timing of puberty and physical growth in obese children: a longitudinal study in boys and girls

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Timing of puberty and physical growth in obese children: a longitudinal study in boys and girls C. De Leonibus 1,2 , M. L. Marcovecchio 1,2 , V. Chiavaroli 1,2 , T. de Giorgis 1,2 , F. Chiarelli 1,2 and A. Mohn 1,2 1 Department of Pediatrics, University of Chieti, Chieti, Italy; 2 Center of Excellence on Aging, ‘G. D’Annunzio’ University Foundation, University of Chieti, Chieti, Italy Received 26 October 2012; revised 25 March 2013; accepted 15 April 2013 What is already known about this subject • There is emerging evidence suggesting that childhood obesity may influence the timing/tempo of puberty and growth patterns. • An earlier onset of puberty generally occurs in obese girls, whereas conflicting data are available for boys. • Obese children tend to be taller during pre-puberty but lose this growth advantage during puberty. What this study adds • Obese boys and girls present an earlier onset of puberty and completion of puberty, with a shorter duration of puberty compared to normal-weight peers. • Obese children tend to have a similar adult height compared to normal-weight children. Summary Background: There is emerging evidence suggesting that childhood obesity may influence the timing of puberty and growth patterns. However, there are scant and controversial data in this field. Objective: To assess whether puberty and physical growth vary in obese when compared to normal- weight children. Methods: One hundred obese pre-pubertal children (44 boys; mean age (SD): 9.01 0.62 years; 56 girls; 8.70 0.57 years) were compared to 55 normal-weight controls (27 boys; 9.17 0.26 years; 28 girls; 8.71 0.62 years). All study participants were followed prospectively with 6-monthly follow-up visits. At each study visit, height, weight, body mass index (BMI) and pubertal stage were assessed. Results: Obese children entered puberty and achieved later stages of puberty earlier than controls (onset of puberty: boys: 11.66 1.00 vs. 12.12 0.91 years, P = 0.049; girls: 9.90 0.78 vs. 10.32 1.70, P = 0.016; late puberty: boys: 13.33 0.71 vs. 14.47 1.00 years, P < 0.001; girls: 11.54 0.99 vs. 12.40 1.02, P = 0.001). Pre-pubertal BMI standard deviation score (SDS) was inversely associated with both age at the onset of puberty (b=-0.506, P < 0.001) and age at late puberty (b=-0.514, P < 0.001). Obese children also showed an earlier age at peak height velocity (PHV) (boys: 12.62 0.82 vs. 13.19 0.96 years, P = 0.01; girls: 11.37 0.89 vs. 12.77 0.76, P < 0.001) and a lower PHV (boys: 7.74 1.49 vs. 9.28 1.64 cm year -1 , P < 0.001; girls: 7.60 1.64 vs. 8.29 1.03, P = 0.03). Height SDS progressively declined over the study period in the obese group (P for trend <0.001), whereas there were no significant changes in the control group (P for trend = 0.5). Conclusions: Obese boys and girls presented an earlier onset of puberty and completion of puberty and an impaired height gain during puberty. Keywords: Children, growth, obesity, puberty. Address for correspondence: Prof. A Mohn, Department of Pediatrics, University of Chieti, Via dei Vestini 5, 66100 Chieti, Italy. E-mail: [email protected] © 2013 The Authors Pediatric Obesity © 2013 International Association for the Study of Obesity. Pediatric Obesity 9, 292–299 PEDIATRICOBESITY ORIGINALRESEARCH doi:10.1111/j.2047-6310.2013.00176.x ORIGINALRESEARCH

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Page 1: Timing of puberty and physical growth in obese children: a longitudinal study in boys and girls

Timing of puberty and physical growth in obesechildren: a longitudinal study in boys and girlsC. De Leonibus1,2, M. L. Marcovecchio1,2, V. Chiavaroli1,2, T. de Giorgis1,2, F. Chiarelli1,2

and A. Mohn1,2

1Department of Pediatrics, University of Chieti, Chieti, Italy; 2Center of Excellence on Aging, ‘G. D’Annunzio’ UniversityFoundation, University of Chieti, Chieti, Italy

Received 26 October 2012; revised 25 March 2013; accepted 15 April 2013

What is already known about this subject• There is emerging evidence suggesting that childhood

obesity may influence the timing/tempo of puberty andgrowth patterns.

