Total Pubertal Growth Research Articles

A Mixed-Longitudinal Study of Height Velocity of Greek Schoolchildren and the Milestones of the Adolescent Growth Spurt.

Height velocity (HV) growth charts constructed from longitudinal studies are scarce as they have inherent difficulties, e.g., time, and costs. These difficulties can be partly overcome by a mixed-longitudinal study that covers the entire age range within 3–6 years. To construct HV charts of Greek children and to estimate the milestones of the adolescent growth spurt (AGS), i.e., the onset of AGS (take-off), peak HV, and total pubertal growth (TPG), we performed a mixed longitudinal study in 1514 Greek schoolchildren (6–18 years) with height measurements every 6 months during three schoolyears. We constructed HV charts for boys and girls. Take-off occurs earlier in girls, and, in both sexes, it precedes by 1–1.5 years the appearance of physical signs of puberty. PHV in boys occurs at 12.61 years and in girls at 10.93 years. At take-off, boys are 5 cm taller than girls and TPG for boys is 35.8 cm and for girls 27.3 cm. We constructed HV charts plotted by age, irrespective of pubertal status, and presented data on the milestones of AGS. Furthermore, we suggest that the gradual increase in IGF-1 and E2 that occurs after 5 to 6 years of age triggers the onset of AGS, which precedes physical signs of puberty.

Estimation of Causal Effect of Age at Menarche on Pubertal Height Growth Using Mendelian Randomization.

We use Mendelian randomization to estimate the causal effect of age at menarche on late pubertal height growth and total pubertal height growth. The instrument SNPs selected from the exposure genome-wide association study (GWAS) are validated in additional population-matched exposure GWASs. Based on the inverse variance weighting method, there is a positive causal relationship of age at menarche on late pubertal growth (, 95% CI: (0.34, 0.78), ) and on total pubertal growth (, 95% CI: (0.14, 0.58), ). If the instrument SNPs are not validated in additional exposure GWASs, the estimated effect on late pubertal height growth increases by 3.6% to (95% CI: (0.42, 0.73), ) while the estimates on total pubertal height growth increases by 41.7% to (95% CI: (0.35, 0.67), ).

Good glycemic control at puberty in boys with type 1 diabetes is important for final height.

Poor glycemic control in children with type 1 diabetes (T1D) may hinder sexual development and the associated growth spurt. This study aims to identify factors that may affect the timing of puberty, total pubertal growth (TPG), and final height (F-Ht) in boys with T1D. This was a retrospective longitudinal study of 68 boys diagnosed with T1D during 1996 to 2009, who were prepubertal at diagnosis and had completed puberty at the time of data collection. Data were accessed regarding anthropometric measurements, Tanner stage, and glycosylated hemoglobin (HbA1c) levels from diagnosis to F-Ht. F-Ht was compared to parental height and Israeli National Health Survey data. The mean F-Ht standard deviation score (F-Ht-SDS) was lower than the mean Ht-SDS at diagnosis (P< .006) but similar to the mean target height SDS (P= .3) and to values from the national survey (P= .12). Mean HbA1c levels in the year preceding pubertal onset were associated with the age at onset of puberty (R= 0.33, P= .009) and inversely with TPG (R= -0.3, P= .03). Mean HbA1c levels during puberty were inversely associated with TPG (R= -0.26, P= .035) and F-Ht (R= -0.28, P= .02). Boys who presented with diabetic ketoacidosis at diagnosis were shorter than those who did not throughout the follow-up. We found associations of age of pubertal onset, pubertal growth spurt, and F-Ht with target height and glycemic control before and during puberty. Targeted interventions to achieve optimal metabolic control during these time periods are needed for normal, timely puberty and for achieving optimal adult height within the genetic target height.

