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Background A common growth hormone receptor polymorphism with deletion of exon 3 (d3-GHR) has previously been linked to increased postnatal growth on the one hand and decreased fetal growth on the other. Regulation of fetal growth is positively dependent on secretion of placental GH (hGH-V). Objective We explored the effect of the fetal d3-GHR genotype on maternal serum levels of hGH-V and fetal growth. The cellular localization of hGH-V synthesis and the GH receptors were determined in normal placentas. Methods 43 healthy mother-child pairs were examined during pregnancy with measurements of hGH-V during third trimester, and serial ultrasound measurements determined fetal growth rate. Birth anthropometrics were obtained. The GHR genotype of the child was analysed postnatally. Immunohistochemical (IHC) analysis was conducted on four placentas. Results The presence of the d3-GHR genotype was associated with a markedly reduced concentration of hGH-V in maternal serum (β −0.52, SE 0.24, p = 0.04) compared to those who had a fl/fl genotype. Accordingly, a tendency towards reduced fetal growth rate during third trimester (β −25.8, SE 12.7, p = 0.05) and a lower birth weight were found among carriers of the d3-GHR allele, but these associations did not reach statistical significance (p = 0.08). IHC analysis showed expression of placental GH and GHR in the villous syncytiotrophoblast, the extravillous trophoblast, and the decidual cells and smooth muscle cells in chorionic vessels. Conclusions The presence of the d3-GHR polymorphism in the fetus was associated with lower maternal serum levels of hGH-V, decreased fetal growth rate in third trimester and lower birth weight compared to the wildtype.

Phthalates are endocrine disruptors of the reproductive system and suspected to influence many other organ and hormone systems. They are also semi-volatile organic compounds present in the gas phase in the environment. Their mode of action has been investigated in numerous in vitro studies. Multi-well culture plates are typically used to study phthalates in cell cultures. In a pilot study, we observed evidence of phthalate migration in 24-well culture plates. As this has not previously been described, we investigated the phenomenon in more detail. Primary human thyroid epithelial cell cultures (n = 8 cultures) were exposed to either di-ethyl phthalate (DEP), di-n-butyl phthalate (DnBP), mono-n-butyl phthalate (MnBP) or di-(2-ethylhexyl) phthalate (DEHP). Measurement of phthalate metabolites by mass spectrometry demonstrated that the short-branched DEP was able to migrate to adjacent wells when added to cell culture plates. DnBP also seemed to be able to migrate, unlike the long-branched DEHP or the monoester MnBP which did not seem to have this ability. High background levels of phthalate metabolites were also observed, which might compromise results from low dose phthalate studies. In conclusion, the migration of phthalates which is probably caused by their volatile properties might lead to false interpretation of study results.

ObjectiveAberrations in maternal thyroid function and autoimmunity during pregnancy have been associated with negative obstetric outcome. In Denmark, a national iodine fortification program was implemented in the year 2000 with the aim to alleviate the mild-moderate iodine deficiency. Following the iodine implementation, there has been an increase in thyroid autoimmunity in the background population. This study investigates the thyroid status of pregnant Danish women following the iodine fortification program, and a possible association with preterm delivery.DesignHistorical cohort study of 1278 randomly selected pregnant Danish women attending the national Down's syndrome screening program.MethodsThe main outcome measures were thyroid status according to laboratory- and gestational-age-specific reference intervals, and association with risk of abnormal obstetric outcome. Antibody-positivity was defined as an antibody-level (thyroid peroxidase and/or thyroglobulin antibodies) above 60 U/ml.ResultsEstablishing laboratory-specific gestational-age-dependent reference intervals, we found a prevalence of maternal thyroid dysfunction of 10%–15.8% by use of the cut-off suggested by the American Thyroid Association. Thyroid dysfunction was significantly associated with antibody-positivity (PConclusionsAfter the implementation of the Danish iodine fortification program, the prevalence of thyroid dysfunction and autoimmunity in Danish pregnant women is high – even higher by use of pre-established reference intervals from international consensus guidelines. However, no associations were found with abnormal obstetric outcome. Large randomized controlled trials are needed to clarify the benefit of treating slight aberrations in pregnant women's thyroid function.