• An earlier onset of puberty generally occurs in obese girls,whereas conflicting data are available for boys.

• Obese children tend to be taller during pre-puberty butlose this growth advantage during puberty.

What this study adds• Obese boys and girls present an earlier onset of puberty

and completion of puberty, with a shorter duration ofpuberty compared to normal-weight peers.

• Obese children tend to have a similar adult heightcompared to normal-weight children.

SummaryBackground: There is emerging evidence suggesting that childhood obesity may influence the timing ofpuberty and growth patterns. However, there are scant and controversial data in this field.

Objective: To assess whether puberty and physical growth vary in obese when compared to normal-weight children.

Methods: One hundred obese pre-pubertal children (44 boys; mean age (�SD): 9.01 � 0.62 years; 56girls; 8.70 � 0.57 years) were compared to 55 normal-weight controls (27 boys; 9.17 � 0.26 years; 28 girls;8.71 � 0.62 years). All study participants were followed prospectively with 6-monthly follow-up visits. Ateach study visit, height, weight, body mass index (BMI) and pubertal stage were assessed.

Results: Obese children entered puberty and achieved later stages of puberty earlier than controls (onsetof puberty: boys: 11.66 � 1.00 vs. 12.12 � 0.91 years, P = 0.049; girls: 9.90 � 0.78 vs. 10.32 � 1.70,P = 0.016; late puberty: boys: 13.33 � 0.71 vs. 14.47 � 1.00 years, P < 0.001; girls: 11.54 � 0.99 vs.12.40 � 1.02, P = 0.001). Pre-pubertal BMI standard deviation score (SDS) was inversely associated withboth age at the onset of puberty (b = -0.506, P < 0.001) and age at late puberty (b = -0.514, P < 0.001).Obese children also showed an earlier age at peak height velocity (PHV) (boys: 12.62 � 0.82 vs.13.19 � 0.96 years, P = 0.01; girls: 11.37 � 0.89 vs. 12.77 � 0.76, P < 0.001) and a lower PHV (boys:7.74 � 1.49 vs. 9.28 � 1.64 cm year-1, P < 0.001; girls: 7.60 � 1.64 vs. 8.29 � 1.03, P = 0.03). HeightSDS progressively declined over the study period in the obese group (P for trend <0.001), whereas therewere no significant changes in the control group (P for trend = 0.5).

Conclusions: Obese boys and girls presented an earlier onset of puberty and completion of puberty andan impaired height gain during puberty.

Keywords: Children, growth, obesity, puberty.

Address for correspondence: Prof. A Mohn, Department of Pediatrics, University of Chieti, Via dei Vestini 5, 66100 Chieti, Italy. E-mail:[email protected]© 2013 The AuthorsPediatric Obesity © 2013 International Association for the Study of Obesity. Pediatric Obesity 9, 292–299

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IntroductionChildhood obesity is a growing and alarmingproblem, associated with several cardio-metabolicrisk factors (1). In addition, there is evidence suggest-ing that excess adiposity during childhood can influ-ence growth patterns and pubertal development(2–4). This is supported by the observation thatduring the last decades, a trend towards earlierpubertal onset has occurred, concomitantly withimprovements in nutrition and the rising numbers ofobese children (5). In addition, several cross-sectional studies have reported an associationbetween a high body mass index (BMI) during child-hood and early pubertal development, mainly in girls,whereas in boys, the evidence is less clear (6–9).However, for both sexes, there is only a handful oflongitudinal studies, which have assessed the effectof pre-pubertal body composition on both the onsetand progression of puberty (7,10–13). The lack oflongitudinal studies limits the possibility of definingthe direction of the relationship between childhoodobesity and pubertal maturation, in terms of whichevent comes first and hence influences the other. Inaddition, only few studies have been based on adirect physical examination of breast and genitalmaturation, whereas the majority of them have reliedon surrogate indexes of pubertal development.

