviation (SD) or median and range (95% confidence interval). a The median age of entry is the age at which 50% of the children entered stage 2 (determined by probit analysis) b Mean age and standard error (SE) for being in a stage.N, number; Y, years; long, longitudinal; x-sec, cross-sectional; mixed, mixed cross-sectional and longitudinal; NHANES, National Health and Nutrition Examination Surveys; NHES, National Health Examination Surveys.

assessments between 1973–1974 and 1992–1993 and reported that the median age at menarche over that period declined by two months in white girls [15]. Anderson et al. [59] analyzed data from National Health Examination Surveys (NHES) (1963–1970) and National Health and Nutrition Examination Surveys (NHANES) III (1988–1994) and concluded that the average age of menarche decreased from 12.75 to 12.54 years over the 25-year period, whereas Chumlea, analyzing the same data, found that the median age at menarche was 12.80 years in NHES (1963–1970) and 12.55 years in NHANES lll (1988–1994) but concluded that this difference of 0.25 years (three months) was not clinically significant [60]. Herman-Giddens reviewed the same data and argued that because the confidence intervals did not overlap, this decline in age of menarche between 1963–1970 to 1988–1994 was significant [61]. Overall, these data indicate that if there has been a decline in the age of menarche over the last 30 years, it is modest (Table 1). The analysis by Anderson and Must of the NHANES III data (1988–1994 versus 1999–2002) on the white girls reported a menarcheal age of 12.57 (12.45–12.69) years for NHANES III and 12.52 (12.38–12.67) years for NHANES 1999–2002 [62]. These data indicate that there has been no change in menarcheal age in white girls over this more recent time period, although this is perhaps too short a period over which to assess secular trends. Isolated breast development can occur in young girls without the activation of the hypothalamic–pituitary– gonadal axis and is termed ‘thelarche’ or ‘thelarche variant’. The lack of a dramatic secular trend towards earlier menarche suggests that recent observations of breast development in very young girls could represent isolated thelarche, thelarche variant or profound alterations in 240

the timing of the sequence of normal hypothalamic–pituitary-driven central puberty. Early puberty in boys Data can be even more difficult to interpret in boys because early staging of genitalia and subsequent progression through puberty (without assessment of testicular volume) is more subjective, with no easily defined pubertal event like menarche in girls. Table 2 presents data on selected studies of pubertal onset in boys. In their interpretation of the NHANES III data on boys, Herman-Giddens et al. [63] suggested that 29% of 8-year-old boys had attained genital stage 2 (G2) (Box 1). This is a worrying statistic and highlights the subjectivity of assessment in boys because it does not fit with clinical experience of pediatric endocrinologists, who have not reported an increased prevalence of precocious puberty in boys [64]. The NHANES III data indicated a mean age of G2 at 9.9 years, but a mean age of pubic hair stage 2 at 11.9 years [65]. This level of discordance is highly unusual and might validate the concern about errors made in genital staging [65]. Data from two recent Danish studies, one in 463 choir boys looking at voice change [66] and the other in 826 boys studying pubertal onset [7], revealed no change in age of pubertal onset between 1964 and 1991 but an earlier age at voice break and an association of this with increased prepubertal BMI. The study on pubertal onset reported a mean (95% confidence interval) age of Tanner stage 2 for boys as 11.83 years (11.66–12.00), showing no change in the past 30 years. The study of voice change, a late event in a boy’s development (associated with stage 3 or 4 of puberty), found that over the ten years of the study (1994–2003), the median age decreased from 14.0 years to 13.7 years and

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Table 2. Selected studies of age at pubertal onset in white boys

Long Mixed

Genital Mean 11.5 11.64

stage 2 SD 0.9 1.07

9.0–17.5 9.5–17.0 8–19

X-sec

11.90 11.2 10.1

1.1 0.7 9.6–10.6

8–19

X-sec 10.03 11.08

9.6–10.4 0.18 (SE)

Studies

N

Age range (Y)

Study type

Reynolds and Wines (1951), Amer. J. Dis. Child, 82, 529–47 Marshall and Tanner (1970), Arch. Dis. Child, 45, 13–23

59 228

9–21 9+

Lee (1980), J. Adol. Health Care, 1, 26–29 Roche et al. (1995), J. Pediatr. Endocrinol. Metab. 8, 11–18 Herman-Giddens (2001), Arch. Pediatr. Adolesc. Med. 155, 1022–1028 NHANES III Sun et al. (2002), Pediatrics 110, 911–919. NHANES III Median age at entry into stage 2 a Mean age for being in stage 2 b

36 78 536 537

Comments and caveats

Photographs, not representative sample Examination Assisted self-examination Examination Examination

Data are expressed as mean and standard deviation (SD) or median and range (95% confidence interval). a The median age of entry is the age at which 50% of the children entered stage 2 (determined by probit analysis). b Mean age and standard error (SE) for being in a stage.N, number; Y, years; long, longitudinal; x-sec, cross-sectional; mixed, mixed cross-sectional and longitudinal; NHANES, National Health and Nutrition Examination Surveys; NHES, National Health Examination Surveys.