Physiological changes during gestation are important to be aware of in measurement and interpretation of thyroid function tests in women with autoimmune thyroid diseases. Thyroid autoimmune activity is decreasing in pregnancy. Measurement of serum TSH is the first-line screening variable for thyroid dysfunction also in pregnancy. However, using serum TSH for control of treatment of maternal thyroid autoimmunity infers a risk for compromised foetal development. Peripheral thyroid hormone values are highly different among laboratories, and there is a need for laboratory-specific gestational age-related reference ranges. Equally important, the intraindividual variability of the thyroid hormone measurements is much narrower than the interindividual variation (reflecting the reference interval). The best laboratory assessment of thyroid function is a free thyroid hormone estimate combined with TSH. Measurement of antithyroperoxidase and/or TSH receptor antibodies adds to the differential diagnosis of autoimmune and nonautoimmune thyroid diseases.

Context: Epidemiological evidence on maternal and paternal heritability of the wide normal variation within pubertal timing is sparse. Objective: We aimed to estimate the impact of parental pubertal timing on the onset of puberty in boys and girls. Design: Annual pubertal examinations of healthy children in a longitudinal cohort study. Information on parental timing of puberty (earlier, comparable to, or later compared to peers) and menarche age was retrieved from questionnaires. Participants: A total of 672 girls and 846 boys. Main Outcome Measures: Age at onset of pubic hair (PH2+), breasts (B2+), and menarche in girls; and PH2+, genital stage (G2+), and testis >3 mL with orchidometer (Tvol3+) in boys. Results: In boys, pubertal onset was significantly associated with pubertal timing of both parents. PH2+ and Tvol3+ were earlier: −11.8 months (95% confidence interval, −16.8, −6.8)/−8.9 (−12.8, −4.9), and −9.5 (−13.9, −5.1)/−7.1 (−10.4, −3.7) if the father/mother, respectively, had early pubertal development compared to late. In girls, menarche was significantly associated with both parents' pubertal timing: −10.5 months (−15.9, −5.1)/−10.1 (−14.3, −6.0) if father/mother had early pubertal development compared to late. For the onset of PH2+ and B2+ in girls, estimates were −7.0 months (−12.6, −1.4) and −4.1 (−10.6, +2.4)/−6.7 (−11.0, −2.5), and −6.7 (−11.0, −2.0) for fathers/mothers, respectively. Maternal age of menarche was significantly associated with the onset of all pubertal milestones except PH2+ in girls. Conclusions: Maternal as well as paternal pubertal timing was a strong determinant of age at pubertal onset in both girls and boys. Age at breast and pubic hair development in girls, which has declined most during recent years, seemed to be least dependent on heritability.

Phthalates are plasticisers added to a wide variety of products, resulting in measurable exposure of humans. They are suspected to disrupt the thyroid axis as epidemiological studies suggest an influence on the peripheral thyroid hormone concentration. The mechanism is still unknown as only few in vitro studies within this area exist. The aim of the present study was to investigate the influence of three phthalate diesters (di-ethyl phthalate, di-n-butyl phthalate (DnBP), di-(2-ethylhexyl) phthalate (DEHP)) and two monoesters (mono-n-butyl phthalate and mono-(2-ethylhexyl) phthalate (MEHP)) on the differentiated function of primary human thyroid cell cultures. Also, the kinetics of phthalate metabolism were investigated. DEHP and its monoester, MEHP, both had an inhibitory influence on 3'-5'-cyclic adenosine monophosphate secretion from the cells, and MEHP also on thyroglobulin (Tg) secretion from the cells. Results of the lactate dehydrogenase-measurements indicated that the MEHP-mediated influence was caused by cell death. No influence on gene expression of thyroid specific genes (Tg, thyroid peroxidase, sodium iodine symporter and thyroid stimulating hormone receptor) by any of the investigated diesters could be demonstrated. All phthalate diesters were metabolised to the respective monoester, however with a fall in efficiency for high concentrations of the larger diesters DnBP and DEHP. In conclusion, human thyroid cells were able to metabolise phthalates but this phthalate-exposure did not appear to substantially influence selected functions of these cells.

