Key features of puberty onset and progression can help distinguish self-limited delayed puberty from congenital hypogonadotrophic hypogonadism.

Introduction: Delayed puberty (DP) is a frequent concern for adolescents. The most common underlying aetiology is self-limited DP (SLDP). However, this can be difficult to differentiate from the more severe condition congenital hypogonadotrophic hypogonadism (HH), especially on first presentation of an adolescent patient with DP. This study sought to elucidate phenotypic differences between the two diagnoses, in order to optimise patient management and pubertal development. Methods: This was a study of a UK DP cohort managed 2015-2023, identified through the NIHR clinical research network. Patients were followed longitudinally until adulthood, with a definite diagnosis made: SLDP if they had spontaneously completed puberty by age 18 years; HH if they had not commenced (complete, cHH), or had commenced but not completed puberty (partial, pHH), by this stage. Phenotypic data pertaining to auxology, Tanner staging, biochemistry, bone age and hormonal treatment at presentation and during puberty were retrospectively analysed. Results: 78 patients were included. 52 (66.7%) patients had SLDP and 26 (33.3%) patients had HH, comprising 17 (65.4%) pHH and 9 (34.6%) cHH patients. Probands were predominantly male (90.4%). Male SLDP patients presented with significantly lower height and weight standard deviation scores than HH patients (height p=0.004, weight p=0.021). 15.4% of SLDP compared to 38.5% of HH patients had classical associated features of HH (micropenis, cryptorchidism, anosmia, etc. p=0.023). 73.1% of patients with SLDP and 43.3% with HH had a family history of DP (p=0.007). Mean first recorded luteinizing hormone (LH) and inhibin B were lower in male patients with HH, particularly in cHH patients, but not discriminatory. There were no significant differences identified in blood concentrations of FSH, testosterone or AMH at presentation, or in bone age delay. Discussion: Key clinical markers of auxology, associated signs including micropenis, and serum inhibin B may help distinguish between SLDP and HH in patients presenting with pubertal delay, and can be incorporated into clinical assessment to improve diagnostic accuracy for adolescents. However, the distinction between HH, particularly partial HH, and SLDP remains problematic. Further research into an integrated framework or scoring system would be useful in aiding clinician decision-making and optimization of treatment. .

Genetic evaluation supports differential diagnosis in adolescent patients with delayed puberty.

CONTEXT: Pubertal delay can be the clinical presentation of both idiopathic hypogonadotropic hypogonadism (IHH) and self-limited delayed puberty (SLDP). Distinction between these conditions is a common but important diagnostic challenge in adolescents. OBJECTIVE: To assess whether gene panel testing can assist with clinical differential diagnosis and to allow accurate and timely management of delayed puberty patients. DESIGN: Retrospective study. METHODS: Patients presenting with delayed puberty to UK Paediatric services, followed up to final diagnosis, were included. Whole-exome sequencing was analysed using a virtual panel of genes previously reported to cause either IHH or SLDP to identify rarely predicted deleterious variants. Deleterious variants were verified by in silico prediction tools. The correlation between clinical and genotype diagnosis was analysed. RESULTS: Forty-six patients were included, 54% with a final clinical diagnosis of SLDP and 46% with IHH. Red flags signs of IHH were present in only three patients. Fifteen predicted deleterious variants in 12 genes were identified in 33% of the cohort, with most inherited in a heterozygous manner. A fair correlation between final clinical diagnosis and genotypic diagnosis was found. Panel testing was able to confirm a diagnosis of IHH in patients with pubertal delay. Genetic analysis identified three patients with IHH that had been previously diagnosed as SLDP. CONCLUSION: This study supports the use of targeted exome sequencing in the clinical setting to aid the differential diagnosis between IHH and SLDP in adolescents presenting with pubertal delay. Genetic evaluation thus facilitates earlier and more precise diagnosis, allowing clinicians to direct treatment appropriately.

Mixed-meal tolerance test to assess residual beta-cell secretion: Beyond the area-under-curve of plasma C-peptide concentration.