The worldwide pandemic of childhood obesity hasalso generated interest in the relationship betweenbeing obese during childhood and growth patterns.There is some evidence suggesting that during pre-pubertal years, obese children have higher heightvelocity compared to their lean peers (3,4,14–16).However, this appears to be followed by a reductionin height gain during pubertal maturation (17). Thislatter effect together with the earlier pubertal matu-ration reported in obese children leads to similaradult heights in obese children compared to normal-weight peers (3,4). Some studies have even reporteda shorter adult height in subjects being obese duringchildhood (15). However, up to now, only few longi-tudinal studies have prospectively assessed growthduring childhood and puberty in obese children.

The aim of the present study was to test thehypothesis as to whether the timing and tempo ofpuberty as well as growth are altered in obese chil-dren when compared to normal-weight peers.

MethodsStudy population

A prospective longitudinal study was conducted,including a total sample of 155 Caucasian children,

who were firstly assessed when they were pre-pubertal and followed thereafter during pubertalyears. The data collection started in January 2005and was completed in September 2012. In details,the study population was made of 100 obese pre-pubertal children (44 boys and 56 girls), who hadbeen referred to the Obesity Clinic of the Departmentof Pediatrics (University of Chieti, Italy). All subjectswere affected by obesity, as defined by a BMI > 95thpercentile for age and gender (18), but were other-wise in good health and were not affected by anychronic disease. Physical disabilities, abnormalitiesof pubertal development or other endocrine disor-ders were excluded. None of the participants weretaking any medication known to affect gonadal func-tion and none had a family history of precocious ordelayed pubertal development. In addition, none pre-sented a history of weight loss or dietary restrictionbefore the study enrolment. As a control group, 55Caucasian normal-weight (BMI > 5th and < 85th per-centile for age and sex) children, comparable forsex (27 boys and 28 girls) and age with the obesegroup, were recruited. Control children wererecruited from those who had been referred to thePaediatric outpatient clinics of our hospital for minorhealth problems not affecting pubertal developmentand growth, in particular for the assessment ofroutine child health and development. Potentialcauses of growth impairment in these childrenwere excluded through clinical and biochemicalassessments.

Methods

The study was approved by the Ethical Committee ofthe University of Chieti. Written informed consentwas obtained from all parents and oral assent from allchildren.

All children underwent the first assessment whenthey were pre-pubertal (visit 1). At the baseline studyvisit, a detailed medical and family history wasobtained from all study participants, including dataon previous and current medical problems. In addi-tion, a complete physical examination was per-formed, including anthropometric parameters andstaging of puberty, on the basis of breast develop-ment in girls and genital development in boys (19).

Thereafter, in both groups, follow-up visits wereperformed every 6 months by the same team untilthe achievement of adult height, in order to followpubertal onset and progression. A complete physicalexamination, including anthropometric parameters,was performed at all visits and four specific timepoints were selected for specific comparisons

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between the obese and control children: visit1 = baseline pre-pubertal visit; visit 2 = onset ofpuberty; visit 3 = late puberty; visit 4 = achievementof adult height. Adult height was defined as thatrecorded when growth velocity was less than 1 cmper year. In addition, all height data were modelled toassess age at take-off (ATO), age at peak heightvelocity (APHV) and peak height velocity (PHV), usingthe Preece and Baines model 1 (PB1) (20).

All the obese patients and control children wereapproached and eligible at each time point visit andnone declined to participate until the end of the studywith no loss to follow-up. The number of observa-tions per child was 11.3 � 2.5.

At each study visit, obese children were encour-aged to follow a balanced diet, and to increasephysical activity. A 3-d dietary recording was per-formed at the start of the study and during follow-upvisits to assess food intake. Physical activity wasassessed by means of direct interview (21).

Puberty variables

Pubertal onset and progression were based on adirect evaluation of breast development in girls andtesticular size in boys at each study visit.