In recent years, many studies of thyroid-disrupting effects of environmental chemicals have been published. Of special concern is the exposure of pregnant women and infants, as thyroid disruption of the developing organism may have deleterious effects on neurological outcome. Chemicals may exert thyroid effects through a variety of mechanisms of action, and some animal experiments and in vitro studies have focused on elucidating the mode of action of specific chemical compounds. Long-term human studies on effects of environmental chemicals on thyroid related outcomes such as growth and development are still lacking. The human exposure scenario with life long exposure to a vast mixture of chemicals in low doses and the large physiological variation in thyroid hormone levels between individuals render human studies very difficult. However, there is now reasonably firm evidence that PCBs have thyroid-disrupting effects, and there is emerging evidence that also phthalates, bisphenol A, brominated flame retardants and perfluorinated chemicals may have thyroid disrupting properties.

Aim: Anti-Mullerian hormone (AMH) is produced by foetal Sertoli cells at the time of sexual differentiation and is responsible for the regression of the Mullerian ducts in the male foetus. AMH is a testis-specific marker of diagnostic value in infants with ambiguous genitalia or with bilateral cryptorchidism. However, little is known about AMH in boys and adult men with normal or abnormal gonadal function. We therefore aimed at determining circulating AMH concentrations in patients with 47,XXY Klinefelter syndrome (KS) with or without cryptorchidism. Methods: AMH was determined in 95 47,XXY patients aged 0.2―64.5 years, of which 12 patients had a history of cryptorchidism. Results: AMH was within the normal range in boys with Klinefelter syndrome until puberty. The pubertal decline was delayed, especially in patients with a history of cryptorchidism. AMH was below ―2 SD in 85% of adult KS. Conclusion: AMH secretion in patients with 47,XXY KS was within normal limits during mini-puberty and until puberty. Thereafter, AMH declined to subnormal levels in all patients. We hypothesize that this decline was a result of the hyalinization of seminiferous tubules in relation to puberty, rather than caused by disrupted regulatory mechanisms at the level of the pituitary―gonadal axis.

Udgivelsesdato: 2010-Aug-18 Context: In adult women, anti-Müllerian hormone (AMH) is related to the ovarian follicle pool. Little is known about AMH in girls. Objective: The objective of the study was to provide a reference range for AMH in girls and adolescents and to evaluate AMH as a marker of ovarian function. Setting: The study was conducted at a tertiary referral center for pediatric endocrinology. Main Outcome Measures: We measured AMH in 926 healthy females (longitudinal values during infancy) as well as in 172 Turner syndrome (TS) patients according to age, karyotype (A: 45,X; B: miscellaneous karyotypes; C: 45,X/46,XX), and ovarian function (1: absent puberty; 2: cessation of ovarian function; 3: ongoing ovarian function). Results: AMH was undetectable in 54% (38 of 71) of cord blood samples (

Background Phthalates are widely used chemicals, and human exposure is extensive. Recent studies have indicated that phthalates may have thyroid-disrupting properties. Objective We aimed to assess concentrations of phthalate metabolites in urine samples from Danish children and to investigate the associations with thyroid function, insulin-like growth factor I (IGF-I), and growth. Methods In 845 children 4–9 years of age, we determined urinary concentrations of 12 phthalate metabolites and serum levels of thyroid-stimulating hormone, thyroid hormones, and IGF-I. Results Phthalate metabolites were detected in all urine samples, of which monobutyl phthalate was present in highest concentration. Phthalate metabolites were negatively associated with serum levels of free and total triiodothyronine, although statistically significant primarily in girls. Metabolites of di(2-ethylhexyl) phthalate and diisononyl phthalate were negatively associated with IGF-I in boys. Most phthalate metabolites were negatively associated with height, weight, body surface, and height gain in both sexes. Conclusions Our study showed negative associations between urinary phthalate concentrations and thyroid hormones, IGF-I, and growth in children. Although our study was not designed to reveal the mechanism of action, the overall coherent negative associations between urine phthalate and thyroid and growth parameters may suggest causative negative roles of phthalate exposures for child health.