AIMS: Residual beta-cell secretion in type 1 diabetes is commonly assessed by area-under-curve of plasma C-peptide concentration (AUCCpep ) following mixed-meal tolerance test (MMTT). We aimed to investigate alternative measures of beta-cell responsiveness. METHODS: We analyzed data from 32 youth (age 7 to 17 years) undergoing MMTT within 6 months of type 1 diabetes diagnosis. We related AUCCpep with (a) validated mechanistic index of postprandial beta-cell responsiveness MI accounting for glucose level during MMTT, and (b) pragmatic marker calculated as baseline plasma C-peptide concentration corrected for baseline plasma glucose concentration. RESULTS: Postprandial responsiveness MI was correlated with age and BMI SDS (Rs = 0.66 and 0.44, P < 0.01 and P < 0.05) and was more correlated with glycated hemoglobin than AUCCpep (Rs = 0.79, P = 0.04). The pragmatic marker was highly correlated with AUCCpep (Rs = 0.94, P < 0.01). CONCLUSIONS: Postprandial responsiveness MI may be more relevant to glucose control than AUCCpep . Baseline C-peptide corrected for baseline glucose appears to be a suitable surrogate of AUCCpep if MMTT is not performed.

Frequent Monitoring of C-Peptide Levels in Newly Diagnosed Type 1 Subjects Using Dried Blood Spots Collected at Home.

Objective: To evaluate an approach to measure ß-cell function by frequent testing of C-peptide concentrations in dried blood spots (DBSs). Patients: Thirty-two children, aged 7 to 17 years, with a recent diagnosis of type 1 diabetes. Design: Mixed-meal tolerance test (MMTT) within 6 and again at 12 months after diagnosis, with paired venous and DBS C-peptide sampling at 0 and 90 minutes. Weekly DBS C-peptide before and after standardized breakfasts collected at home. Results: DBS and plasma C-peptide levels (n = 115) correlated strongly (r = 0·91; P < 0.001). The Bland-Altman plot indicated good agreement. The median number of home-collected DBS cards per participant was 24 over a median of 6.9 months. Repeated DBS C-peptide levels varied considerably within and between subjects. Adjustment for corresponding home glucose measurements reduced the variance, permitting accurate description of changes over time. The correlation of the C-peptide slope over time (assessed by repeated home DBS) vs area under the curve during the two MMTTs was r = 0.73 (P < 0.001). Mixed models showed that a 1-month increase in diabetes duration was associated with 17-pmol/L decline in fasting DBS C-peptide, whereas increases of 1 mmol/L in glucose, 1 year older age at diagnosis, and 100 pmol/L higher baseline plasma C-peptide were associated with 18, 17, and 61 pmol/L higher fasting DBS C-peptide levels, respectively. In addition, glucose responsiveness decreased with longer diabetes duration. Conclusion: Our approach permitted frequent assessment of C-peptide, making it feasible to monitor ß-cell function at home. Evaluation of changes in the slope of C-peptide through this method may permit short-term evaluation of promising interventions.

Tolvaptan use during hyperhydration in paediatric intracranial lymphoma with SIADH.

An 11-year-old boy developed severe syndrome of inappropriate antidiuretic hormone secretion (SIADH) after diagnosis of an intracranial B-cell lymphoma. His sodium levels dropped to 118-120 mmol/L despite 70% fluid restriction. For chemotherapy, he required hyperhydration, which posed a challenge because of severe hyponatraemia. Tolvaptan is an oral, highly selective arginine vasopressin V2-receptor antagonist, which has been licensed in adults for the management of SIADH and has been used in treating paediatric heart failure. Tolvaptan gradually increased sodium levels and allowed liberalisation of fluid intake and hyperhydration. Tolvaptan had profound effects on urinary output in our patient with increases up to 8 mL/kg/h and required close monitoring of fluid balance, frequent sodium measurements and adjustments to intake. After hyperhydration, tolvaptan was stopped, and the lymphoma went into remission with reversal of SIADH. We report one of the first uses of tolvaptan in a child with SIADH, and it was an effective and safe treatment to manage severe SIADH when fluid restriction was not possible or effective. However, meticulous monitoring of fluid balance and sodium levels and adjustments of fluid intake are required to prevent rapid sodium changes. LEARNING POINTS: Tolvaptan can be used in paediatric patients with SIADH to allow hyperhydration during chemotherapy.Tolvaptan has profound effects on urinary output and meticulous monitoring of fluid balance and sodium levels is therefore warranted.Tolvaptan was well tolerated without significant side effects.

