Individualized treatment to optimize eventual cognitive outcome in congenital hypothyroidism.

BACKGROUND: In congenital hypothyroidism (CH), age-specific reference ranges (asRR) for fT4 and thyrotropine (TSH) are usually used to signal over/under-treatment. We compared the consequences of individual fT4 steady-state concentrations (SSC's) and asRR regarding over-treatment signaling and intelligence quotient at 11 y (IQ11) and the effect of early over-treatment with high L-T4 dosages on IQ11. METHODS: Sixty-one patients (27 severe, 34 mild CH) were psychologically tested at 1.8, 6, and 11 y. Development scores were related to over-treatment in the period 0-24 mo, relative to either individual fT4SSC's or asRR. Three groups were formed, based on severity of over/under-treatment 0-5 mo (severe, mild, and no over/under-treatment). RESULTS: FT4 and TSH asRR missed 41-50% of the over-treatment episodes and consequently 22% of the over-treated patients, classified as such by fT4SSC's. Severe over-treatment 0-5 mo led to lowered IQ11's and to a 5.5-fold higher risk of IQ11 < 85 than other treatment regimes. Under-treatment had no effect on development scores. Initial L-T4 dosages >10 µg/kg resulted in a 3.7-fold higher risk of over-treatment than lower dosages. CONCLUSIONS: Data suggest that asRR, compared to fT4SSC's, signal over-treatment insufficiently. Using fT4SSC's and avoiding over-treatment may optimize cognitive outcome. Lowered IQ11's are usually a late complication of severe early over-treatment.

Women with high early pregnancy urinary iodine levels have an increased risk of hyperthyroid newborns: the population-based Generation R Study.

OBJECTIVE: Iodine deficiency during pregnancy results in thyroid dysfunction and has been associated with adverse obstetric and foetal effects, leading to worldwide salt iodization programmes. As nowadays 69% of the world's population lives in iodine-sufficient regions, we investigated the effects of variation in iodine status on maternal and foetal thyroid (dys)function in an iodine-sufficient population. DESIGN, PARTICIPANTS AND MEASUREMENTS: Urinary iodine, serum TSH, free T4 (FT4) and TPO-antibody levels were determined in early pregnancy (13·3 (1·9) week; mean (SD)) in 1098 women from the population-based Generation R Study. Newborn cord serum TSH and FT4 levels were determined at birth. RESULTS: The median urinary iodine level was 222·5 µg/l, indicating an iodine-sufficient population. 30·8% and 11·5% had urinary iodine levels <150 and >500 µg/l, respectively. When comparing mothers with urinary iodine levels <150 vs ≥150 µg/l, and >500 vs ≤500 µg/l, there were no differences in the risk of maternal increased or decreased TSH, hypothyroxinaemia or hyperthyroidism. Mothers with urinary iodine levels >500 µg/l had a higher risk of a newborn with decreased cord TSH levels (5·6 ± 1·4 (mean ± SE) vs 2·1 ± 0·5%, P = 0·04), as well as a higher risk of a hyperthyroid newborn (3·1 ± 0·9 vs 0·6 ± 0·3%, P = 0·02). These mothers had newborns with higher cord FT4 levels (21·7 ± 0·3 vs 21·0 ± 0·1 pm, P = 0·04). Maternal urinary iodine levels <150 µg/l were not associated with newborn thyroid dysfunction. CONCLUSIONS: In an iodine-sufficient population, higher maternal urinary iodine levels are associated with an increased risk of a hyperthyroid newborn.

Different surgical findings in congenital and acquired undescended testes.