The age at the onset of puberty was consideredfor girls as the appearance of breast bud stage;elevation of breast and papilla as a small moundand enlargement of areola diameter (correspondingto pubertal stage 2 in girls). In boys, the onset ofpuberty corresponded to the time when thescrotum and testes have enlarged and reached avolume of 4 mL (corresponding to pubertal stage 2in boys).

The age at late puberty was defined as age atmenarche in girls and as the achievement of testicu-lar volume of 25 mL in boys, corresponding to puber-tal stage 5 in boys (9).

At each study visit, girls were also regularly askedwhether menarche had already occurred in betweenstudy visits, and if so, in which month and day.

Pubertal stages were assessed by inspection andpalpation, by the same study team at each visit.Genital maturation grading was performed by physi-cians who had been specially trained prior to thestudy. A supervisory physician conducted qualitycontrol visits during the study period to review phy-sician assessment of pubertal staging. The supervi-sor observed approximately 20–30 examinationsand performed a number of replicate examinations.Discrepancies in the assessment of testicular volumewere less than one stage between raters and super-visory physician.

For each subject, ATO (i.e. the age at onset ofpubertal growth spurt), APHV, together with PHVwere estimated using PB1 (20,22). Model param-eters were estimated using the non-linear regressionmodel in SPSS (SPSS Inc., Chicago, IL, USA). Thegoodness of fit was assessed by residual variance orits square root (the standard error of estimate) (23).ATO could not be estimated for 17 subjects (14obese and 3 controls), where it likely occurred beforethe first study visit.

Anthropometric measurements

Weight and height were measured with the child inlight clothing and without shoes. Body weight wasmeasured to the nearest 0.1 kg with a calibratedscale (Salus, Inc., Milan, Italy). Height was measuredthree times to the nearest 0.1 cm with a portable andHarpenden stadiometer (Holtain, Wales, UK). Eachsubjects stood straight, with feet placed togetherand flat on the ground, heels, buttock and scapulaeagainst the vertical backboard, arm loose andrelaxed with the palms facing medially and the headpositioned in the Frankfurt plane. All equipment(scale, stadiometer) was calibrated at the beginningof each study visit.

The technical error of measurement (TEM) wasused to evaluate anthropometric measure impreci-sion. TEM was considered as the standard deviationbetween repeated measurements taken independ-ently by one observer (intra-observer) or betweenobservers (inter-observer) throughout the studyperiod. TEM values were of the order 0.3 cm forheight, accordingly to acceptable values as indicatedin the literature (24).

Calculations

Body mass index was calculated as the weight inkilograms divided by the square of the height inmeters and was converted in standard deviationscores (SDS) using published reference values forage and gender (18,25).

Height measurements were converted to SDSadjusted for age and sex based on published nor-mative data for Italian children (25).

Parental heights were measured with the sameprocedure used for children on the day of the firststudy visit. Target height was calculated as the meanof maternal and paternal height using the formula(paternal height + [maternal height + 13])/2 cm forboys, and (maternal height + [paternal height - 13])/2 cm for girls (26).

In addition, in order to take into account thepatient's genetic potential for growth, we calculated

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parentally adjusted height SDS, which is representedby the difference between the child's height SDS andtarget height SDS (27).

Statistical analysis

All data were expressed as mean � SD unless oth-erwise specified. P values <0.05 were consideredstatistically significant. Statistical analysis was per-formed using the SPSS program version 19.0 soft-ware for Windows.

Differences in continuous variables between obeseand control children were assessed by unpairedt-test. Differences in categorical variables wereassessed by c2 test or Fisher exact test.

Repeated measurement analysis of variance withBonferroni post hoc was applied to assess differ-ences across the longitudinal study visits. Linearregression analysis was performed to assess thepotential association between variables of interest.

Based on a sample size of 155 and using age atpubertal onset as the primary outcome, the studyhad an 80% power of detecting a difference of 1 yearbetween the two study groups, assuming an SD of2.4 (4), at an alpha level of 0.05.