Normal Variation in Pubertal Timing: Genetic Determinants in Relation to Growth and Adiposity.

In humans, there is a considerable variation in age of onset of puberty. Twin studies have indicated that pubertal timing is a highly heritable trait. Recently, a few rare genetic causes of precocious puberty have been reported as well as genetic mutations associated with isolated hypogonadotropic hypogonadism. Genome-wide association (GWA) studies have helped to explore the genetic determinants of the normal variation in pubertal timing, but have been able to explain only 2.7% of the variance in age at menarche, highlighting the involvement of multiple genes with small effect sizes. These studies indicate an overlap of genes involved in pubertal timing and adiposity, and epidemiological data suggest the existence of a pathway of early infancy weight gain, increased height gain in childhood, earlier pubertal timing and increased adiposity in adulthood. This chapter summarises the data from GWA and epidemiological studies on the normal variation in pubertal timing in relation to growth and adiposity. We discuss putative mechanisms linking early life events to pubertal timing, potential short-term and life-course consequences of earlier pubertal timing, and the impact of these data on clinical management of pubertal disorders.

Pros and cons of GnRHa treatment for early puberty in girls.

The timing of puberty has considerable biological, psychosocial and long-term health implications. Secular trends in age at pubertal development, the effects of obesity and the potential effects of environmental endocrine disruptors challenge the standard definitions of precocious puberty and the indications for intervention with gonadotropin-releasing hormone agonists (GnRHa) in girls with precocious puberty. GnRHa therapy is effective in improving adult height in patients who present with classic central precocious puberty (at <8 years old), without causing adverse effects on body composition, BMD and reproductive function. However, its benefits in patients with atypical forms of early puberty not driven by luteinising hormone are not well defined. The role of GnRHa in these patients and the potential benefits in terms of later growth, psychosocial functioning and long-term risk of adult diseases that are associated with early menarche, such as breast cancer and the metabolic syndrome, have not been established.

Bloom syndrome in short children born small for gestational age: a challenging diagnosis.

BACKGROUND: GH treatment has become a frequently applied growth-promoting therapy in short children born small for gestational age (SGA). In some disorders GH treatment is contraindicated, eg, chromosomal breakage syndromes. Bloom syndrome is a rare chromosomal breakage syndrome characterized by severe pre- and postnatal growth deficiency, a photosensitive facial erythema, immunodeficiency, mental retardation or learning disabilities, endocrinopathies, and a predisposition to develop a wide variety of cancers. OBJECTIVE: We report 2 patients with Bloom syndrome illustrating the variety in clinical manifestations. They were initially diagnosed with short stature after SGA birth and Silver Russell syndrome and treated with GH. CASES: Both patients presented with pre- and postnatal growth failure but no clear other characteristic features associated with Bloom syndrome. Photosensitive skin lesions developed only at a pubertal age and were minimal. Also, both children showed normal immunoglobulin levels, normal development, and no signs of endocrinopathies at start of GH. Dysmorphic features resembling Silver Russell syndrome were observed in both patients. Remarkably, during GH treatment IGF-1 levels increased to values greater than 3.5 SD score, with normal IGF binding protein-3 levels. CONCLUSION: Short children born SGA comprise a heterogeneous group. Bloom syndrome should be tested for in children with consanguineous parents, dysmorphic features (particularly resembling Silver Russell syndrome), skin abnormalities, and/or IGF-1 levels greater than 2.5 SD score during standard GH treatment with normal IGF binding protein-3 levels.

Health profile of young adults born preterm: negative effects of rapid weight gain in early life.

INTRODUCTION: Early postnatal weight gain is associated with determinants of cardiovascular disease (CVD) and type 2 diabetes mellitus (DM2) in adults born term. We aimed to investigate the association of weight gain during different periods, and weight trajectories in early life after preterm birth, with determinants of CVD and DM2 in early adulthood. METHODS: Associations of first-year growth and tempo of weight gain with determinants of CVD and DM2 in 162 young adults (18-24 yr) born preterm (gestational age <36 wk) were determined and compared with data of young adults born term (n = 217). RESULTS: Gain in weight for length in the period from preterm birth up to term age, and in the first 3 months after term age, was positively associated with body fat percentage and waist circumference at 21 yr. Gain in weight for length in the first 3 months after term age was also positively associated with total cholesterol and low-density lipoprotein cholesterol levels in early adulthood. Subjects with the highest gain in weight from birth to term age (highest quartile) had significantly higher body fat percentage, waist circumference, acute insulin response, and disposition index in early adulthood than the subgroups with moderate and low gain in weight. Rapid catch-up in weight during the first 3 months after term age resulted in a higher fat percentage, waist circumference, and serum triglycerides level than slower catch-up in weight. CONCLUSION: Accelerated neonatal gain in weight relative to length after preterm birth (immediately after birth and during the first 3 months after term age) is associated with determinants of CVD in early adulthood and should therefore be avoided.