OBJECTIVE: To compare surgical findings in congenital and acquired undescended testes (UDT). PATIENTS AND METHODS: A review of 139 boys with 158 congenital UDT and 69 boys with 84 acquired UDT was performed. The most caudal testicular position preoperatively, testis position at surgery, patency of the processus vaginalis and epididymal anomalies were prospectively recorded. RESULTS: In the congenital group, orchiopexy had been performed at median age (range) 4.9 (1.5-14.6) years, while the median age (range) in the acquired group was 11.9 (3.8-23.3) years. Preoperatively, only congenital UDT were found not palpable or emergent inguinal, while only acquired UDT could be manipulated in an unstable scrotal position. In comparison with congenital UDT, acquired UDT were significantly more often located at the scrotal entrance, 27/158 vs 32/84 respectively (P < 0.001). At surgery anorchia, vanished testis or testes lying intra-abdominally were only registered in the congenital UDT group. Also 37/158 congenital UDT were located in the superficial inguinal pouch vs 52/84 of the acquired UDT (P = 0.04). In congenital UDT the processus vaginalis was wide open in 74/158, while in acquired UDT the processus vaginalis was closed in 46/84 (P < 0.001) and small open in 26/84 (P = 0.04). Epididymal anomalies were more often seen in the congenital UDT group (37%) than in the acquired group (11%). CONCLUSION: The most caudal position of congenital UDT after manipulation before surgery was at the scrotal entrance. These testes were frequently associated with epididymal anomalies and wide open processus vaginalis. This was in contrast to acquired UDT, which can often be pushed down well below the scrotal entrance and are more likely to be situated in the superficial inguinal pouch, with a normal epididymis and closed processus vaginalis.

Maternal thyroid function during pregnancy and behavioral problems in the offspring: the generation R study.

Maternal thyroid function during pregnancy is implicated in the neurodevelopment of the offspring, yet little is known about the effect of maternal thyroid parameters on the behavior of children. We investigated the association of maternal thyroid function during the first half of pregnancy with parent-reported problem behavior of the offspring up to age of 3 y. In the Generation R study, a population-based cohort of 3736 children and their mothers, data on maternal thyroid function and child's behavior were examined. The degree of internalizing and externalizing problems in the children were assessed with the Child Behavior Checklist at ages 1½ and 3 y. Higher levels of maternal TSH during pregnancy predicted a higher externalizing scores in children at 1½ and 3 y (B = 0.22 per SD of TSH; 95% CI: 0.04, 0.40; B = 0.10 per SD for internalizing scores; 95% CI: -0.01, 0.21). Maternal free thyroxine (T4) and total T4 were not associated with internalizing or externalizing scores of children. The linear relationship with more externalizing scores was across the range of TSH; this implies that subtle impairments of maternal thyroid function may affect the child. The results suggest that thyroid function is crucial for fetal brain development, which determines problem behavior later in life.

The relation between 25-hydroxyvitamin D with peak bone mineral density and body composition in healthy young adults.

OBJECTIVE: The associations between peak bone mineral density (BMD) and body composition with 25 hydroxyvitamin D (25OHD) levels in healthy young adults were evaluated. METHODS: The number of participants was 464; 347 women and 117 men. The mean age was 24.3 years (range 17-31 years). BMD of the lumbar spine, total body and femoral neck (FN) and body composition were measured by dual energy X-ray absorptiometry. Volumetric BMD, bone mineral apparent density (BMAD), of the lumbar spine and FN was calculated. RESULTS: In females, 25OHD level was positively associated with FN BMD and BMAD (both p<0.01) and negatively with percentage body fat (p<0.001). In males, 25OHD levels had a positive association with total body BMD and lean body mass (p=0.03 and p=0.01). CONCLUSIONS: 25OHD level is a determinant of peak BMD in both sexes. Vitamin D status was associated with body fat in females and with lean body mass in males.

The effect of oxandrolone on body proportions and body composition in growth hormone-treated girls with Turner syndrome.

OBJECTIVE: Untreated girls with Turner syndrome (TS) have short stature, relatively broad shoulders, a broad pelvis, short legs, a high fat mass and low muscle mass. Our objective was to assess the effect of the weak androgen oxandrolone (Ox) on body proportions and composition in growth hormone (GH)-treated girls with TS. DESIGN/PATIENTS: 133 patients were included in a randomized, placebo-controlled, double-blind study. METHODS: Patients were treated with GH (1.33 mg/m(2) per day) from baseline, combined with placebo (Pl) or Ox in a low (0.03 mg/kg per day) or previously conventional (0.06 mg/kg per day) dose from the age of eight, and oestrogens from the age of twelve. Sitting height, biacromial and biiliacal distances compared with height (i.e. shape values), BMI, waist circumference, sum of 4 skinfolds (sum4skin) and upper arm muscle area (UAMA) SD scores (SDS) were assessed half-yearly. RESULTS: Compared with GH + Pl, adult shape values on GH + Ox tended to be higher for sitting height (Ox 0.03, P = 0.2; Ox 0.06, P = 0.02) and biacromial distance (Ox 0.03, P = 0.2; Ox 0.06, P = 0.07) and lower for biiliacal distance (Ox 0.03, P = 0.004; Ox 0.06, P = 0.08). Sum4skin SDS tended to decrease more (Ox 0.03, P = 0.2; Ox 0.06, P = 0.005) while UAMA SDS increased more (Ox 0.03, P < 0.001; Ox 0.06, P < 0.001) than on GH + Pl. The increase in BMI and waist circumference SDS was comparable between the dosage groups. CONCLUSIONS: In GH-treated girls with TS, Ox 0.06 increases sitting height and tends to increase biacromial distance and decrease biiliacal distance, while Ox 0.03 significantly decreases biiliacal distance compared with height. Furthermore, Ox 0.06 reduces subcutaneous fat mass, and both Ox dosages increase muscle mass.