ResultsStudy population at baseline

At baseline, the obese and control groups weresimilar for age (boys: P = 0.21; girls: P = 0.95). Asexpected, BMI SDS was significantly higher in obesethan in normal-weight children (P < 0.001 for bothboys and girls). In addition, obese boys and girlswere significantly taller than normal-weight children(P = 0.003 and P < 0.001, for comparisons of heightand height SDS, respectively).

BMI over time

Although obese children were encouraged to followa balanced diet and to increase physical activity, theirBMI SDS remained stable from pre-puberty until latepuberty, whereas a significant decline was onlydetected from late puberty to the stage of adultheight achievement (Table 1). Within the controlgroup, BMI remained within the normal weight rangethroughout the study period (Table 1).

Timing and tempo of puberty:intra-group differences

The onset of puberty occurred at a younger age inobese than in normal-weight children.

For boys, mean age at the onset of puberty was11.66 � 1.00 years in the obese group vs. 12.12 �

0.91 years in the normal-weight group (P = 0.049).For girls, mean age at the onset of puberty was9.90 � 0.78 years in obese vs. 10.32 � 1.70 years incontrol children (P = 0.016; Table 1).

Similarly, late puberty was reached at a youngerage in obese children. For boys, mean age at latepuberty was 13.33 � 0.71 years in obese childrenvs. 14.47 � 1.00 years in normal-weight children(P < 0.001). For girls, mean age at menarche was11.54 � 0.99 years in obese children vs. 12.40 �1.02 years in controls (P = 0.001; Table 1).

Pre-pubertal BMI SDS was inversely and signifi-cantly associated with both age at the onset ofpuberty (b = -0.506, P < 0.001) and age at latepuberty (b = -0.514, P < 0.001).

Obese boys and girls showed an earlier ATO andan earlier APHV; in addition, obese children showeda lower PHV (Table 1). Pre-pubertal BMI SDS wasinversely and significantly associated with ATO(b = -0.30, P < 0.001), APHV (b = -0.38, P < 0.001)and PHV (b = -0.21, P = 0.01).

The time interval between beginning of puberty(pubertal stage 2) and APHV was significantly shorterin obese girls than control (1.25 � 1.07 vs.1.72 � 1.32 years, P = 0.02), but there were no dif-ferences in boys. In contrast, the time intervalbetween APHV and attainment of adult height wasshorter in obese boys than controls (2.21 � 1.18 vs.2.49 � 1.36 years, P = 0.02), but not betweenobese and normal-weight girls.

Physical growth in obese andnormal-weight children

Overtime physical growth, as assessed by heightSDS, was significantly different between the twogroups. Whereas in the obese group, height SDSprogressively and significantly declined from visit 1until visit 4 (boys: from 1.26 � 0.64 to 0.38 � 0.70,P < 0.001; girls: from 0.94 � 0.70 to 0.36 � 0.54,P < 0.001); in the control group, mean height SDSdid not significantly change from visit 1 until visit 4(P = 0.5; Table 1).

Height SDS was significantly higher in obese thanin normal-weight boys and girls at the first study visit(pre-puberty) as well as at the onset of puberty,whereas there was no statistically significant differ-ence in height SDS at late puberty and at achieve-ment of adult height (Table 1).

Parentally adjusted adult height SDS minus paren-tally adjusted baseline SDS was significantly lowerin obese compared to normal-weight children(–0.72 � 0.62 vs. –0.01 � 0.46, P < 0.001), in bothboys and girls.

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Overall height gain from pre-puberty until adultheight was significantly lower in obese boys and girlscompared to their sex-matched normal-weight peers(Table 1).

