Environmental Impacts on Male Reproductive Development: Lessons from Experimental Models.

BACKGROUND: Male reproductive development in mammals can be divided into a gonadal formation phase followed by a hormone-driven differentiation phase. Failure of these processes may result in Differences in Sex Development (DSD), which may include abnormalities of the male reproductive tract, including cryptorchidism, hypospadias, infertility, and testicular germ cell cancer (TGCC). These disorders are also considered to be part of a testicular dysgenesis syndrome (TDS) in males. Whilst DSDs are considered to result primarily from genetic abnormalities, the development of TDS disorders is frequently associated with environmental factors. SUMMARY: In this review, we will discuss the development of the male reproductive system in relation to DSD and TDS. We will also describe the experimental systems, including studies involving animals and human tissues or cells that can be used to investigate the role of environmental factors in inducing male reproductive disorders. We will discuss recent studies investigating the impact of environmental chemicals (e.g., phthalates and bisphenols), lifestyle factors (e.g., smoking) and pharmaceuticals (e.g., analgesics) on foetal testis development. Finally, we will describe the evidence, involving experimental and epidemiologic approaches, for a role of environmental factors in the development of specific male reproductive disorders, including cryptorchidism, hypospadias, and TGCC. KEY MESSAGES: Environmental exposures can impact the development and function of the male reproductive system in humans. Epidemiology studies and experimental approaches using human tissues are important to translate findings from animal studies and account for species differences in response to environmental exposures.

Maternal Gestational Diabetes Mellitus and Newborn DNA Methylation: Findings From the Pregnancy and Childhood Epigenetics Consortium.

OBJECTIVE: Maternal gestational diabetes mellitus (GDM) has been associated with adverse outcomes in the offspring. Growing evidence suggests that the epigenome may play a role, but most previous studies have been small and adjusted for few covariates. The current study meta-analyzed the association between maternal GDM and cord blood DNA methylation in the Pregnancy and Childhood Epigenetics (PACE) consortium. RESEARCH DESIGN AND METHODS: Seven pregnancy cohorts (3,677 mother-newborn pairs [317 with GDM]) contributed results from epigenome-wide association studies, using DNA methylation data acquired by the Infinium HumanMethylation450 BeadChip array. Associations between GDM and DNA methylation were examined using robust linear regression, with adjustment for potential confounders. Fixed-effects meta-analyses were performed using METAL. Differentially methylated regions (DMRs) were identified by taking the intersection of results obtained using two regional approaches: comb-p and DMRcate. RESULTS: Two DMRs were identified by both comb-p and DMRcate. Both regions were hypomethylated in newborns exposed to GDM in utero compared with control subjects. One DMR (chr 1: 248100345-248100614) was located in the OR2L13 promoter, and the other (chr 10: 135341870-135342620) was located in the gene body of CYP2E1. Individual CpG analyses did not reveal any differentially methylated loci based on a false discovery rate-adjusted P value threshold of 0.05. CONCLUSIONS: Maternal GDM was associated with lower cord blood methylation levels within two regions, including the promoter of OR2L13, a gene associated with autism spectrum disorder, and the gene body of CYP2E1, which is upregulated in type 1 and type 2 diabetes. Future studies are needed to understand whether these associations are causal and possible health consequences.

Idiopathic short stature and growth hormone sensitivity in prepubertal children.