Does preterm birth influence cardiovascular risk in early adulthood?

OBJECTIVE: To investigate the effect of preterm birth on risk factors for cardiovascular disease (CVD), independent of birth size. STUDY DESIGN: Observational study using data of 406 healthy participants aged 18-24 years, from the PROgramming factors for Growth And Metabolism and Prematurity and Small for Gestational Age studies. Associations between gestational age (GA), systolic blood pressure (SBP), diastolic blood pressure (DBP), pulse pressure (PP), blood pressure variability, heart rate (HR), pulse wave velocity, and carotid intima media thickness (cIMT) were studied. To study the differential effects of preterm birth and small birth size for gestational age, these parameters were also analyzed in subgroups born either preterm or term: young adults born small for gestational age with short or normal adult stature, and young adults born appropriate for gestational age with normal adult stature. RESULTS: Subjects born preterm (GA <36 weeks) had higher unadjusted SBP, PP, SBP and DBP variability, and HR, but a lower DBP than subjects born term. GA was inversely associated with SBP, PP, blood pressure variability, and HR, and positively associated with DBP, also after adjustment for confounders. There was no effect of GA on pulse wave velocity and cIMT, a marker of atherosclerosis. Of all the CVD risk factors measured, higher PP affected cIMT the most. CONCLUSIONS: Young adults born preterm might have a higher risk for CVD than those born term.

Preterm birth does not affect bone mineral density in young adults.

OBJECTIVE: Previous studies showed conflicting data on the effect of prematurity on bone mineral density (BMD) in infants and children. Only a few studies investigated the long-term effects of prematurity on BMD in early adulthood. The objective of our study was to assess the long-term effects of preterm birth on BMD of the total body (BMD(TB)), lumbar spine (BMD(LS)) and bone mineral apparent density of the LS (BMAD(LS)). DESIGN: Cross-sectional study. METHODS: It consists of two hundred and seventy-six healthy subjects without serious postnatal complications, aged 18-24 years. The contribution of gestational age to the variance in BMD in young adulthood and the differences in BMD between 151 subjects born preterm (median gestational age 32.2 weeks (interquartile range (IQR) 30.3-34.0)) and 125 subjects born at term (median gestational age 40.0 weeks (IQR 39.0-40.0)) were investigated. BMD was determined by dual-energy X-ray absorptiometry. RESULTS: There were no significant linear correlations between gestational age and BMD(TB) (r=0.063, P=0.30), BMD(LS) (r=0.062, P=0.31) and BMAD(LS) (r=0.069, P=0.26). Also after adjustment for possible confounders, gestational age was no significant contributor to the variance in BMD(TB) (P=0.27), BMD(LS) (P=0.91) and BMAD(LS) (P=0.87). No significant differences were found between preterm and term subjects with regard to BMD(TB), BMD(LS) and BMAD(LS). CONCLUSION: In our cohort of 276 young adults, aged 18-24 years, gestational age was not a significant determinant in the variance of BMD. Preterm birth without serious postnatal complications is not associated with a lower BMD in young adulthood.

Influence of preterm birth and birth size on gonadal function in young men.