MON-659 Course of Puberty and Growth Spurt in Boys with Type 1 Diabetes

Background: Data on the course of puberty and pubertal growth in boys with Type 1 diabetes (T1D) are sparse. Objectives: To study the course of puberty, pubertal growth and final height in boys with T1D as well as possible factors affecting these. Methods: In this retrospective longitudinal study, 68 boys diagnosed with T1D between 1996-2009 who were pre-pubertal at diagnosis and had completed puberty served as the cohort. Collected were data on anthropometric measurements, Tanner stage, and HbA1c levels from diagnosis to final height (F-Ht). F-Ht was compared to parental height and to the data of the national health survey Results – In the study cohort final height-SDS was lower than that at diagnosis. It was similar to parental Ht-SDS as well as to that of the national health survey (p=0.126). F-Ht was inversely related to average HbA1c during puberty (R=-0.27, p=0.045). Boys who presented with diabetic ketoacidosis at diagnosis were shorter than those who did not throughout the entire follow-up. Age at onset of puberty was significantly related to the age of maternal menarche (R=0.44, p=0.01) and to HbA1c levels in the year preceding puberty onset (R=0.36, p=0.01). Total pubertal growth was inversely related to HbA1c levels in the year preceding onset of puberty (average R=-0.3, p=0.03) Conclusions: Boys with T1D diagnosed before puberty achieve final height similar to that of their parents and that of the general population. Diabetic ketoacidosis at the diagnosis is associated with diminished F-Ht. Age of pubertal onset and F-Ht are affected by genetic factors as well as by glycemic control before and during puberty.These results emphasize the importance of tight metabolic control in adolescents, to enable growth within the genetic target.

Hydrocortisone Therapy and Growth Trajectory in Children with Classical Congenital Adrenal Hyperplasia

Poor linear growth is one of the main concerns in children with congenital adrenal hyperplasia (CAH). We aimed to analyze factors affecting growth trajectory in children with classical CAH. Clinical records of children followed from infancy up to the end of growth at two Italian tertiary referral hospitals were reviewed. Fifty-seven patients (31 males), treated with hydrocortisone and fludrocortisone only, were included. Clinical observations were divided into three groups: 0 to 2 years, 172 observations; from 2 years to puberty onset, 813 observations; after puberty onset, 527 observations. Height velocity, pubertal growth spurt, and final height were evaluated as outcomes. Final height standard deviation score (SDS) was lower than target height SDS (-0.74 ± 1.1 versus -0.31 ± 1.01; P<.001). Target-adjusted final height SDS was -0.44 ± 1.8 in males and -0.13 ± 1.1 in females (P = .001). Total pubertal growth was 21.9 ± 7.3 cm in males and 19.2 ± 8.2 cm in females (P = .19). Hydrocortisone dose increased and height-velocity SDS decreased during puberty. At multivariable analysis, height-velocity SDS was adversely affected by hydrocortisone dose (P = .038) and directly related to adrenocorticotropic hormone (ACTH) levels (P = .023). Target-adjusted final-height SDS was adversely affected by hydrocortisone dose (P<.001) and positively related to mineralocorticoid therapy (P = .001) and ACTH levels (P = .02). Total pubertal growth (cm) was positively related to ACTH levels (P = .01). Height outcome of CAH patients is now better than previously reported. During puberty, the lowest effective dose of hydrocortisone should be used to optimize pubertal growth spurt and final height. 17-OHP = 17-alpha-hydroxyprogesterone ACTH = adrenocorticotropic hormone BMI = body mass index CAH = congenital adrenal hyperplasia GH = growth hormone HPA = hypothalamus-pituitary-adrenal PRA = plasma renin activity SDS = standard deviation score SV = simple virilizing SW = salt-wasting.

Total pubertal growth in patients with juvenile idiopathic arthritis treated with growth hormone: Analysis of a single center