OBJECTIVE: We compared growth hormone sensitivity to an insulin-like growth factor I (IGF-I) generation test in children with idiopathic short stature (ISS) and of normal stature (NS) across the birthweight range. METHODS: Forty-six prepubertal children (~7.1 years) born at term were studied: ISS (n = 23; 74% boys) and NS (n = 23; 57% boys). Children underwent a modified IGF-I generation test with recombinant human growth hormone (rhGH; 0.05 mg/kg/d) over four consecutive days. Hormonal concentrations were measured at baseline and day 5. RESULTS: Children with idiopathic short stature were 1.90 SDS lighter (P < 0.0001) but had 4.5% more body fat (P = 0.0007) than NS children. Overall, decreasing birthweight SDS across the normal range (-1.9 to +1.5 SDS) was associated with lower percentage IGF-I response to rhGH stimulation in univariable (r = 0.45; P = 0.002) and multivariable models (ß = 24.6; P = 0.006). Plasma IGF-I concentrations rose in both groups with rhGH stimulation (P < 0.0001). GHBP levels (P = 0.002) were suppressed in ISS children (-19%; P = 0.029) but increased among NS children (+18%; P = 0.028), with contrasting responses also observed for leptin and IGFBP-1. Further, the increase in insulin concentrations in response to rhGH stimulation was ~3-fold greater in NS children (142% vs 50%; P = 0.006). CONCLUSIONS: A progressive decrease in birthweight SDS was associated with a reduction in GH sensitivity in both NS and ISS children. Thus, the lower IGF-I response to rhGH stimulation in association with decreasing birthweight indicates that the ISS children at the lower end of the birthweight spectrum may have partial GH resistance, which may contribute to their poorer growth.

Predicting puberty in partial androgen insensitivity syndrome: Use of clinical and functional androgen receptor indices.

BACKGROUND: PAIS exhibits a complex spectrum of phenotypes and pubertal outcomes. The paucity of reliable prognostic indicators can confound management decisions including sex-of-rearing. We assessed whether external masculinisation score (EMS) at birth or functional assays correlates with pubertal outcome in PAIS patients and whether the EMS is helpful in sex assignment. METHODS: We collected pubertal outcome data for 27 male-assigned PAIS patients, all with confirmed androgen receptor (AR) mutations, including two previously uncharacterized variants (I899F; Y916C). Patients were grouped as follows; EMS at birth <5 and ≥ 5 (EMS in normal males is 12; median EMS in PAIS is 4·7) and pubertal outcomes compared. FINDINGS: Only 6/9 patients (67%) with EMS <5 underwent spontaneous onset of puberty, versus all 18 patients with EMS ≥5 (p = .03). Only 1/6 patients (17%) with EMS <5 developed adult genitalia reaching Tanner stage 4 or 5, versus 11/13 (85%) with EMS ≥5 (p = 0·01). There was no significant difference between the two groups of patients in being prescribed androgen replacement, who reached adult testicular volume ≥ 15 ml, pubic hair Tanner stage 4 or 5, above average adult height, had gynaecomastia, and mastectomy. No correlation was observed between EMS and in vitro AR function. INTERPRETATION: In PAIS with AR mutation, birth EMS is a simple predictor of spontaneous pubertal onset and satisfactory adult genitalia. This provides useful information when discussing the likely options for management at puberty. FUND: European Commission Framework 7 Programme, NIHR Cambridge Biomedical Research Centre, BBSRC DTP.

Society for Endocrinology UK guidance on the initial evaluation of an infant or an adolescent with a suspected disorder of sex development (Revised 2015).

It is paramount that any child or adolescent with a suspected disorder of sex development (DSD) is assessed by an experienced clinician with adequate knowledge about the range of conditions associated with DSD. If there is any doubt, the case should be discussed with the regional DSD team. In most cases, particularly in the case of the newborn, the paediatric endocrinologist within the regional team acts commonly as the first point of contact. This clinician should be part of a multidisciplinary team experienced in management of DSD and should ensure that the affected person and parents have access to specialist psychological support and that their information needs are comprehensively addressed. The underlying pathophysiology of DSD and the strengths and weaknesses of the tests that can be performed should be discussed with the parents and affected young person and tests undertaken in a timely fashion. Finally, in the field of rare conditions, it is imperative that the clinician shares the experience with others through national and international clinical and research collaboration.

Response to IGF-1 Generation Test in Short Prepubertal Children Born Very Preterm or at Term.