BACKGROUND/OBJECTIVES: Preterm birth has been associated with reduced reproduction rates and being born small for gestational age (SGA) with reduced gonadal function. We hypothesized that alterations concerning gonadal function in young men are not due to preterm birth or being born SGA, but are due to other (environmental) factors. METHODS: In 207 young men of the PROGRAM/PREMS cohort study, aged 18-24 yr, the influence of preterm birth, birth length, and birth weight on serum levels of anti-Mullerian hormone, inhibin B, testosterone, SHBG, non-SHBG-bound testosterone, LH, and FSH was analyzed with multiple regression modeling. In addition, markers of male gonadal function were analyzed in four subgroups: men born SGA with either short stature or catch-up growth, or men born appropriate for gestational age with idiopathic short stature or with normal stature (control). RESULTS: Preterm birth and SGA did not affect gonadal function. After adjustment for age, birth size, adult height, fat mass, and socioeconomic status (SES), preterm birth even showed a positive relation with inhibin B. Higher SES was associated with higher inhibin B levels. Higher fat mass was associated with decreased testosterone and SHBG levels and maternal smoking with increased LH and non-SHBG-bound testosterone levels. After adjustment for confounders, there were no significant differences in gonadal function between the subgroups. CONCLUSION: Preterm birth and SGA did not affect gonadal function in young men. Factors that affected gonadal function were: lower SES, a higher fat mass, and maternal smoking during pregnancy.

Prematurity is not associated with reduced insulin sensitivity in adulthood.

BACKGROUND: In 2005, 12.7% of all babies were born preterm, and the incidence is rising. Nowadays, due to improved survival, an increasing number of children born preterm reach young adulthood. A recent report suggested lower insulin sensitivity in children born preterm, which may put them at risk for the development of type 2 diabetes. It is, however, still unknown whether this reduced insulin sensitivity persists into adulthood. METHODS: We determined insulin sensitivity and beta-cell function with frequently sampled iv glucose tolerance tests in 305 young adults (aged 18-24 yr; 169 preterm and 136 term). Adult body composition was measured by dual energy x-ray absorptiometry. We investigated the effect of gestational age, size at birth, and adult body composition on insulin sensitivity. RESULTS: In contrast to previous reports, we found no evidence that preterm birth has a deleterious effect on insulin sensitivity in young adulthood. Adult trunk fat and the use of oral contraceptives in women were the most important determinants of insulin insensitivity, independently of size at birth and duration of pregnancy. CONCLUSION: Contrary to our hypothesis, preterm birth was not associated with reduced insulin sensitivity in young adulthood.

Does preterm birth influence the response to growth hormone treatment in short, small for gestational age children?

OBJECTIVE: To investigate whether prematurity has an independent influence on the response to GH treatment in short, small for gestational age (SGA) children. DESIGN: A longitudinal 3-year GH study. PATIENTS: A total of 392 prepubertal non-GH-deficient, short SGA children, comprising 138 preterm (< 36 weeks) and 254 term (>or= 36 weeks) children. MEASUREMENTS: Height, weight, head circumference, skinfolds and serum IGF-I and IGFBP-3 levels were measured before start of GH treatment and after 6 months, 1, 2 and 3 years of treatment. RESULTS: Preterm short SGA children were significantly lighter and shorter at birth after correction for gestational age than term short SGA children (P < 0.001). At start of GH treatment, preterm children were significantly shorter than term children when height was corrected for target height (TH). Preterm children were also significantly leaner as shown by a lower body mass index (BMI) standard deviation score (SDS) and a lower sum of four skinfolds SDS. Prematurity had no influence on childhood IGF-I and IGFBP-3 levels. The response to GH treatment was similar for preterm and term SGA children. CONCLUSIONS: Within a population of short SGA children, prematurity is associated with a smaller size for gestational age and a shorter height corrected for TH and leaner phenotype in childhood. The response to GH treatment is similar for preterm and term short SGA children.

The effect of growth hormone treatment on metabolic and cardiovascular risk factors is similar in preterm and term short, small for gestational age children.

CONTEXT: We previously reported that short, small for gestational age (SGA) children who were born preterm have a lower body fat percentage and a higher blood pressure, insulin secretion and disposition index than short SGA children born at term. Whether preterm birth also influences these parameters during GH treatment is unknown. OBJECTIVE: To compare blood pressure, insulin sensitivity, beta-cell function and body composition during 4 years of GH treatment, between preterm and term short SGA children. PATIENTS: A total of 404 prepubertal non-GH-deficient short SGA children were divided into 143 preterm (< 36 weeks) and 261 term children. OUTCOME MEASURES: Height, blood pressure (n = 404), body composition measured by dual energy X-ray absorptiometry (DXA) (n = 138) and insulin sensitivity and beta-cell function calculated from a frequent sampling intravenous glucose tolerance test (FSIGT) with tolbutamide (n = 74) or from the homeostasis model assessment of insulin resistance (HOMA-IR) (n = 204). RESULTS: In preterm and term children, GH treatment resulted in a similar decrease in systolic and diastolic blood pressure, body fat percentage, limb fat/total fat ratio and insulin sensitivity, and a similar increase in insulin secretion and disposition index. Lean body mass (LBM) corrected for gender and height increased in term children and did not change in preterm children. Multiple regression analysis revealed that this difference in GH effect on LBM was not associated with gestational age. CONCLUSION: The effect of GH treatment on metabolic and cardiovascular risk factors is similar in preterm and term short, SGA children.