ObjectivesGrowth failure is a permanent sequelae in juvenile idiopathic arthritis (JIA).The aim of the study was to compare pubertal growth in control and growth hormone (GH) treated JIA subjects. Design64 children with JIA at a mean age of 10.38±2.80 years were enrolled and followed until final height (measured in standard deviation (SD) scores). 39 children (20m) received GH therapy and 24 (9m) served as controls. GH dose was 0.33mg/kg/week. Linear regression analysis was performed to identify factors influencing total pubertal growth. ResultsMean total pubertal growth was 21.1±1.3cm (mean±SD) in GH treated JIA patients and 13.8±1.5cm in controls. Final height was significantly higher with GH treatment (−1.67±1.20 SD) compared to controls (−3.20±1.84 SD). Linear regression model identified age at onset of puberty (ß=−4.2,CI: −5.9, −2.6 in controls and ß=−2.3,CI: −3.6, −1.1 in GH treated) as the main factor for total pubertal growth. Final height SDS was determined by the difference to target height at onset of puberty (ß=−0.59;CI: −0.80, −0.37 in controls and ß=−0.30,CI: −0.52, −0.08 in GH treated), age at onset of puberty (ß=0.47;CI:0.02,0.93 in controls and 0.23;CI: −0.00,0.46 in GH treated) and height gain during puberty (ß=0.13;CI:0.05,0.21 in controls and ß=0.11;CI:0.07,0.16 in GH treated). ConclusionTotal pubertal growth in JIA patients treated with GH was increased by a factor of 1.5 greater in comparison to controls leading to a significantly better final height. To maximize final height GH treatment should be initiated early to reduce the height deficit at onset of puberty.

Prediction models for short children born small for gestational age (SGA) covering the total growth phase. Analyses based on data from KIGS (Pfizer International Growth Database)

BackgroundMathematical models can be developed to predict growth in short children treated with growth hormone (GH). These models can serve to optimize and individualize treatment in terms of height outcomes and costs. The aims of this study were to compile existing prediction models for short children born SGA (SGA), to develop new models and to validate the algorithms.MethodsExisting models to predict height velocity (HV) for the first two and the fourth prepubertal years and during total pubertal growth (TPG) on GH were applied to SGA children from the KIGS (Pfizer International Growth Database) - 1st year: N = 2340; 2nd year: N = 1358; 4th year: N = 182; TPG: N = 59. A new prediction model was developed for the 3rd prepubertal year based upon 317 children by means of the all-possible regression approach, using Mallow's C(p) criterion.ResultsThe comparison between the observed and predicted height velocity showed no significant difference when the existing prediction models were applied to new cohorts. A model for predicting HV during the 3rd year explained 33% of the variability with an error SD of 1.0 cm/year. The predictors were (in order of importance): HV previous year; chronological age; weight SDS; mid-parent height SDS and GH dose.ConclusionsModels to predict growth to GH from prepubertal years to adult height are available for short children born SGA. The models utilize easily accessible predictors and are accurate. The overall explained variability in SGA is relatively low, due to the heterogeneity of the disorder. The models can be used to provide patients with a realistic expectation of treatment, and may help to identify compliance problems or other underlying causes of treatment failure.

A mathematical model in the analysis of the response to growth hormone treatment in pediatric patients with diagnosis of growth hormone deficiency

In the literature, few studies analyze the effect of GH therapy on height, preferring a more indirect approach, where factors influencing the total pubertal and pre-pubertal growth in GH-deficient patients are evaluated and subsequently used to estimate the overall effect at the end of the therapy; unfortunately, this approach does not quantify the real growth gain in treated patients. Using a non-parametric Empirical Bayes approach, our study analyzes the growth response to GH treatment in a homogeneous cohort of 317 patients with pituitary GH deficiency who were enrolled during their pre-pubertal stage in the GH Piedmont Registry (Italy), between January 2000-October 2008, and have at least 2 yr of follow-up. To estimate the growth curve for males and females, a non-parametric regression model was fitted, applying Empirical Bayes techniques. A validation of the model was also performed. Improvement was evident in both genders, since both males and females mean growth curve, which started below the 3rd percentile at the beginning of the therapy, reached the 10th percentile of the Tanner curve at the end of observation (17 yr old for males and 14 yr old for females); the estimation procedure achieved a good precision. The methodological approach allows for fitting a model able to evaluate longitudinally the response to GH treatment, by means of estimating the overall growth curve, even in presence of sparse information about children heights.