BackgroundAdaptive alterations in maternal physiology cause changes in thyroid hormone levels throughout pregnancy, and precise biochemical evaluation is thus highly dependent on gestation-specific reference intervals and expected intra-individual variation.ObjectiveThe aim of the study was the assessment of the intra-individual variation as well as the longitudinal course of thyroid hormones during normal pregnancy and factors that influence the normal reference range for thyroid function. For this purpose, a longitudinal statistical model was applied.DesignIn a cohort of 132 pregnant women, serial blood samples were obtained and ultrasound scans were performed throughout pregnancy.MethodsSerum levels of TSH, free and total thyroxine (T4), free and total triiodothyronine (T3) as well as autoantibodies against thyroid peroxidase and thyroglobulin were measured in 979 serum samples.ResultsIntra-individual variations of thyroid hormone concentrations were smaller than inter-individual variations (individuality index range: 0.38–0.71). Maternal height was positively associated with free T4 (FT4) (b=0.003; P=0.031) and pre-pregnancy body mass index with T3 and free T3 (b=0.017; b=0.007; P4 and FT4, but it was modulated by gestational age. Gestation-specific reference intervals for thyroid function variables from autoantibody-negative participants are presented.ConclusionsIn accordance with the data from nonpregnant adults, intra-individual variations of thyroid hormones were smaller than inter-individual variations also during pregnancy. In the evaluation of thyroid function in pregnancy, the individual longitudinal course of thyroid hormones rather than absolute values should be considered. We present a longitudinal model for the prediction of maternal thyroid function tests in pregnant women.

Udgivelsesdato: 2009-Oct CONTEXT AND OBJECTIVE: Few studies have focused on the interrelation between thyroid size, anthropometric variables, and IGF-I in adults, but such data are lacking for children. We have investigated thyroid gland volume and several hormonal and anthropometric variables in prepubertal children. DESIGN AND PARTICIPANTS: A total of 859 prepubertal euthyroid Danish children aged 4-9 yr underwent a thorough clinical investigation, including anthropometrical measurements and determination of TSH, thyroid hormones, autoantibodies, urinary iodine excretion, and thyroid volume (TV) by ultrasound. Longitudinal growth data from birth were available. RESULTS: TV increased significantly with age (r = 0.487; P < 0.001). Mean TV +/- sd for different age groups were as follows: 4 yr, 2.2 +/- 1.4 ml; 5 yr, 2.5 +/- 1.3 ml; 6 yr, 2.8 +/- 1.3 ml; 7 yr, 3.2 +/- 1.3 ml; 8 yr, 3.5 +/- 1.3 ml; 9 yr, 3.7 +/- 1.3 ml. We found a significant positive association between IGF-I and TV (P < 0.001). Furthermore, in multiple regression analyses, TSH (P < 0.013), free T(4) (P < 0.001), lean body mass (P < 0.001), and body surface area (P < 0.001) as well as other anthropometrical measurements were identified as factors significantly associated with TV. Family history of thyroid disease and presence of incidental abnormal ultrasound findings were also positively associated with TV (P = 0.025 and 0.022, respectively). CONCLUSIONS: In our cohort of prepubertal Danish children, the GH/IGF-I-axis was positively correlated with thyroid size, suggesting a role in the regulation of thyroid growth. Moreover, anthropometric measurements, in particular body surface area, were the best predictors of TV.