Longitudinal changes in insulin sensitivity and body composition of small-for-gestational-age adolescents after cessation of growth hormone treatment.

CONTEXT: GH treatment reduces insulin sensitivity (Si). For small-for-gestational-age (SGA) subjects, who might have an increased risk to develop cardiovascular disease and type 2 diabetes, it is still uncertain how Si, beta-cell function, and body composition change over time after stopping GH treatment. OBJECTIVE: Our objective was to investigate longitudinal changes in Si, beta-cell function, and body composition after cessation of long-term GH treatment. DESIGN AND PATIENTS: We conducted a longitudinal study that included 48 SGA adolescents studied at adult height, while still on GH, and 6 months after GH stop and compared them with 38 appropriate-for-gestational-age (AGA) controls at both time points. OUTCOME MEASURE: We took paired measurements of Si and beta-cell function, assessed by frequently sampled iv glucose tolerance tests with tolbutamide, and body composition, measured by dual-energy x-ray absorptiometry. RESULTS: After stopping GH, Si (P = 0.006), glucose effectiveness (Sg; P = 0.009) and beta-cell function (disposition index; P = 0.024) increased, whereas insulin secretion (acute insulin response; not significant) decreased. Fat percentage increased (P < 0.0005), and lean body mass decreased (P < 0.0005), but fat distribution remained unaltered, and body composition remained within the normal range. Compared with AGA controls, Si was lower during GH and became similar after GH stop, acute insulin response was higher at both time points, and glucose effectiveness and disposition index became higher. CONCLUSIONS: The GH-induced lower Si in SGA adolescents increases after stopping long-term GH treatment and becomes similar to that of AGA controls. Discontinuation of GH treatment is, however, also associated with an increase in percent body fat and with a decrease in lean body mass, without changes in fat distribution.

Cardiovascular risk factors in parents of short children born small for gestational age.

Small for gestational age (SGA) children have a higher prevalence of cardiovascular risk factors at a young age. It is not known whether this increased risk is caused by their size at birth, a familial predisposition for cardiovascular disease or smallness at birth or a combination of these factors. The cardiovascular risk profile of parents of SGA children is unknown. We compared anthropometry, blood pressure, fasting serum lipid, glucose, and insulin levels of 482 parents (mean age 41 y) and 286 short SGA children with age- and sex-matched references. We also investigated whether these parameters correlated between parents and their offspring. Mothers had higher systolic blood pressure, fathers had a higher body mass index and parents had more frequently high fasting glucose levels than age- and sex-matched references. Children had significantly higher systolic and diastolic blood pressure than sex- and height-matched references. Twenty-four percent (mothers) and 10% (fathers) were born SGA but they did not have more cardiovascular risk factors than those born appropriate for gestational age. Cardiovascular risk factors did not correlate between parents and children. In conclusion, parents of short SGA children have a modest increase in some cardiovascular risk factors but risk factors did not correlate between parents and children.

Plasma matrix metalloproteinase-9 levels and blood pressure in short children born small for gestational age and effects of growth hormone treatment.