Reduced Final Height Outcome in Congenital Adrenal Hyperplasia under Prednisone Treatment: Deceleration of Growth Velocity during Puberty

Normal to decreased final height (FH) has been reported in patients with congenital adrenal hyperplasia (CAH). The objective was to determine FH outcome and influences of steroid treatment. The effects of glucocorticoid treatment for classical CAH were retrospectively studied in 125 patients (77 females). Growth pattern, FH, and pubertal development were recorded. Corrected FH was in the lower range of genetic potential [females with simple virilizing (SV)-CAH, -0.6 +/- 1.0 sd score (SDS) vs. females with salt-wasting (SW)-CAH, -0.6 +/- 0.9 SDS; males with SV-CAH, -1.1 +/- 0.9 SDS vs. males with SW-CAH, -0.9 +/- 0.9 SDS]. Total pubertal growth was significantly reduced in comparison with a reference population (females with SV-CAH, 11.9 +/- 6.5 cm, and females with SW-CAH, 13.8 +/- 7.6 cm vs. reference 20.3 +/- 6.8 cm, P < 0.01; and males with SV-CAH, 15.4 +/- 6.6 cm, and males with SW-CAH, 18.5 +/- 6.9 cm vs. reference 28.2 +/- 8.2 cm, P < 0.01). Thirty-three patients had been treated with prednisone, which resulted in reduced FH compared with patients (n = 92) treated with hydrocortisone (-1.0 +/- 0.9 SDS vs.-0.6 +/- 0.9 SDS; P < 0.05). FH correlated negatively with hydrocortisone dose given at the start of puberty (r = -0.3; P < 0.05). Pubertal development started early in boys [9.8 +/- 2.3 yr (SV) and 10.6 +/- 1.9 yr (SW)] and was timely in girls [9.8 +/- 1.9 yr (SV) and 10.3 +/- 1.5 yr (SW), menarche at 13.3 +/- 1.7 yr (SV) and 13.7 +/- 1.5 yr (SV)]. Patients with CAH are able to achieve adequate FH with conventional therapy. Total pubertal growth is significantly decreased, and treatment with prednisone results in decreased FH. In addition to biochemical analysis, treatment should be adjusted to normal growth velocity, especially during puberty.

Final Height in Children with Medulloblastoma Treated with Growth Hormone

Background: Medulloblastoma is the most frequent primary solid central nervous system tumour in children. The 5-year survival rate is at present at about 60%. Height in general is severely compromised in survivors. The present study is an extension of the investigation by the author’s group of the effect of exogenous growth hormone (GH) among medulloblastoma patients. Methods: A total of 113 patients with medulloblastoma (out of 682 cases documented in KIGS, Pfizer International Growth Database) were treated with GH till final height was achieved. At the start of GH therapy (median dose 0.18 mg/kg/week), patients were 8.9 years old and had a median height SDS of –1.6. Results: After 6.8 years of GH, final height SDS was –1.9, reflecting an overall loss in height of 0.3 SDS. This contrasted with an age-matched group of patients with idiopathic growth hormone deficiency (iGHD, n = 1,986), whose gain in height was 1.6 SDS on the same dose. The index of responsiveness averaged –0.9 during the first prepubertal year and –2.0 during total pubertal growth, thus indicating a major impairment in responsiveness to GH as compared to iGHD. Height at GH start, which correlated positively with the age at disease onset, was found to be the major determinant of final height. Conclusions: Our findings show that attempts to improve the height outcome in medulloblastoma must involve earlier recognition and treatment with higher-than-replacement doses of GH; additionally, modifications in cancer treatment programs need to be considered, such as lowering the dose of craniospinal irradiation or avoiding it as far as possible.