DiscussionThis longitudinal study showed that pre-pubertalboys and girls were predisposed to an earlier onsetof puberty and achievement of pubertal maturation.In addition, obesity was associated with taller statureduring pre-puberty, but thereafter, there was a loss ofthis height advantage, leading to similar adult heightsbetween obese and normal-weight children. Duringrecent years, several studies have reported a seculartrend towards earlier pubertal development in girls

(6,10,13,14,28–32). An explanation for this findingcould be the dramatic increase in the prevalence ofchildhood obesity in all developed countries, whichhas occurred during the same time period (5). Anassociation between excess adiposity and earlierpubertal onset has been reported in several studiesassessing girls belonging to different ethnic groups(10,28–32). Although the majority of these studieshave been cross-sectional, the results have beenquite consistent in showing a positive relationshipbetween a larger body size during childhood and anearlier onset and progression of puberty (10,30). Itneeds to be acknowledged that only few studieshave been based on a direct physical examination ofbreast development, whereas in the majority ofstudies, age at menarche, or some indirect measures

Table 1 Clinical characteristics of the study population by sex.

Clinical characteristics Boys (n = 71) Girls (n = 84)

Obese (n = 44) Controls (n = 27) P Obese (n = 56) Controls (n = 28) P

Prepubertal stage (visit 1)Age (years) 9.01 � 0.62 9.17 � 0.26 0.21 8.70 � 0.57 8.71 � 0.62 0.95Height (cm) 141.34 � 5.93 137.23 � 4.05 0.003 137.10 � 5.39 132.84 � 6.64 0.003Height SDS 1.26 � 0.64 0.40 � 0.57 <0.001 0.94 � 0.70 0.21 � 0.77 <0.001BMI (kg m-2) 36.04 � 8.38 18.45 � 1.90 <0.001 37.51 � 9.50 17.48 � 1.56 <0.001BMI SDS 2.59 � 0.39 0.29 � 0.68 <0.001 2.76 � 0.54 0.03 � 0.60 <0.001

Onset of puberty (visit 2)Age (years) 11.66 � 1.00 12.12 � 0.91 0.049 9.90 � 0.78 10.32 � 1.70 0.016Height (cm) 153.28 � 6.63 158.04 � 10.42 0.006 141.79 � 6.28 144.67 � 6.31 0.05Height SDS 0.76 � 0.75 0.38 � 0.43 0.014 0.64 � 0.73 0.38 � 0.53 0.049BMI (kg m-2) 35.58 � 7.12 20.71 � 1.98 <0.001 37.57 � 7.04 19.73 � 1.49 <0.001BMI SDS 2.63 � 0.59 0.14 � 0.58 <0.001 2.93 � 0.35 0.21 � 0.59 <0.001

Late puberty (visit 3)Age (years) 13.33 � 0.71 14.47 � 1.00 <0.001 11.54 � 0.99 12.40 � 1.02 0.001Height (cm) 163.59 � 5.74 170.54 � 4.28 <0.001 150.89 � 6.14 154.79 � 7.25 0.013Height SDS 0.42 � 0.81 0.47 � 0.53 0.82 0.40 � 0.65 0.41 � 0.51 0.92BMI (kg m-2) 34.77 � 6.36 21.68 � 1.85 <0.001 36.89 � 6.49 21.03 � 1.85 <0.001BMI SDS 2.58 � 0.81 0.11 � 0.50 <0.001 2.86 � 0.57 0.25 � 0.62 <0.001

Adult height (visit 4)Age (years) 14.58 � 0.57 16.16 � 1.27 <0.001 13.77 � 1.12 14.70 � 0.87 <0.001Height (cm) 170.65 � 6.06 175.33 � 2.11 <0.001 160.19 � 4.90 162.77 � 4.12 0.013Height SDS 0.38 � 0.70 0.35 � 0.51 0.89 0.36 � 0.54 0.36 � 0.51 0.89BMI (kg m-2) 30.12 � 3.50 22.22 � 1.76 <0.001 31.01 � 3.44 21.70 � 1.40 <0.001BMI SDS 1.98 � 0.46 0.16 � 0.58 <0.001 2.30 � 0.49 0.24 � 0.47 <0.001Target height (cm) 165.08 � 5.23 164.44 � 5.62 0.65 168.70 � 7.74 166.50 � 9.88 0.31Target height SDS -0.12 � 0.87 0.12 � 0.68 0.27 -0.39 � 0.81 -0.48 � 0.87 0.68ATO (year) 9.89 � 0.95 10.76 � 0.90 0.004 9.48 � 0.80 10.69 � 0.91 0.003APHV (year) 12.62 � 0.82 13.19 � 0.96 0.01 11.37 � 0.89 12.77 � 0.76 <0.001PHV (cm year-1) 7.74 � 1.49 9.28 � 1.64 <0.001 7.60 � 1.64 8.29 � 1.03 0.03Total height gain (cm) 29.31 � 5.45 38.11 � 4.74 <0.001 23.20 � 5.35 29.93 � 4.44 <0.001