Pharmacogenetic risk factors for altered bone mineral density and body composition in pediatric acute lymphoblastic leukemia.

BACKGROUND: This study investigates pharmacogenetic risk factors for bone mineral (apparent) density (BM(A)D) and body composition in pediatric acute lymphoblastic leukemia DESIGN AND METHODS: We determined the influence of SNPs in 4 genes (vitamin-D receptor (VDR: BsmI/ApaI/TaqI and Cdx-2/GATA), collagen type I alpha 1 (SpI), estrogen receptor 1 (ESR1: PvuII/XbaI), glucocorticoid receptor (BclI)) on body composition, BM(A)D and fracture risk during dexamethasone-based pediatric acute lymphoblastic leukemia treatment. Body composition and BMD were measured repeatedly during and after treatment using dual energy X-ray absorptiometry. RESULTS: Non-carriers of VDR 5'-end (Cdx-2/GATA) haplotype 3 revealed a significant larger fat gain than carriers (Delta%fat: non-carriers: +1.76SDS, carriers: +0.77SDS, P<0.001). At diagnosis and during therapy, lumbar spine BMD was significantly higher in non-carriers of VDR 5'-end (Cdx-2/GATA) haplotype 3 than in carriers. The other SNPs did not influence BMD or fracture risk during/after treatment. The year after treatment completion, lean body mass increased in non-carriers of ESR1 (PvuII/XbaI) haplotype 3 and decreased in carriers (Delta lean body mass: non-carriers:+0.28SDS, carriers: -0.55SDS, P<0.01). CONCLUSIONS: Only VDR 5'-end (Cdx-2/GATA) haplotype 3 was identified as protective factor against excessive fat gain and as a risk factor for lower lumbar spine BMD during treatment. Carrying ESR1 (PvuII/XbaI) haplotype 3 negatively influenced recovery of lean body mass after pediatric acute lymphoblastic leukemia treatment.

The effect of the weak androgen oxandrolone on psychological and behavioral characteristics in growth hormone-treated girls with Turner syndrome.

The weak androgen oxandrolone (Ox) increases height gain in growth-hormone (GH) treated girls with Turner syndrome (TS), but may also give rise to virilizing side effects. To assess the effect of Ox, at a conventional and low dosage, on behavior, aggression, romantic and sexual interest, mood, and gender role in GH-treated girls with TS, a randomized, placebo-controlled, double-blind study was conducted. 133 patients were treated with GH (1.33 mg/m(2)/d) from baseline, combined with placebo (Pl), Ox 0.03 mg/kg/d, or Ox 0.06 mg/kg/d from the age of eight, and with estrogens from the age of 12. The child behavior checklist (CBCL), Junior Dutch Personality Questionnaire (DPQ-J), State-subscale of the Spielberger's State-Trait Anger Scale, Romantic and Sexual Interest Questionnaire, Mood Questionnaire, and Gender Role Questionnaire were filled out before, during, and after discontinuing Ox/Pl. The changes during Ox/Pl therapy were not significantly different between the dosage groups. In untreated patients, the mean CBCL total (P=0.002) and internalizing (P=0.003) T scores, as well as the mean DPQ-J social inadequacy SD score (SDS) (P=0.004) were higher than in reference girls, but decreased during GH+Ox/Pl therapy (P<0.001, P=0.05, P<0.001, respectively). Whereas the mean total (P=0.01) and internalizing (P<0.001) T score remained relatively high, the mean social inadequacy SDS became comparable with reference values. We conclude that in GH-treated girls with TS, Ox 0.03 mg/kg/d or 0.06 mg/kg/d does not cause evident psychological virilizing side effects. Problem behavior, frequently present in untreated girls with TS, decreases during therapy, but total and internalizing problem behavior remain increased.