AIMS: To investigate whether short children born very preterm (<32 weeks of gestation) exhibit features of growth hormone (GH) resistance compared to term peers. METHODS: We studied 26 prepubertal children (aged 7.0 ± 2.0 years) with short stature (height adjusted for parents' heights <10th percentile), who were born appropriate for gestational age and either very preterm (n = 11) or at term (n = 15). Children underwent insulin-like growth factor-1 (IGF-1) generation test via a daily recombinant human GH (rhGH) dose (0.05 mg/kg/day) over 4 consecutive days. Hormone and binding proteins were measured at baseline and day 5. RESULTS: At baseline, preterm children had lower IGF-binding protein 1 (IGFBP-1; -22%; p = 0.049) and IGFBP-3 (-24%; p = 0.013) concentrations than term children. Preterm children also had insulin concentrations that tended to be 39% higher (p = 0.059) than term peers. After stimulation, IGF-1 and IGFBP-3 concentrations increased similarly in term and preterm groups, while GH-binding protein (GHBP) concentrations decreased in both groups. Preterm children had higher GHBP (+50%; p = 0.049), insulin (+86%; p = 0.005), and leptin (+107%; p = 0.020) but lower IGFBP-1 (-47%; p = 0.006) concentrations than term children following rhGH stimulation. CONCLUSIONS: Preterm children who are short for genetic height potential show no evidence of GH resistance that would explain their short stature. However, there was indirect evidence of insulin resistance in the preterm children, as previously described in this group.

Anthropometry, glucose homeostasis, and lipid profile in prepubertal children born early, full, or late term.

To examine differences in growth and metabolism in prepubertal children born early term, full term, and late term. We retrospectively studied 294 prepubertal children aged 7.3 years (range 3.0-12.1 years). Children were separated into those born early term (37 0/7-38 6/7 weeks of gestation; n = 68), full term (39 0/7-40 6/7 weeks; n = 179), and late term (41 0/7-41 6/7 weeks; n = 47). Clinical assessments included anthropometry, DXA-derived body composition, fasting lipids, and glucose homeostasis. Statistical models accounted for important confounding factors, such as gender, age, birth weight SDS, birth order, and parental variables. When birth weight was adjusted for sex and gestational age (birth weight SDS), late terms were heavier than both early (p = 0.034) and full (p = 0.020) terms. Early term children were shorter than both full (p = 0.010) and late (p = 0.049) term children, but differences in height disappeared following correction for parents' heights. There were no differences in glucose homeostasis, BMI SDS, adiposity, or fat distribution between groups. Lipid profiles were also similar. When important confounding factors were accounted for, there were no meaningful differences in anthropometry, glucose homeostasis, and lipid profile among children born early term, full term, or late term.

Low frequency of androgen receptor gene mutations in 46 XY DSD, and fetal growth restriction.

OBJECTIVE: The diagnosis of partial androgen insensitivity syndrome (PAIS) should be reserved for infants with a pathogenic androgen receptor gene (AR) mutation. However, only about 20% of infants with a clinical phenotype akin to PAIS have an AR mutation. We aimed to identify clinical features associated with the presence of an AR mutation. METHODS: The external masculinisation score (EMS; normal=12), birth weight (BW), gestational age and BW SD score (BW-SDS) of 164 infants with a 'PAIS-like' phenotype were analysed in the Cambridge Disorders of Sex Development (DSD) Database, of whom 128 (78%) had no AR mutation ('AR mutation-negative') and 36 (22%) had an AR mutation ('AR mutation-positive'). RESULTS: The EMS was similar in AR mutation-negative and AR mutation-positive infants (median, IQR: 5.0, 3.0 to 6.0 vs 4.8, 3.0 to 6.0; p=0.33). AR mutation-negative infants had lower BW (2.33, 1.38 to 3.20 vs 3.18, 2.87 to 3.61 kg; p<0.001), lower gestational age (37.0, 34.0 to 40.0 vs 40.0, 39.0 to 40.0 weeks; p<0.001), and lower BW-SDS (-1.31, -2.33 to -0.46 vs -0.57, -1.19 to 0.33; p=0.001) compared to AR mutation-positive infants. More AR mutation-negative infants (47/128; 37%) than AR mutation-positive infants (2/36; 6%) had BW-SDS <-2 (p<0.001). CONCLUSIONS: The severity of genital anomalies in this large cohort of infants with a 'PAIS-like' phenotype did not differentiate their AR status. Almost all the infants born small-for-gestational-age do not have an AR mutation. A category of 'XY DSD and fetal growth restriction, as yet unexplained' should be recognised.