Accurate prevalence data for acquired cryptorchidism are currently sparse and systematic prospective studies have not yet been reported. Our aim was to determine the prevalence of testicular ascent in childhood. In a prospective longitudinal population-based child cohort from Copenhagen, Denmark (1997-2007), testicular position was examined according to a standardised protocol in a total of 1072 boys, at birth (n = 1051), at 3 months (n = 983), 18 months (n = 888), 36 months (n = 790) and again once between 4 1/2 and 10 years of age (n = 509). Ascensus testis was defined as ascent of the testis into a cryptorchid position after normal scrotal position at birth. A congenital cryptorchid testis with spontaneous postnatal descent followed by recurrence of cryptorchidism was named recurrent cryptorchidism. Ascensus testis occurred in 0.2%, 0.6% and 0.6% of boys at 3, 18 and 36 months of age respectively. When including recurrent cryptorchidism the prevalence was 0.2%, 1.2% and 0.8% respectively. Ascensus testis accounts for 58% of all cases of cryptorchidism (congenital and acquired) at 18 months, 71% at 36 months and thereafter 69%. Ascensus testis accounts for more than half of cryptorchid testes seen in childhood and occurs in both previously scrotal and cryptorchid testes. We therefore recommend that all boys should have testis position checked regularly during childhood, at least up to 3 years of age.

There is growing evidence that environmental chemicals can disrupt endocrine systems. Most evidence originates from studies on reproductive organs. However, there is also suspicion that thyroid homeostasis may be disrupted. Several groups of chemicals have potential for thyroid disruption. There is substantial evidence that polychlorinated biphenyls, dioxins and furans cause hypothyroidism in exposed animals and that environmentally occurring doses affect human thyroid homeostasis. Similarly, flame retardants reduce peripheral thyroid hormone (TH) levels in rodents, but human studies are scarce. Studies also indicate thyroid-disruptive properties of phthalates, but the effect of certain phthalates seems to be stimulative on TH production, contrary to most other groups of chemicals. Thyroid disruption may be caused by a variety of mechanisms, as different chemicals interfere with the hypothalamic–pituitary–thyroid axis at different levels. Mechanisms of action may involve the sodium–iodide symporter, thyroid peroxidase enzyme, receptors for THs or TSH, transport proteins or cellular uptake mechanisms. The peripheral metabolism of the THs can be affected through effects on iodothyronine deiodinases or hepatic enzymes. Even small changes in thyroid homeostasis may adversely affect human health, and especially fetal neurological development may be vulnerable. It is therefore urgent to clarify whether the animal data showing effects of chemicals on thyroid function can be extended to humans.

Objective: Infant boys show a brief activation of their hypothalamic–pituitary–gonadal axis shortly after birth, the physiological significance of which is poorly understood. The objective of the study was to investigate the correlation between endogenous testosterone levels and penile size and growth. Design: Prospective, longitudinal population-based study taking place at two large primary obstetric centres at the University Hospitals of Copenhagen, Denmark, and Turku, Finland. Methods: Infant boys, 728 Danish and 1234 Finnish, underwent clinical examinations at 0, 3, 18 and 36 months in Denmark and at 0, 3 and 18 months in Finland with blood samples taken at 3 months (n = 630). Penile length and growth were registered and reproductive hormones (testosterone, sex hormone binding globulin, oestradiol) were analysed. Results: Penile length increased from birth (3.49±0.4 cm) to 3 years of age (4.53±0.51 cm) with the highest growth velocity from birth to 3 months (1.0 mm/month). Penile length and growth were significantly, positively correlated to serum testosterone (r = 0.31 and 0.076, P = 0.006 and 0.001 respectively) and to free testosterone index (r = 0.385 and 0.094, P = 0.0001 and 0.0001 respectively). Conclusions: We found that endogenous testosterone was significantly associated with penile size and growth rate in infant boys. Thus, the postnatal surge in reproductive hormones appears to be important for genital growth. Our data may serve as an updated reference for normal penile length in Caucasian boys up to 3 years of age.