The hypothalamus-pituitary-testis axis in boys during the first six months of life: a comparison of cryptorchidism and hypospadias cases with controls.

It is inconclusive whether the feedback mechanisms of the hypothalamus-pituitary-testis (HTP) axis are already established in the first 6 months of life, partly due to the dramatic changes in HPT-axis hormone levels over this period. Moreover, it is unclear whether these hormone levels are aberrant in boys with cryptorchidism or hypospadias, and therefore predictive for future fertility. We studied the regulation mechanisms of the HTP axis, and the effect of age, in boys 1-6 months of age. Secondly, we studied testicular function - as reflected by HPT hormones - in newborns with cryptorchidism or hypospadias. Sera from a population sample of infants with cryptorchidism (n = 43), hypospadias (n = 41) and controls (n = 113) were analyzed for inhibin B, anti-Müllerian hormone (AMH), testosterone, luteinizing hormone (LH), follicle stimulating hormone (FSH) and sex hormone binding globulin (SHBG). LH, testosterone, non-shbg-bound testosterone (NSBT), and AHM levels showed significant age-related trends. After age-correction, a negative correlation between FSH and inhibin B was observed (r = -0.43). The only significant group-differences were lower testosterone and NSBT levels in cryptorchidism cases, with a mean testosterone of 1.8 and 2.6 nmol/L and a mean NSBT of 0.48 and 0.70 nmol/L for cryptorchidism cases and controls, respectively. The higher levels of LH, testosterone, and NSBT in boys born pre-term or with a low birthweight indicate that abnormal prenatal development may determine postnatal testis function. Our results support the hypothesis that the inhibin B - FSH feedback loop is already functional before puberty. The lower testosterone and NSBT levels indicate that disturbed Leydig cell function can already be detected early after birth in cryptorchid boys.

Bone mineral density and body composition in adolescents with childhood-onset growth hormone deficiency.

BACKGROUND/AIMS: The aim of the present study was to evaluate bone mineral density (BMD) and body composition of patients with childhood-onset growth hormone (GH) deficiency (GHD) treated with GH during the transition period. METHODS: BMD and body composition, measured by dual-energy X-ray absorptiometry, were evaluated at final height and yearly thereafter during 2 years. Twenty-nine of the 40 patients had also been measured before start and during GH therapy. RESULTS: Mean lumbar spine BMD and bone mineral apparent density (BMAD) as well as total body BMD and lean body mass (LBM) SD score (SDS) were significantly lower than normal at final height and during the 2 years thereafter for all patients. Final-height SDS was related to the change in height SDS as well as in LBM SDS during the first year of GH treatment. LBM SDS decreased significantly in the group of patients with GHD without GH treatment (p < 0.01, n = 19). Fat mass SDS increased in all patients. CONCLUSION: Mean BMD, BMAD and LBM SDS were significantly lower than normal in adolescents with childhood-onset GHD at and 2 years after the attainment of final height.

Diagnostic approach in children with short stature.

For early detection of pathological causes of growth failure proper referral criteria are needed, as well as a thorough clinical, radiological and laboratory assessment. In this minireview we first discuss the two consensus-based and one evidence-based guidelines for referral that have been published. The evidence-based guidelines result in a sensitivity of approximately 80% at a false-positive rate of 2%. Then, relevant clues from the medical history and physical examination are reviewed, and specific investigations based on clinical suspicion listed. In the absence of abnormal clinical findings, an X-ray of the hand/wrist and a laboratory screen are usually performed. Scientific evidence for the various components of laboratory screening is scarce, but accumulated experience and theoretical considerations have led to a list of investigations that may be considered until more evidence is available.

Long-term follow-up of GH-treated girls with Turner syndrome: BMI, blood pressure, body proportions.