Increasing paternal age at childbirth is associated with taller stature and less favourable lipid profiles in their children.

BACKGROUND: Paternal age at childbirth has been increasing worldwide, and we assessed whether this increase affects growth, body composition and metabolism in their children. METHODS: We studied 277 children (aged 3-12 years) born to fathers aged 19·8-51·8 years. Clinical assessments were height and weight adjusted for parental measurements, DEXA-derived body composition, fasting lipids, glucose homoeostasis and hormonal profiles. RESULTS: Children born to fathers aged 31-35 (P = 0·009) and >35 years (P = 0·021) were 2 cm taller than those of fathers aged ≤30 years. Children of fathers aged >35 years at childbirth had a lower body mass index (BMI) (-0·32 SDS) than offspring of fathers aged 31-35 (-0·01 SDS; P = 0·043) and ≤30 (0·22 SDS; P = 0·019). There were marked effects of paternal age at childbirth on childhood blood lipids. LDL-C concentrations in children born to fathers aged >35 years were 11% and 21% higher than in children of fathers aged 31-35 and ≤30 years, respectively (P < 0·01). Total cholesterol to HDL-C ratio was also higher among the children of fathers aged 31-35 (12%; P = 0·014) and >35 (16%; P = 0·004) years at childbirth compared with the ≤30 group. In addition, HOMA-IR in girls (but not boys) born of fathers aged 31-35 (0·99) and >35 years (1·11) indicated better insulin sensitivity compared with offspring in the ≤30 group (1·63; P < 0·05). CONCLUSIONS: Increasing paternal age at childbirth is associated with a more favourable phenotype in their children (taller and slimmer, with better insulin sensitivity in girls) but with a less favourable lipid profile.

Increasing maternal age is associated with taller stature and reduced abdominal fat in their children.

BACKGROUND: Maternal age at childbirth continues to increase worldwide. We aimed to assess whether increasing maternal age is associated with changes in childhood height, body composition, and metabolism. METHODS: 277 healthy pre-pubertal children, born 37-41 weeks gestation were studied. Assessments included: height and weight corrected for parental measurements, DEXA-derived body composition, fasting lipids, glucose, insulin, and hormonal profiles. Subjects were separated according to maternal age at childbirth: <30, 30-35, and >35 years. RESULTS: Our cohort consisted of 126 girls and 151 boys, aged 7.4 ± 2.2 years (range 3-10); maternal age at childbirth was 33.3 ± 4.7 years (range 19-44). Children of mothers aged >35 and 30-35 years at childbirth were taller than children of mothers aged <30 years by 0.26 (p = 0.002) and 0.23 (p = 0.042) SDS, respectively. There was a reduction in childhood BMISDS with increasing maternal age at childbirth, and children of mothers aged >35 years at childbirth were 0.61 SDS slimmer than those of mothers <30 years (p = 0.049). Children of mothers aged 30-35 (p = 0.022) and >35 (p = 0.036) years at childbirth had abdominal adiposity reduced by 10% and 13%, respectively, compared to those in the <30 group. Children of mothers aged 30-35 years at childbirth displayed a 19% increase in IGF-I concentrations compared to offspring in <30 group (p = 0.042). Conversely, IGF-II concentrations were lower among the children born to mothers aged 30-35 (6.5%; p = 0.004) and >35 (8.1%; p = 0.005) compared to those of mothers aged <30 years. Girls of mothers aged 30-35 years at childbirth also displayed improved HOMA-IR insulin sensitivity (p = 0.010) compared to girls born to mothers aged <30 years. CONCLUSIONS: Increasing maternal age at childbirth is associated with a more favourable phenotype (taller stature and reduced abdominal fat) in their children, as well as improved insulin sensitivity in girls.