ObjectivesCorrect interpretation of thyroid status during pregnancy is vital to secure fetal development. Pregnancy-related changes in maternal thyroid status necessitate the use of gestational age-specific reference ranges. In this study, we investigated between-laboratory reproducibility of thyroid reference ranges in pregnant women.DesignComparison of two longitudinal prospective cohort studies including 255 (cohort 1) and 101 (cohort 2) healthy antibody-negative Danish pregnant women attending prenatal care at Copenhagen University Hospital.MethodsDifferent immunoassays were used to measure thyroid hormone levels in the two cohorts. Thyroid hormone reference ranges were established for every 5 weeks of gestation. Differences between cohorts were explored through mixed-model repeated measures regression analyses. By applying reference ranges from one cohort to the other, the proportion of women who would be misclassified by doing so was investigated.ResultsTSH increased and free thyroxine (FT4) decreased as pregnancy progressed. Results indicated highly significant differences between cohorts in free triiodothyronine (F=21.3, P4 (F=941, PP=0.09). Up to 90.3% of the women had FT4 levels outside their laboratory's nonpregnant reference range, and up to 100% outside the other cohort's gestational-age-specific reference ranges. Z-score-based reference ranges markedly improved comparison between cohorts.ConclusionEven in the same region, the use of gestational-age-specific reference ranges from different laboratories led to misclassification. Up to 100% of maternal FT4 levels fell outside the other cohort's reference range despite similar TSH levels. In clinical practice, thyroid testing of pregnant women without adding method specificity to gestational age-dependent reference ranges will compromise patient safety.

Interviews are mandatory in Denmark when selecting doctors for training positions. We used multiple mini interviews (MMI) at four recruitment rounds for the main training posts in paediatrics. In total, 125 candidates were evaluated and assessed by CV and MMI (4-5 stations). Reliability for individual stations in MMI assessed by Cronbach's alpha was adequate (0.63-0.92). The overall reliability assessed by G-theory was lower, suggesting that different skills were tested. The acceptability was high. Our experiences with MMI suggest good feasibility and reliability. An increasing number of stations may improve the overall reliability.

Total body fat percentage (%BF) evaluated by dual energy X-ray absorptiometry (DXA) scans (DXA %BF) is widely recognized as a precise measure of fatness. We aimed to establish national reference curves for DXA %BF, %BF calculated from skinfolds (SF %BF) and waist circumference (WC) in healthy children, and to compare agreement between the different methods. Based on 11 481 physical examinations (anthropometry) and 1200 DXA scans from a longitudinal cohort of Danish children (n=2647), we established reference curves (LMS-method) for SF %BF, WC (birth to 14 years) and DXA %BF (8–14 years). Age- and sex-specific Z-scores for body mass index (BMI), WC and SF %BF were compared. Sensitivity and specificity were calculated for agreement of WC, SF %BF and BMI with DXA %BF to identify obese children (>+1 s.d.). %BF differed with age, sex, pubertal stage and social class. SF %BF correlated strongly with DXA %BF (r=0.86). BMI and WC also correlated positively with DXA %BF (Z-scores; r= 0.78 and 0.69). Sensitivity and specificity were 79.5 and 93.8 for SF %BF, 75.9 and 90.3 for BMI and 59.2 and 95.4 for WC. SF %BF showed the highest correlation and best agreement with DXA %BF in identifying children with excess fat (+1 s.d.).

Anti-Müllerian hormone (AMH) is produced by foetal Sertoli cells at the time of sexual differentiation and is responsible for the regression of the Müllerian ducts in the male foetus. AMH is a testis-specific marker of diagnostic value in infants with ambiguous genitalia or with bilateral cryptorchidism. However, little is known about AMH in boys and adult men with normal or abnormal gonadal function. We therefore aimed at determining circulating AMH concentrations in patients with 47,XXY Klinefelter syndrome (KS) with or without cryptorchidism.AMH was determined in 95 47,XXY patients aged 0.2-64.5 years, of which 12 patients had a history of cryptorchidism.AMH was within the normal range in boys with Klinefelter syndrome until puberty. The pubertal decline was delayed, especially in patients with a history of cryptorchidism. AMH was below -2 SD in 85% of adult KS.AMH secretion in patients with 47,XXY KS was within normal limits during mini-puberty and until puberty. Thereafter, AMH declined to subnormal levels in all patients. We hypothesize that this decline was a result of the hyalinization of seminiferous tubules in relation to puberty, rather than caused by disrupted regulatory mechanisms at the level of the pituitary-gonadal axis.