APHV, age at peak height velocity; ATO, age at take-off; BMI, body mass index; PHV, peak height velocity; SDS, standard deviation score.

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of pubertal development (i.e. APHV) have been themain study end points. Furthermore, studies basedon secondary characteristics could have been asso-ciated with some bias, mainly due to the difficulty indistinguishing between fat and breast tissue in girls,when using only inspection. In addition, obesitycould be the consequence rather than the cause ofearlier pubertal onset, but cross-sectional studies donot allow discerning which event comes first, there-fore highlighting the importance of longitudinal pro-spective studies in this context.

In line with previous data, in the present longitudi-nal study, based on a direct physical examination ofpubertal stage, we found that girls presented anearlier pubertal onset, by around 0.5 years, andattainment of later pubertal stages (about 1 yearearlier). Interestingly, the same was also true for boysand this latter finding is of note, given that up to now,evidence in boys has been less clear, with discordantfindings across different studies. Whereas someEuropean studies have shown earlier pubertal onsetin obese boys (3,12,33,34), American studies havemainly shown a delay in pubertal onset in obese boys(10,11,30). These discordant findings are partlyexplained by differences in the way of assessingpuberty. A direct assessment of pubertal stage hasbeen performed only in few studies, whereas othershave used some surrogate markers of pubertalonset/progression, such as age at voice break orAPHV (35–37). In our study, we directly assessedtesticular size at each study visit, and this led to thefinding of an earlier pubertal onset and maturation inobese boys than normal-weight peers, in line withfindings in girls.

In addition, in accord with previous studies, wefound that APHV also occurred at a younger age inobese than in normal-weight boys and girls, and wasassociated with a lower PHV in the obese group.Furthermore, in the subgroup of children where wehad enough pre-pubertal height measurements, wefound that ATO also occurred at a younger age whencompared to normal-weight peers, in line with find-ings in previous studies (13).

Several potential mechanisms and intriguinghypotheses explaining the association betweenchildhood obesity and earlier pubertal onset havebeen described. Adiposity has been proposed as ametabolic gatekeeper of central pubertal initiation,with a premature activation of the GnRH pulse gen-erator (17). One of the key factors mediating thiseffect of adiposity on puberty could be leptin, whichcan exert direct effects on gonadotropin secretion(2,38). Additionally, the relationship between child-hood obesity and early puberty could be explained

by the status of hyperinsulinemia/insulin resistanceassociated with obesity. In particular, increasedinsulin levels can stimulate sex steroid production byacting on the adrenal glands and gonads. Increasedandrogen levels can, in turn, promote pubertal devel-opment acting peripherally and/or centrally on thehypothalamic pituitary axis (17). The same factorscould mediate other endocrine manifestations asso-ciated with obesity, such as hyperandrogenemia andincreased risk of polycystic ovary syndrome (39).

In addition, we showed that obese children pre-sented a faster rate of pubertal progression.

A shorter duration of puberty has been previouslyreported in obese girls, as reflected by an earlieronset of puberty and an earlier age at menarchewhen compared with normal-weight peers (6).

An explanation for this finding could be the rapidweight gain in infancy with the development of insulinresistance and an exaggerated adrenarche, whichcould affect rate of progression of pubertal develop-ment in obese subjects (14).