Phenotypic differences in children conceived from fresh and thawed embryos in in vitro fertilization compared with naturally conceived children.

OBJECTIVE: To determine whether anthropometric and biochemical features differ in in vitro fertilization (IVF) children conceived via fresh (IVFF) or thawed (IVFT) embryo transfer compared with naturally conceived controls. DESIGN: A cross-sectional controlled study. SETTING: University clinical research unit. PATIENT(S): Healthy prepubertal children (3.5-11.0 years), singletons, born at term (>37 weeks), who were either naturally conceived (controls; n = 94) or IVF children conceived via the transfer of a fresh (IVFF; n = 72) or thawed (IVFT; n = 43) embryo. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Assessments of anthropometry (adjusted for parental variables), dual-energy X-ray absorptiometry-derived body composition, fasting plasma growth factors, lipids, and parameters of glucose regulation. RESULT(S): The IVFF but not the IVFT children weighed less at birth than the control children. The IVFF children were taller than both the controls and IVFT children. Sex-specific analyses showed height differences among girls, with IVFF girls being taller than their control and IVFT counterparts. Taller stature in IVFF children was associated with increased insulin-like growth factor I (IGF-I) concentrations compared with controls, whereas the IVFT children displayed increased IGF-II and decreased insulin-like growth factor binding protein 3 (IGFBP-3) concentrations compared with the controls. More favorable lipid profiles were also evident in IVFF but not IVFT children compared with the control children. CONCLUSION(S): These preliminary findings highlight that the transfer of a fresh versus a thawed IVF embryo affects height, plasma growth factor, and lipid profiles in childhood. Therefore, embryo derivation should be considered when assessing physical and biochemical phenotype of IVF children.

Birth order progressively affects childhood height.

BACKGROUND: There is evidence suggesting that first-born children and adults are anthropometrically different to later-borns. Thus, we aimed to assess whether birth order was associated with changes in growth and metabolism in childhood. METHODS: We studied 312 healthy prepubertal children: 157 first-borns and 155 later-borns. Children were aged 3-10 years, born 37-41 weeks gestation, and of birth weight appropriate-for-gestational-age. Clinical assessments included measurement of children's height, weight, fasting lipid and hormonal profiles and DEXA-derived body composition. RESULTS: First-borns were taller than later-borns (P < 0·0001), even when adjusted for parents' heights (0·31 vs 0·03 SDS; P = 0·001). There was an incremental height decrease with increasing birth order, so that first-borns were taller than second-borns (P < 0·001), who were in turn taller than third-borns (P = 0·007). Further, among sibling pairs both height SDS (P = 0·009) and adjusted height SDS (P < 0·0001) were lower in second- vs first-born children. Consistent with differences in stature, first- (P = 0·043) and second-borns (P = 0·003) had higher IGF-I concentrations than third-borns. Both first- (P < 0·001) and second-borns (P = 0·004) also had reduced abdominal adiposity (lower android fat to gynoid fat ratio) when compared with third-borns. Other parameters of adiposity and blood lipids were unaffected by birth order. CONCLUSIONS: First-borns were taller than later-born children, with an incremental height reduction from first to third birth order. These differences were present after correction for genetic height, and associated to some extent with alterations in plasma IGF-I. Our findings strengthen the evidence that birth order is associated with phenotypic changes in childhood.

Ovarian stimulation leads to shorter stature in childhood.