Physiological changes during gestation are important to be aware of in measurement and interpretation of thyroid function tests in women with autoimmune thyroid diseases. Thyroid autoimmune activity is decreasing in pregnancy. Measurement of serum TSH is the first-line screening variable for thyroid dysfunction also in pregnancy. However, using serum TSH for control of treatment of maternal thyroid autoimmunity infers a risk for compromised foetal development. Peripheral thyroid hormone values are highly different among laboratories, and there is a need for laboratory-specific gestational age-related reference ranges. Equally important, the intraindividual variability of the thyroid hormone measurements is much narrower than the interindividual variation (reflecting the reference interval). The best laboratory assessment of thyroid function is a free thyroid hormone estimate combined with TSH. Measurement of antithyroperoxidase and/or TSH receptor antibodies adds to the differential diagnosis of autoimmune and nonautoimmune thyroid diseases.

Context: Recent studies have indicated that internationally adopted girls are at high risk of developing precocious puberty. Clinical studies including a contemporary control group are lacking. Objective: The objective was to study clinical, biochemical, and ultrasonographic markers of pituitary-gonadal activation in prepubertal adopted girls and a control group in the same age categories. Setting: The study took place at University Hospital, Copenhagen, Denmark. Design and Participants: The study included randomly selected internationally adopted girls [(n = 99; mean age, 6.9 (5.1–8.5) yr] and controls of Danish origin [n = 93; mean age, 6.8 (5.2–8.5) yr] who were studied cross-sectionally. Methods: Height, weight, and pubertal stage were assessed with serum levels of reproductive hormones. Size and morphology of internal genitals were evaluated by ultrasonography. Bone age was evaluated by x-ray of the left hand. Results: Serum values of FSH were significantly higher in prepubertal adopted girls compared with controls [median, 1.4 (95% confidence interval, 0.4–3.6) vs. 1.0 (0.4–2.4) IU/liter; P 18 pmol/liter) in 46.5% of prepubertal adopted girls and 20.7% of controls (P = 0.001). In prepubertal adopted girls, the proportion of measurable samples increased significantly with age [odds ratio, 2.5 (95% confidence interval, 1.3–5.0; P = 0.009]. In controls, the odds ratio was 1.0 (0.6–1.7) (P = 0.9). Serum SHBG levels were significantly lower in prepubertal adopted girls compared with controls [99.0 (50.4–153.0) vs. 115.0 (53.1–202.1); P < 0.001]. Conclusion: Five- to 8-yr-old adopted girls showed signs of increased pituitary as well as gonadal activity despite prepubertal phenotype in the majority of girls. Our findings suggest that early onset of puberty in adopted girls is centrally driven.

Background Phthalates are a group of endocrine disrupting chemicals suspected to influence the immune system. The aim of this systematic review is to summarise the present knowledge on the influence of phthalates on monocyte and macrophage production and secretion of cytokines, an influence which could affect both pro- and anti-inflammatory abilities of these cells. Strategy and Results A systematic search was performed in Medline, Embase and Toxline in June 2013, last updated 3rd of August 2014. Criteria used to select studies were described and published beforehand online on Prospero (http://www.crd.york.ac.uk/NIHR_PROSPERO, registration number CRD42013004236). In vivo, ex vivo and in vitro studies investigating the influence of phthalates on cytokine mRNA expression and cytokine secretion in animals and humans were included. A total of 11 reports, containing 12 studies, were found eligible for inclusion. In these, a total of four different phthalate diesters, six primary metabolites (phthalate monoesters) and seven different cytokines were investigated. Though all studies varied greatly in study design and species sources, four out of five studies that investigated di-2-ethylhexyl phthalate found an increased tumour necrosis factor-α secretion/production from monocytes or macrophages. A summary of cytokine measurements was not possible since few studies were comparable in study design and due to insufficient reporting of raw data for most of the included studies. Conclusion Results from this review have suggested that at least one phthalate (di-2-ethylhexyl phthalate) has the ability to enhance tumour necrosis factor-α production/secretion from monocytes/macrophages in vitro, but also observed ex vivo. Influence of other phthalates on other cytokines has only been investigated in few studies. Thus, in vitro studies on primary human monocytes/macrophages as well as more in vivo studies are needed to confirm or dispute these findings.