Total Pubertal Growth and Markers of Puberty Onset in Adolescents with GHD: Comparison between Mathematical Growth Analysis and Pubertal Staging Methods

Two methods of determining puberty onset (Preece- Baines model 1 (PB1) and Tanner staging) were used to calculate total pubertal growth (TPG) in adolescents with growth hormone deficiency (GHD). Patients and Methods: 34 patients (11 girls) met the following inclusion criteria: isolated GHD, >2 years growth hormone therapy prior to puberty onset, regular weight-adjusted GH dosage, known final height (age >21 years or height velocity <0.5 cm/year), no induction of puberty. PB1 was used to define age and height at onset of the pubertal growth spurt (‘take-off’). Results: The results (mean ± SD) were as follows: in girls, mean age at take-off was 9.8 years; 2.0 ± 1.1 years before breast stage B2. In boys, mean age at take-off was 11.3 years; 1.4 ± 0.8 years before testes volume >3 ml. Height at take-off was lower than at Tanner stage 2 by 12.4 ± 7.6 cm in girls and 7.7 ± 5.3 cm in boys. TPG was thus markedly greater (p < 0.001) using the PB1 method, as compared with Tanner stage2. Peak height velocity was normal. Final height was –0.5 ± 0.7 SDS in females and –0.4 ± 0.9 SDS in males. Conclusions: The method of measuring TPG from take-off is more objective, and has potentially greater implications for GH therapeutics than the Tanner stage method. In our study, 40% of TPG occurred before ‘breast stage B2’ was attained in GHD girls; whereas 23% of TPG occurred before ‘testes >3 ml’ in GHD boys.

Pubertal course of persistently short children born small for gestational age (SGA) compared with idiopathic short children born appropriate for gestational age (AGA)

Few data are available on the pubertal development of children born small for gestational age (SGA) who fail to show catch-up growth. A longitudinal analysis compared the pubertal course of persistently short children born SGA compared to children with idiopathic short stature who were appropriate for gestational age (AGA). One hundred and twenty-eight short children (height SDS<-1.7), including 76 (31 boys) born SGA and 52 (22 boys) born AGA, were regularly followed from early childhood to completion of puberty. Puberty was attained at normal age (10.5-14 Years in boys, 9.5-13 Years in girls) for most children in both the SGA and AGA groups (boys, 80% and 77%; girls, 76% and 78% respectively). The duration of puberty was similar in the SGA and AGA groups. Menarche occurred at normal age range but was significantly earlier in the SGA girls (P<0.01 by ANOVA). Despite the similar total pubertal growth, the patterns of growth differed significantly: SGA group - accelerated growth and bone maturation rates from onset of puberty with peak height velocity at Tanner stages 2-3, followed by a decelerated growth rate and earlier fusion of the epiphyses; AGA group - steady progression of bone elongation and maturation throughout puberty (pubertal growth, P<0.05 in both sexes; bone maturation, P<0.001 in both sexes). Final height in the SGA group was compromised compared with their target height (P<0.001). Children born SGA have a normal pubertal course with a distinct pubertal growth pattern. This pattern may represent an altered regulation of their growth modalities.

The Mathematical Model for Total Pubertal Growth in Idiopathic Growth Hormone (GH) Deficiency Suggests a Moderate Role of GH Dose

The role of GH treatment during total pubertal growth (TPG) is still unclear. We developed a prediction model for TPG (centimeters) through a multiple regression analysis of various prepubertal parameters in 303 adolescents with idiopathic GH deficiency from the KIGS database. Prepubertal catch-up growth and near-adult height were achieved, and GH dose was kept constant at approximately 30 micro g/kg.d. The model was validated on a cohort of 36 patients from one center. Four TPG predictors explained 70% of the variability with an error SD of 4.2 cm: gender (TPG in males was >11.3 cm vs. that in females), age at onset of puberty (negative), height SD score minus midparental height SD score at puberty onset (negative), and mean GH dose during puberty (positive). Our analysis suggests that TPG in idiopathic GH deficiency is only moderately dependent on GH dose. The use of a higher GH dosage at the onset of puberty should thus depend on the individual's height development. The TPG model aids in the planning of individually optimized and cost-effective GH treatment.