BACKGROUND: We aimed to determine whether children conceived with ovarian stimulation alone (OS(A)) would differ phenotypically and biochemically from naturally conceived children of fertile and subfertile parents. METHODS: Healthy pre-pubertal children aged 3-10 years, born at term, after singleton pregnancies were recruited in Auckland (New Zealand) and were allocated into three groups: (i) children conceived following OS(A) and naturally conceived children of (ii) subfertile and (iii) fertile parents. Anthropometric, endocrine and metabolic parameters were recorded. Children's heights and body mass index (BMI) were expressed as standard deviation scores (SDS) and corrected for genetic potential (i.e. parental height or BMI). RESULTS: Three hundred fifty-two children were studied: 84 OS(A) subjects and 268 naturally conceived controls consisting of 54 children of subfertile parents and 214 children of fertile parents. Children of subfertile and fertile parents did not differ in measured outcomes. Overall, OS(A) children were shorter than children of both subfertile (SDS: -0.08 ± 0.09 versus 0.32 ± 0.07; P= 0.001) and fertile (SDS: -0.08 ± 0.09 versus 0.45 ± 0.10; P= 0.004) parents when corrected for genetic height potential. OS(A) boys were shorter than boys of subfertile (SDS:-0.18 ± 0.14 versus 0.42 ± 0.16; P= 0.03) and fertile (SDS: -0.18 ± 0.14 versus 0.35 ± 0.08; P= 0.01) parents. There was also a trend towards OS(A) girls being shorter than girls of subfertile parents (P= 0.06), but not significantly shorter than those of fertile parents (P= 0.17). OS(A) children also had a lower corrected BMISDS than children of subfertile (SDS-0.90 ± 0.15 versus -0.37 ± 0.17; P= 0.06) and fertile (-0.90 ± 0.15 versus -0.34 ± 0.10; P= 0.008) parents. Among metabolic parameters, fasting glucose was lower in OS(A) children than that in children of fertile parents (4.62 ± 0.07 versus 4.81 ± 0.04; P= 0.006). CONCLUSIONS: Conception after OS(A) was associated with shorter stature, particularly in boys, compared with naturally conceived children of fertile and subfertile parents.

Defects in imprinting and genome-wide DNA methylation are not common in the in vitro fertilization population.

OBJECTIVE: To examine an IVF cohort for imprinted and genome-wide DNA methylation abnormalities. DESIGN: Retrospective study. SETTING: Research laboratory. PATIENT(S): DNA samples from a previously described IVF cohort that comprised 66 IVF-conceived prepubertal children (IVF, n = 34; intracytoplasmic sperm injection, n = 32) and 69 matched naturally conceived controls. INTERVENTION(S): DNA methylation was examined at four imprinted gene loci (H19, SNRPN, KCNQ1OT1, and IGF2) and satellite 2 using methylation-sensitive quantitative polymerase chain reaction (MSQ-PCR) followed by bisulfite sequencing at H19, SNRPN, and KCNQ1OT1. Methylated DNA immunoprecipitation (MeDIP) microarray with validation using the Sequenom MassARRAY EpiTYPER(®) platform was also used. MAIN OUTCOME MEASURE(S): Percentage of DNA methylation by MSQ-PCR, differential methylation based on microarray signal intensity, and percentage DNA methylation as determined by Sequenom MassARRAY EpiTYPER were compared. RESULT(S): No differences in percentage of methylation between the IVF and control group were observed at H19, KCNQ1OT1, SNRPN, or IGF2. Absence of aberrant imprinting was confirmed using bisulfite sequencing. Methylation of satellite 2 repeats (a surrogate for global methylation) showed no difference between the IVF and control groups. MeDIP was used to screen for differences in promoter methylation. Subsequent quantification of methylation of eight candidate genes using the Sequenom MassARRAY EpiTYPER system did not reveal any differential methylation. CONCLUSION(S): Low-level imprinting errors are not common in the IVF population.

UK guidance on the initial evaluation of an infant or an adolescent with a suspected disorder of sex development.

It is paramount that any child or adolescent with a suspected disorder of sex development (DSD) is assessed by an experienced clinician with adequate knowledge about the range of conditions associated with DSD. If there is any doubt, the case should be discussed with the regional team. In most cases, particularly in the case of the newborn, the paediatric endocrinologist within the regional DSD team acts as the first point of contact. The underlying pathophysiology of DSD and the strengths and weaknesses of the tests that can be performed should be discussed with the parents and affected young person and tests undertaken in a timely fashion. This clinician should be part of a multidisciplinary team experienced in management of DSD and should ensure that the affected person and parents are as fully informed as possible and have access to specialist psychological support. Finally, in the field of rare conditions, it is imperative that the clinician shares the experience with others through national and international clinical and research collaboration.