Childhood obesity seems to influence not onlypubertal maturation and progression, but alsogrowth in terms of height. Nutritional status has beenshown to play a major role in regulating childhoodgrowth, as clearly supported by the associationbetween short stature and malnutrition (31), whereasovernutrition has been linked to taller stature (40).Up to now, only few studies have prospectivelyassessed growth from pre-puberty, throughoutpubertal development until adult height. Some pre-vious data suggested that obesity is associated withtaller childhood stature and reduced height gainduring adolescence, resulting in no beneficial effecton adult height (3,4). Advanced bone maturation inobese children has also been reported, parallelingthe height trend, and this could explain the loss of thepre-pubertal growth advantage in obese children(4,17,41).

In the present study, we observed that obese chil-dren were significantly taller during pre-pubertalyears when compared to their normal-weight peers.However, we found that they tended to lose theirpre-pubertal growth advantage over time, as shownby the progressive decline in height SDS and to thedecreased pubertal growth spurt. This led to similaradult heights SDS between obese and normal-weight children, although comparisons betweenheights SDS at final visits as well at previous studyvisits were likely confounded by the different chrono-logical ages between the two study groups at attain-ment of different stage of pubertal maturation. Theprogressive loss in the pre-pubertal growth advan-tage could be explained by concomitant advanced

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bone maturation in obese children, thus resulting inan earlier epiphyseal closure. Given that, we did notassess bone age in our study population; thishypothesis remains speculative. However, fastergrowth maturation was suggested by the APHV,which occurred in obese children when compared tonormal-weight peers. APHV was inversely correlatedwith pre-pubertal BMI SDS, as previously shown(13), suggesting that pre-pubertal body compositionmay affect the progression of pubertal development,which results in an earlier attainment of later pubertalstages. Interestingly, obese children also showed alower PHV, supporting previous findings of anobesity-related prepubertal growth advantage, whichseems to disappear during pubertal years.

In addition, we found that parentally adjustedheight gain was significantly less in obese thannormal-weight children, in both girls and boys, thusconfirming that growth is significantly influenced bynutritional status and adipose mass, independentlyof the genetic background. In addition, with regardsto our study, it needs to be acknowledged thatalthough a lifestyle intervention was proposed to allobese participants, adherence was poor as sug-gested by lack of significant changes in BMI SDSover time.

The main strength of the present study is the lon-gitudinal design based on a direct and repeatedassessment of pubertal staging. However, some limi-tations of the study need to be acknowledged. Theseinclude lack of information on bone age and pubertalbiochemical markers (i.e. DHEAS, oestrogen andtestosterone, GH and IGF-1 levels), a small samplesize and a clinical-based instead of a population-based study design. In addition, we used only BMI asa fatness index, without better measures of bodycomposition, which would have allowed the differen-tiation between visceral and subcutaneous adiposetissue. Another potential study limitation is related tothe 6-monthly assessments, which might have led tosome errors in cases where key pubertal changesoccurred in between study visits. In addition, the lackof data at younger ages limited the possibility ofestimating ATO for the whole study population.Finally, a potential selection bias could have occurredfor the control group.

In conclusion, the present longitudinal studyshowed that being obese during childhood can pre-dispose to an earlier onset of puberty and potentiallyincrease the risk of complications associated withearly puberty. Interestingly, the effect of obesity onpuberty was evident for both boys and girls. Beingobese during childhood did not lead to any advan-tage on adult height in our study population. Overall,

these findings underline a further reason for fightingthe epidemics of childhood obesity in the clinicalsetting. They highlight the importance of assessingphysical growth and pubertal onset and progressionin obese children.

Conflicts of InterestStatementThe authors declare that there is no conflict of inter-est that could be perceived as prejudicing the impar-tiality of the research reported.

Author contributionAll the authors were involved in data collection. CDLcollected and analyzed data, and drafted the manu-script. MLM collected and analysed data, anddrafted the manuscript. VC collected data and con-tributed to discussion. TdG collected data and con-tributed to discussion. FC revised the manuscript,contributed to data interpretation and discussion.AM contributed to the conception and design of thestudy, revised the manuscript, contributed to datainterpretation and discussion. This research did notreceive any specific grant from any funding agency inthe public, commercial or not-for-profit sector.

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