Prediction Model of Total Pubertal Growth in Idiopathic Growth Hormone Deficiency: Analysis of Data from KIGS

Accessible online at: www.karger.com/hre When discussing total pubertal growth, it is essential that the times of onset and completion of puberty are defined accurately. For example, Gasser and colleagues [1] studied growth curves from boys and girls and defined the onset of puberty as the nadir of growth velocity (i.e. zero growth acceleration). The end of puberty was defined as the point of minimum growth acceleration. This is in contrast to Marshall and Tanner’s definition of puberty, which is based on clinical signs such as genital and breast development [2]. Marshall and Tanner found that the onset of puberty was at 11.6 years in boys and 11.2 years in girls, with a total pubertal duration of about 3 years [2], whereas Gasser et al., using growth data, showed that the onset of puberty was at 10.9 years in boys and 9.7 years in girls, with a pubertal duration of 4 years [1]. Total pubertal growth was therefore greater when assessed using the methods of Gasser et al. with a difference of 3.7 cm in boys and 9.4 cm in girls [1]. We studied 303 children from KIGS (Pharmacia International Growth Database) who had idiopathic growth hormone (GH) deficiency and a GH level of less than 10 ng/ml in response to provocative testing. Patients had received at least 5 years of GH replacement, with at least 2 years of pre-pubertal and 2 years of post-pubertal therapy. For this study, the age at onset of puberty had to be between 10 and 17 years in boys and between 9 and 16 years in girls. The age at the end of puberty was over 16 years in boys and over 14 years in girls. Height velocity at the time of the analysis needed to be less than 2 cm/year and patients were receiving a constant dose of GH, administered as six or more injections per week. The results are summarized in table 1. Final height was reached at about 18 years in boys and 16 years in girls. Final height in boys was 0.7 standard deviations (SD) with a total pubertal growth of 25.3 cm. In girls, the final height was –1.7 SD, with a total pubertal growth of only 16 cm. Similar results were seen in an analysis of 36 patients (24 boys, 12 girls) from the University Children’s Hospital, Tubingen, Germany. When simple linear correlations were performed on the KIGS data, total pubertal growth correlated positively with both the age at onset of puberty and with the distance from target height, expressed as SD. Total pubertal growth also correlated positively with GH dose. Thus, a prediction model was developed with four variables: distance to target height (the greater the distance to target height, the greater the growth when receiving GH); mean GH dose; age at onset of puberty (the younger the age at

Pubertal Growth Assessment

Almost all available sets of height growth reference values are constructed in a cross-sectional manner, except for a few studies in which longitudinal sampling was used. Such reference values are, however, flawed because of considerable individual variation in the timing of puberty, especially among children with early or late pubertal maturation. An additional complicating factor is that the magnitude of the total pubertal growth spurt is significantly larger among those individuals with early pubertal maturation, compared with late maturation. Based on the growth records of 145 healthy Swedish children followed longitudinally, this study introduces a pre-pubertal standard for the assessment of pre-pubertal height for children with late onset of puberty. By plotting the height values of a child in a chart containing pre-pubertal reference values, the onset of the pubertal growth spurt can be identified by a change in the pre-pubertal height standard deviation score values of 0.3 standard deviations or more over a period of 1 year. Once the pubertal onset is established, a highly accurate final height prediction method can be applied to the data, as described in this article, in which height and age at pubertal onset are the only two measures required. The r² value of the prediction model was over 0.80 for both sexes. Finally, a method for assessing total pubertal height gain is presented. The method adjusts for the timing of puberty and is based on the height and age at pubertal onset, plus the observed final height.

Gonadotropin-Suppressive Therapy in Girls with Early and Fast Puberty Affects the Pace of Puberty but Not Total Pubertal Growth or Final Height

Gonadotropin-Suppressive Therapy in Girls with Early and Fast Puberty Affects the Pace of Puberty but Not Total Pubertal Growth or Final Height

Amplitude of Pubertal Growth in Short Stature Children with Intrauterine Growth Retardation