The role of androgens in fetal growth: observational study in two genetic models of disordered androgen signalling.

OBJECTIVE: To examine the role of androgens on birth weight in genetic models of altered androgen signalling. SETTING: Cambridge Disorders of Sex Development (DSD) database and the Swedish national screening programme for congenital adrenal hyperplasia (CAH). PATIENTS: (1) 29 girls with XY karyotype and mutation positive complete androgen insensitivity syndrome (CAIS); (2) 43 girls and 30 boys with genotype confirmed CAH. MAIN OUTCOME MEASURES: Birth weight, birth weight-for-gestational-age (birth weight standard deviation score (SDS)) calculated by comparison with national references. RESULTS: Mean birth weight SDS in CAIS XY infants was higher than the reference for girls (mean, 95% CI: 0.4, 0.1 to 0.7; p=0.02) and was similar to the national reference for boys (0.1, -0.2 to 0.4). Birth weight SDS in CAH girls was similar to the national reference for girls (0.0, -0.2 to 0.2) and did not vary by severity of gene mutation. Birth weight SDS in CAH boys was also similar to the national reference for boys (0.2, -0.2 to 0.6). CONCLUSION: CAIS XY infants have a birth weight distribution similar to normal male infants and birth weight is not increased in infants with CAH. Alterations in androgen signalling have little impact on birth weight. Sex dimorphism in birth size is unrelated to prenatal androgen exposure.

Enhanced insulin sensitivity in prepubertal children with constitutional delay of growth and development.

OBJECTIVE: To test the hypothesis that prepubertal children with presumed constitutional delay of growth and development (CDGD) have enhanced insulin sensitivity and, therefore, insulin sensitivity is associated with later onset of puberty. STUDY DESIGN: Twenty-one prepubertal children with presumed CDGD and 23 prepubertal control children, underwent a frequently sampled intravenous glucose tolerance test to evaluate insulin sensitivity and other markers of insulin, glucose, and growth regulation. RESULTS: Children in the CDGD group were shorter and leaner than control subjects. Children with presumed CDGD were 40% more insulin sensitive (17.0 x 10(-4) min(-1)/[mU/L] versus 12.1 x 10(-4) min(-1)/[mU/L]; P = .0006) and had reduced acute insulin response, thus maintaining euglycemia (216 mU/L versus 330 mU/L; P = .02) compared with control subjects. In addition, the CDGD group had lower serum insulin-like growth factor binding protein 3 levels (3333 ng/mL versus 3775 ng/mL; P = .0004) and a trend toward lower serum insulin-like growth factor-II levels (794 ng/mL versus 911 ng/mL; P = .06). CONCLUSION: Prepubertal children with presumed CDGD have enhanced insulin sensitivity, supporting the hypothesis that insulin sensitivity is associated with timing of puberty. It may signify long-term biological advantages with lower risk of metabolic syndrome and malignancy.

Insulin analog preparations and their use in children and adolescents with type 1 diabetes mellitus.

Standard or 'traditional' human insulin preparations such as regular soluble insulin and neutral protamine Hagedorn (NPH) insulin have shortcomings in terms of their pharmacokinetic and pharmacodynamic properties that limit their clinical efficacy. Structurally modified insulin molecules or insulin 'analogs' have been developed with the aim of delivering insulin replacement therapy in a more physiological manner. In the last 10 years, five insulin analog preparations have become commercially available for clinical use in patients with type 1 diabetes mellitus: three 'rapid' or fast-acting analogs (insulin lispro, aspart, and glulisine) and two long-acting analogs (insulin glargine and detemir). This review highlights the specific pharmacokinetic properties of these new insulin analog preparations and focuses on their potential clinical advantages and disadvantages when used in children and adolescents with type 1 diabetes mellitus. The fast-acting analogs specifically facilitate more flexible insulin injection timing with regard to meals and activities, whereas the long-acting analogs have a more predictable profile of action and lack a peak effect. To date, clinical trials in children and adolescents have been few in number, but the evidence available from these and from other studies carried out in adults with type 1 diabetes suggest that they offer significant benefits in terms of reduced frequency of nocturnal hypoglycemia, better postprandial blood glucose control, and improved quality of life when compared with traditional insulins. In addition, insulin detemir therapy is unique in that patients may benefit from reduced risk of excessive weight, particularly during adolescence. Evidence for sustained long-term improvements in glycosylated hemoglobin, on the other hand, is modest. Furthermore, alterations to insulin/insulin-like growth factor I receptor binding characteristics have also raised theoretical concerns that insulin analogs may have an increased mitogenic potential and risk of tumor development, although evidence from both in vitro and in vivo animal studies do not support this assertion. Long-term surveillance has been recommended and further carefully designed prospective studies are needed to evaluate the overall benefits and clinical efficacy of insulin analog therapy in children and adolescents with type 1 diabetes.