that this was a significant trend [66]. In this Danish sample of boys, therefore, it seems that age of pubertal onset has not altered in 30 years, but the progression through puberty to stage 4 seems to be faster. The data on the association of adiposity or BMI with pubertal onset in boys reveals a lack of concurrence. In a small Israeli study [67], obese boys showed no difference in age at testicular or genital enlargement compared to agematched controls. However, a Spanish study by Vizmanos [68] observed a positive relationship between BMI and age of pubertal onset in boys. Yet analysis by Karpati et al. [65] of NHANES III data in boys concluded that higher BMIs were not associated with earlier ages of puberty, and the cross-sectional nature of the data precluded any attempt at causal relationships [65]. Also examining NHANES III data, Wang [69] suggested that obesity might result in later, not earlier, puberty in boys. Thus, the relationship of obesity to puberty in boys is not clear. Kaplowitz [13] proposed that these studies might suggest that the relationship between obesity and the timing of puberty differs among populations. There is inadequate comparable data to make conclusive decisions relating to a secular trend in age of puberty onset in boys or to a relationship of age of pubertal onset and adiposity. Concluding remarks and future directions The potential implications of increasing rates of overweight and obesity on earlier development of gonadotrophin-initiated puberty are profound and could alter disease risk in future populations. Although the data are limited and not completely representative of ethnic and geographic distributions, they do not support the proposition that there is a continuing rapid secular trend towards an earlier age of menarche in girls. However, reports of very early breast development in US populations and anecdotal reports from pediatric endocrinologists of increasing rates of premature thelarche and thelarche variant suggest earlier exposure to sex steroids without activation of centrally driven precocious puberty. Whether this relates to ‘endocrine disruptors’ or obesity-related changes in SHBG, aromatase activity and/or adrenarche remain to be determined. The resolution of these issues will require detailed longitudinal studies. Data from boys are even more limited. Direct assessment of the early stages of pubertal development in large epidemiological studies might no longer be acceptable, and

there are no reliable markers evaluating spermarche in boys [70]. Potential hormonal markers could be used to evaluate initiation and duration of pubertal development in boys but again, large longitudinal studies are needed to validate such markers. Dependence on suboptimal evaluation of pubertal staging or reliance on age of menarche in girls, with no comparable markers in boys, is inadequate, and further robust markers of the biological consequences of both early and late pubertal exposure are essential. References 1 Patton, G.C. and Viner, R. (2007) Pubertal transitions in health. Lancet 369, 1130–1139 2 Marshall, W.A. and Tanner, J.M. (1969) Variations in pattern of pubertal changes in girls. Arch. Dis. Child. 44, 291–303 3 Marshall, W.A. and Tanner, J.M. (1970) Variations in the pattern of pubertal changes in boys. Arch. Dis. Child. 45, 13–23 4 Largo, R.H. and Prader, A. (1983) Pubertal development in Swiss girls. Helv. Paediatr. Acta 38, 229–243 5 Largo, R.H. and Prader, A. (1983) Pubertal development in Swiss boys. Helv. Paediatr. Acta 38, 211–228 6 Roche, A.F. et al. (1995) The timing of sexual maturation in a group of US white youths. J. Pediatr. Endocrinol. Metab. 8, 11–18 7 Juul, A. et al. (2006) Pubertal development in Danish children: comparison of recent European and US data. Int. J. Androl. 29, 247–255 8 Ong, K.K. et al. (2006) Lessons from large population studies on timing and tempo of puberty (secular trends and relation to body size): the European trend. Mol. Cell. Endocrinol. 254–255, 8–12 9 Cole, T.J. (2000) Secular trends in growth. Proc. Nutr. Soc. 59, 317–324 10 Ogden, C.L. et al. (2006) Prevalence of overweight and obesity in the United States, 1999–2004. J. Am. Med. Assoc. 295, 1549–1555 11 Reilly, J.J. et al. (1999) Prevalence of overweight and obesity in British children: cohort study. BMJ 319, 1039 12 Cole, T. (2006) Childhood obesity: assessment and prevalence. In Childhood Obesity, Contemporary Issues (Cameron, N. et al., eds), pp. 3–12, CRC Press, Taylor & Francis Group, LLC 13 Kaplowitz, P.B. (2008) Link between body fat and the timing of puberty. Pediatrics 121 (Suppl 3), S208–S217 14 Herman-Giddens, M.E. et al. (1997) Secondary sexual characteristics and menses in young girls seen in office practice: a study from the Pediatric Research in Office Settings network. Pediatrics 99, 505– 512 15 Freedman, D.S. et al. (2002) Relation of age at menarche to race, time period, and anthropometric dimensions: the Bogalusa Heart Study. Pediatrics 110, e43 16 Frisch, R.E. and Revelle, R. (1970) Height and weight at menarche and a hypothesis of critical body weights and adolescent events. Science 169, 397–399 17 Johnston, F.E. et al. (1971) Height, weight and age at menarche and the ‘critical weight’ hypothesis. Science 174, 1148–1149 18 Zhang, Y. et al. (1994) Positional cloning of the mouse obese gene and its human homologue. Nature 372, 425–432 241

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