Objective: Pubertal growth contributes to 15–18% of adult height. A blunted pubertal peak could contribute to short adult height in short children born with intrauterine growth retardation (IUGR). Design and Methods: Pubertal growth, from onset of puberty to final height, was investigated in 75 short IUGR children: 47 were treated with recombinant human growth hormone (GH) (tx) before pubertal onset (mean dose: 0.4 IU/kg/week); 28 were not treated (no-tx). They were compared with 98 normal children. Results: Puberty occurred later in IUGR children than in controls (boys 14.2 ± 1 years vs. 12.1 ± 0.8 years; girls 12 ± 1 years vs. 11.2 ± 0.8 years; p < 0.0001). In girls, total pubertal growth was similar in all three groups (tx: 19.3 ± 4.8 cm; no-tx 19.8 ± 4.9 cm; controls 20.2 ± 3.9 cm; non-significant). IUGR boys had a reduced pubertal growth (tx: 21.3 ± 6.2 cm; no-tx: 23.9 ± 6.1; controls 26.9 ± 3.9 cm; p < 0.05). The age at puberty onset was the major determinant of pubertal growth amplitude (boys: r = 0.53, p < 0.001; girls: r = 0.45, p < 0.001). IUGR children exhibited little catch-up growth during puberty. Conclusions: In the present study, we describe a delayed onset of puberty in short children born with IUGR. Moreover, prepubertal GH treatment was associated in boys with a decrease in the amplitude of the pubertal spurt, a finding that should be further evaluated in clinical trials.

Prepubertal and pubertal growth, timing and duration of puberty and attained adult height in patients with congenital hypothyroidism (CH) detected by the neonatal screening programme for CH--a longitudinal study.

We have evaluated parameters of growth, the pubertal process and attained adult height in patients with congenital hypothyroidism (CH) of various aetiologies, diagnosed by the neonatal screening programme, and followed up longitudinally. To the best of our knowledge, no such data are available in the published literature. Our aim was to define the most important factors affecting these parameters. Thirty patients with CH (20 females and 10 males) diagnosed by neonatal screening (dysgenetic (n = 15), ectopic thyroid (n = 11), and enzymatic defect (n = 4)), treated with levo-thyroxine (L-T4) since the age of < or = 4 months, and followed up at intervals of 1-6 months for a mean period of 11.4 (range 5-19.6) years were evaluated. Detailed anthropometric measurements were performed by the same trained nurse, and pubertal stages were evaluated according to Tanner's criteria for breast or genitalia and pubic hair. Serum T4 and TSH levels were measured at each clinic visit using commercial kits. Bone age (BA) was determined at 6-12 months intervals using the Greulich & Pyle method. Seventeen patients attained adult height at the time of the report. Mean L-T4 dose of 7.9 (range 5.2-14.0) to 2.4 (range 1.3-3.4) micrograms/kg/day at various ages corrected the serum free T4(f-T4) levels to normal (> 10 pmol/l) in 95% of determinations, and the TSH level was reduced to < 10 mIU/l in 54% of the determinations during the follow-up period. Length at initiation of therapy (mean -0.15, (range -2.5-2.1) SDS), height at onset of puberty (mean -0.4, (range -1.8-1.8) SDS) and adult height (mean 0.2 (range -1.4-2.0) SDS, n = 17) were within the normal range (0.00 +/- 2 SDS). Onset and duration of puberty were normal in both sexes, and total pubertal growth contributed 19.1% (M) and 16.4% (F) to adult height. Peak height velocity (mean 10-6 (range 7.3-15.1) (M) and mean 8.0 (range 6.2-15.5) (F) cm/year) was within the normal range and occurred at the expected BA (14y; M and 12y; F). The attained average adult height was in close proximity to the average target height in both males and females. A significant positive correlation was found between the average L-T4 daily dose administered during the first 6 months of treatment and the attained adult height. Early detection by neonatal screening and treatment of congenital hypothyroidism enables normal prepubertal and pubertal growth and achievement of normal adult height, following normal puberty. Adult height in congenital hypothyroidism is significantly correlated with parental height and the mean L-T4 daily dose administered over the first 6 months of treatment. A dose of at least 8.5 micrograms/kg/day is recommended during this period. Periodical adjustments of L-T4 daily dose should be guided by clinical observation and serum free T4 levels.

Pubertal growth, sexual maturation, and final height in children with IDDM. Effects of age at onset and metabolic control.