In vitro fertilization improves childhood growth and metabolism.

BACKGROUND: There is limited information regarding the long-term outcome of children born after in vitro fertilization (IVF), although an increase in rare imprinted gene disorders such as Beckwith-Wiedemann syndrome has been reported. METHODS: We recruited healthy, prepubertal children born at term after singleton pregnancy. The children in the study group were conceived using IVF with fresh embryo transfer, whereas controls were naturally conceived. Anthropometric measurements, bone age, dual-energy x-ray absorptiometry, fasting serum glucose, insulin, lipid profile, IGF-I and -II, and IGF-binding proteins 1, 2, and 3 were performed. RESULTS: There were 69 IVF children aged 5.9 +/- 0.2 yr and 71 control children aged 6.9 yr. IVF children were taller than controls when corrected for parents' heights (height sd score of 1.05 +/- 0.1 vs. 0.51 +/- 0.11, P = 0.001) with higher levels of serum IGF-II (850 +/- 24 vs. 773 +/- 24 microg/liter, P = 0.03), higher IGF-I to IGF-binding protein 3 ratio (P = 0.04), and a trend toward higher IGF-I (105 +/- 4 vs. 92 +/- 4 microg/liter, P = 0.06). IVF children had higher high-density lipoprotein (1.67 +/- 0.04 mmol/liter vs. 1.53 +/- 0.04 mmol/liter, P = 0.02), lower triglycerides (0.65 +/- 0.04 mmol/liter vs. 0.78 +/- 0.04 mmol/liter, P = 0.02), and a lower total to high-density lipoprotein cholesterol ratio (2.58 vs. 2.86, P = 0.01). There were no differences in body composition. CONCLUSIONS: IVF children are taller with higher IGF-I and IGF-II levels and have a slightly more favorable lipid profile. We speculate that IVF results in epigenetic change through altered methylation of genes involved in growth and metabolism. IVF programs should consider long-term longitudinal follow-up of IVF offspring.

Fetal origins of adult disease: a paediatric perspective.

Prepubertal children born SGA or VLBW premature exhibit marked insulin resistance. There are similarities between SGA and VLBW children in that both are exposed to sub-optimal environments that encompass undernutrition and/or malnutrition during the equivalent of the last trimester of pregnancy. Although both SGA and VLBW groups fail to reach genetic height potential and are recognized causes of short stature in childhood, there are differences between the groups with respect to the growth hormone and IGF-I axis.SGA children have elevated IGFI levels, possibly due to either hyperinsulinism or partial IGF-I resistance, whereas VLBW children have low IGF-I and IGFBP-3 levels suggestive of GH resistance. Thus the nature and timing of the early insult may lead to discordant changes to the metabolic and endocrine axes.IVF children are taller with increased IGF I, IGF II and IGFBP3 expression. These changes could be due to alterations in the environment of the periconceptual embryo resulting in changes in imprinting of genes involved in growth and development. The phenotypic, endocrine and metabolic consequences of alterations in the periconceptual, fetal and early neonatal periods is an area of intense investigation. Future research in this field is likely to focus on the mechanisms through which environmental changes lead to these programmed effects.