Background Endocrine disrupting chemicals have been hypothesized to play a role in the obesity epidemic. Long-term effects of prenatal exposure to non-persistent pesticides on body composition have so far not been investigated. The purpose of this study was to assess possible effects of prenatal exposure to currently used pesticides on children's growth, endocrine and reproductive function. Methods In a prospective study of 247 children born by women working in greenhouses in early pregnancy, 168 were categorized as prenatally exposed to pesticides. At three months (n = 203) and at 6 to11 years of age (n = 177) the children underwent a clinical examination and blood sampling for analysis of IGF-I, IGFBP3 and thyroid hormones. Body fat percentage at age 6 to11 years was calculated from skin fold measurements. Pesticide related associations were tested by linear multiple regression analysis, adjusting for relevant confounders. Results Compared to unexposed children birth weight and weight for gestational age were lower in the highly exposed children: -173 g (-322; -23), -4.8% (-9.0; -0.7) and medium exposed children: -139 g (-272; -6), -3.6% (-7.2; -0.0). Exposed (medium and highly together) children had significantly larger increase in BMI Z-score (0.55 SD (95% CI: 0.1; 1.0) from birth to school age) and highly exposed children had 15.8% (0.2; 34.6) larger skin folds and higher body fat percentage compared to unexposed. If prenatally exposed to both pesticides and maternal smoking (any amount), the sum of four skin folds was 46.9% (95% CI: 8.1; 99.5) and body fat percentage 29.1% (95% CI: 3.0; 61.4) higher. There were subtle associations between exposure and TSH Z-score -0.66(-1.287; -0.022) and IGF-I Z-score (girls: -0.62(-1.0; -0.22), boys: 0.38(-0.03; 0.79)), but not IGFBP3. Conclusions Occupational exposure to currently used pesticides may have adverse effects in spite of the added protection offered to pregnant women. Maternal exposure to combinations of modern, non-persistent pesticides during early pregnancy was associated with affected growth, both prenatally and postnatally. We found a biphasic association with lower weight at birth followed by increased body fat accumulation from birth to school age. We cannot rule out some residual confounding due to differences in social class, although this was adjusted for. Associations were stronger in highly exposed than in medium exposed children, and effects on body fat content at school age was potentiated by maternal smoking in pregnancy.

Anti-Müllerian hormone (AMH), which is secreted by immature Sertoli cells, triggers the involution of the fetal Müllerian ducts. AMH is a testis-specific marker used for diagnosis in infants with ambiguous genitalia or bilateral cryptorchidism.The aim of the study was to describe the ontogeny of AMH secretion through life in healthy males.This was a population-based study of healthy volunteers.PARTICIPANTS included 1027 healthy males from birth (cord blood) to 69 yr. A subgroup was followed up longitudinally through the infantile minipuberty [(in cord blood, and at 3 and 12 months), n=55] and another group through puberty [(biannual measurements), n=83].Serum AMH was determined by a sensitive immunoassay. Serum testosterone, LH, and FSH were measured, and pubertal staging was performed in boys aged 6 to 20 yr (n=616).Serum AMH was above the detection limit in all samples with a marked variation according to age and pubertal status. The median AMH level in cord blood was 148 pmol/liter and increased significantly to the highest observed levels at 3 months (P0.0001). AMH declined at 12 months (P0.0001) and remained at a relatively stable level throughout childhood until puberty, when AMH declined progressively with adults exhibiting 3-4% of infant levels.Based on this extensive data set, we found detectable AMH serum levels at all ages, with the highest measured levels during infancy. At the time of puberty, AMH concentrations declined and remained relatively stable throughout adulthood. The potential physiological role of AMH and clinical applicability of AMH measurements remain to be determined.