To evaluate growth and pubertal development in children with IDDM and the influence of the age at onset of IDDM and the degree of metabolic control on final height. We conducted a retrospective evaluation of 62 subjects followed longitudinally both clinically and metabolically from the onset of IDDM until final height was reached. Height at diagnosis was within the normal percentiles in boys (0.5 +/- 1.0 standard deviation score [SDS]) and girls (0.4 +/- 1.0 SDS), but above the genetic target height (-1.0 +/- 0.9 SDS in boys and -1.1 +/- 0.6 SDS in girls; P = 0.0001 for both comparisons). Although a lesser height gain was observed during the ensuing years, the final height reached by boys (-0.4 +/- 1.1 SDS) and girls (-0.4 +/- 0.9 SDS) was higher than the genetic target height. Blunted total pubertal growth was observed both in boys (24.5 +/- 3.6 cm) and girls (20.1 +/- 4.2 cm). The decrease in height gain was independent of the duration of IDDM, the degree of metabolic control, or the insulin requirement. The greater the height at diagnosis, with respect to the genetic target height, the lesser was the subsequent height gain to reach final adult height (r = 0.34, p < 0.01). BMI increased with age as normally occurs in healthy children, independent of the duration of disease and the degree of metabolic control. Pubertal development began and progressed normally both in boys and girls. In boys, a testicular volume of 4 ml was reached at a mean age of 12.1 +/- 0.9 years. In girls, breast enlargement occurred at a mean age of 10.4 +/- 1.2 years and the mean age of menarche was 12.8 +/- 1.4 years. Pubertal development and progression occurred independent of the age at onset of IDDM, the glycemic control, or the insulin requirement during the pubertal period. Children with IDDM have normal onset of puberty and normal sexual maturation. Even though final height falls within the normal percentiles, the diminished height gain after diagnosis requires further investigation.

Dose-response relationship in the treatment of hypopituitary children with human growth hormone: a retrospective survey.

During the past 15 years, dose-response studies of hGH have been limited to prepubertal patients with complete somatotrophic deficiency, who have usually been treated with hGH three times/week within a dose range of 10-40 IU/kg/year. In such studies a weak positive correlation has been found (r = 0.429, p less than 0.001) with marked important individual variations. Very few or no data have been published regarding the dose-response relationship after the first year of hGH treatment, or when the dose is increased because the growth rate is waning, or during puberty. The present paper reports some data on these issues. A group of 32 young hGH deficient children, whose bone age was 0-4 years, was followed up for at least 3 years with hGH given intramuscularly three times weekly at doses of 12-48 IU/kg/year (mean, 25 +/- 9 IU/kg/year - i.e. approximately 0.15 IU/kg/injection). A dose-response relationship existed during the first year but not during the following 2 years nor for the height gain obtained at the end of the third year of treatment. The results of an increase of the dose of hGH by 33-66% in 13 prepubertal hGH deficient children whose growth rate had decreased after 2-5 years of treatment were fair in 6, limited in 4 and absent in 3, and did not relate to the extent of dose increase. However, this series is too small to allow definite conclusions. The growth rate of 67 adolescents with complete hGH deficiency and normal spontaneous puberty was close to the normal mean in the 45 males but much less in the 22 females. Although the least favourable results came from cases with post-radiotherapy hypopituitarism, the mean total pubertal growth spurt in patients with idiopathic hGH deficiency was also below the average, mainly in the girls, and with a large range of individual variation. An important fact was that bone age increased more than height age or chronological age in these hypopituitary pubertal patients. No dose-response relationship was found in this group, within a limited range of doses (40 patients receiving 16-20 IU/kg/year injected three times weekly, 19 receiving less than 16 IU/kg/year and 8 receiving more than 20 IU/kg/year). It may be concluded that in prepubertal hypopituitary children, hGH at a dose of approximately 20 IU/kg/year at the onset of treatment is probably appropriate. The lack of a dose-response relationship after the first year of treatment suggests that higher initial doses should be avoided.(ABSTRACT TRUNCATED AT 400 WORDS)