CONTEXT: Short small-for-gestational-age (SGA) children have an increased systolic blood pressure (BP) that decreases during long-term GH treatment. The underlying mechanism is still unknown. Matrix metalloproteinases (MMPs) are zinc-dependent endoproteinases that are involved in the remodelling of the extracellular matrix (ECM) and are thought to play a role in atherosclerosis. High MMP-9 levels are found in hypertensive patients and predict cardiovascular mortality. OBJECTIVES: To investigate whether GH treatment affects plasma MMP-9 levels in short SGA children and whether these are related to BP. DESIGN: Case-control study. INTERVENTION: GH treatment vs. no treatment during 36 months. Patients Thirty-eight short SGA children receiving GH treatment vs. 17 sex- and age-matched untreated short SGA controls. OUTCOME MEASURE: Plasma MMP-9 levels and BP were measured at baseline, and after 6, 12 and 36 months of study. RESULTS: MMP-9 decreased significantly during 3 years of GH treatment but remained similar in untreated SGA controls. After 3 years of GH treatment, MMP-9 levels were significantly lower in the GH group than in the untreated SGA controls. Systolic BP SDS significantly decreased in the GH group but remained unaltered in the untreated SGA controls. MMP-9 levels did not correlate with systolic or diastolic BP. CONCLUSIONS: Plasma MMP-9 levels and systolic BP SDS decreased to almost 50% of baseline values in the GH group but remained unchanged in untreated SGA controls. Our data indicate that GH has a positive effect on both MMP-9 levels and systolic BP SDS.

Independent effects of prematurity on metabolic and cardiovascular risk factors in short small-for-gestational-age children.

CONTEXT: Both small-for-gestational-age (SGA) and preterm birth have been associated with an increased incidence of adult cardiovascular disease and diabetes mellitus type 2. However, it is unclear whether preterm birth has an additional effect on cardiovascular risk factors in short children born SGA. OBJECTIVE: Our objective was to investigate whether prematurity has an independent influence on several cardiovascular risk factors within a population of short SGA children. DESIGN: A cross-sectional observational study was performed. PATIENTS: A total of 479 short SGA children (mean age 6.8 yr), divided into preterm (<36 wk) and term (> or =36 wk) children, was included in the study. OUTCOME MEASURE: Insulin sensitivity, beta-cell function, body composition, and lipid levels were studied in subgroups, and blood pressure (BP), anthropometry at birth and during childhood in the total group. RESULTS: Preterm SGA children were significantly lighter and shorter at birth after correction for gestational age than term SGA children (P < 0.001) but had a comparable head circumference. In preterm SGA children, we found a significantly higher systolic (P = 0.003) and diastolic BP sd score (P = 0.026), lower percent body fat sd score (P = 0.011), and higher insulin secretion (P = 0.033) and disposition index (P = 0.021), independently of the degree of SGA. Insulin sensitivity, serum lipid levels, muscle mass, and body fat distribution were comparable for preterm and term SGA children. CONCLUSIONS: Within a population of short SGA children, preterm birth has divergent effects on several cardiovascular risk factors. Whereas preterm SGA children had a higher systolic and diastolic BP, they also had a lower percent body fat and a higher insulin secretion and disposition index than term SGA children.

Long-term GH treatment is not associated with disadvantageous changes of inflammatory markers and adipocytokines in children born small for gestational age.

CONTEXT: Low birth weight is associated with increased risks for adult cardiovascular disease (CVD) and diabetes mellitus type 2 (DM2). Adiponectin and resistin are hormones, considered, respectively, protective and disadvantageous regarding these risks. No data exist on the effect of long-term GH treatment on these hormones and inflammatory markers in children born small for gestational age (SGA). OBJECTIVE: To describe longitudinal changes in inflammatory markers and adipocytokines during and after a long-term dose-response GH study. DESIGN: Longitudinal dose-response study [group A: 1 mg/m(2) body surface area (BSA) (approximately 0.033 mg/kg/day) vs. group B: 2 mg/m(2) BSA (approximately 0.067 mg/kg/day)] and comparison with age-related controls. PATIENTS: One hundred and three SGA children. MEASUREMENTS: We measured adiponectin, resistin, interleukin-6 (IL-6) and C-reactive protein (CRP) levels at baseline, after 1 and 7 years of GH treatment and 6 months after discontinuation of GH. RESULTS: Adiponectin levels decreased over time, but remained comparable with controls. Resistin levels increased and remained lower or comparable with controls. There were no significant differences between the GH dosage groups. After the GH treatment was stopped, adiponectin was decreased in group B and resistin increased in group A. GH therapy did not affect IL-6 and CRP levels at any time point. An increase in body mass index (BMI) standard deviation score (SDS) over time was associated with a decrease in adiponectin levels. None of the markers were associated with insulin sensitivity. CONCLUSIONS: Long-term GH treatment is not associated with disadvantageous changes in adiponectin, resistin, IL-6 and CRP levels, neither during nor after GH treatment.