AIMS: To investigate whether long-term growth hormone (GH) treatment influenced blood pressure (BP), body proportions and BMI in young Turner syndrome (TS) women several years after GH discontinuation. METHODS: A follow-up study of a randomized GH dose-response trial with 3 GH dosages (1.3, 2.0, and 2.7 mg/m(2)/day). 39 TS patients (20.0 +/- 2.1 years) participated 4.8 (1.9) years after GH discontinuation. Mean GH duration was 8.7 (2.0) years. MEASUREMENTS: BP, BMI and body proportions. RESULTS: During GH treatment, DBP had decreased. At the long-term follow-up study, DBP had increased and was similar to pretreatment levels. DBP was negatively influenced by GH dose. SBP was not influenced by GH dose or duration. The BMI increased gradually during and after GH therapy. During GH therapy, shape values of sitting height had decreased to normal values, of foot had increased, and both remained constant after GH discontinuation. CONCLUSIONS: GH therapy in girls with TS has, besides height, additional beneficial effects on BP and body proportions, except foot length. Nearly 5 years after ending GH, the favorable effect of GH on BP was still noticeable. The BMI increased gradually over the years, not influenced by GH.

Long-term follow-up of GH-treated girls with Turner syndrome: metabolic consequences.

AIMS: To investigate the metabolic consequences of long-term GH treatment in young women with Turner syndrome (TS), several years after GH discontinuation. METHODS: Follow-up study of a randomized GH dose-response trial, with 3 GH dosages (1.3, 2.0, and 2.7 mg/m(2)/day). Thirty-nine TS patients (20.0 +/- 2.1 years) participated 4.8 +/- 1.9 years after GH discontinuation. Mean GH treatment duration was 8.7 +/- 2.0 years. Fasting glucose, insulin, and serum lipids were measured. RESULTS: Several years after GH discontinuation, insulin sensitivity remained lower, while beta-cell function and fasting insulin levels remained higher than before treatment. Only BMI influenced beta-cell function. Serum total cholesterol (TC), low-density lipoprotein and high-density lipoprotein (HDL) had further increased compared to 6 months after GH, resulting in higher TC, but also higher HDL levels compared to controls. The atherogenic index remained constant, but lower than controls. CONCLUSIONS: Besides height, GH therapy in girls with TS has additional beneficial effects on serum lipids. Nearly 5 years after discontinuation of GH therapy the favorable effect of GH was still noticeable. The GH-induced decrease in insulin sensitivity, however, remained unchanged, possibly due to having TS.

Growth monitoring to detect children with cystic fibrosis.

BACKGROUND/AIMS: Cystic fibrosis (CF) in infancy and childhood is often associated with failure to thrive (FTT). This would suggest that in countries without a newborn screening program for CF, FTT could be used as a clinical screening tool. The aim of this study is to assess the diagnostic performance of FTT for identifying children with CF. METHODS: Longitudinal length and weight measurements up to 2.5 years of age were used from CF patients (n = 123) and a reference group (n = 2,151) in The Netherlands. Growth measurements after diagnosis were excluded. We developed five potential screening rules based upon length, weight and body mass index (BMI) standardized by age and gender (SDS). Outcome measures were sensitivity, specificity and positive predictive value (PPV). RESULTS: BMI SDS had the highest sensitivity at low false-positive rates. An efficient scenario is a BMI SDS below -2.5 SD in combination with a decrease in BMI SDS of at least 0.5 SD. This scenario had a sensitivity of 32%, a specificity of 98.3% and a PPV of 0.75%. CONCLUSION: In the absence of a newborn screening program, young children with FTT for BMI are candidates to consider testing for CF.

[Acquired undescended testes: treatment and consequences for future fertility]. / Verworven niet-scrotale testis.

1-3% of boys develop an acquired undescended testes (UDT), meaning that the testes cannot be returned into the scrotum after previously having been located in a stable scrotal position. Fertility issues for patients with acquired UDT are comparable to those for patients with congenital UDT. Hypothetically speaking, patients with acquired UDT are at lower risk of testicular cancer than patients with congenital UDT. The appearance of an asymmetrical scrotum, which is associated with UDT, may negatively influence quality of life. Over 50% of the acquired UDTs will spontaneously descend at the start of puberty, thereby justifying conservative management of the condition. Orchidopexy directly after diagnosis does not have any advantages over awaiting spontaneous descent until puberty when fertility in later life of patients with unilateral acquired UDT is concerned; however, it may be beneficial in bilateral acquired UDT.

Cardiac status after childhood growth hormone treatment of Turner syndrome.

CONTEXT: In Turner syndrome (TS), GH treatment is well established. Data on cardiac status after discontinuation of treatment are scarce. This study aimed to assess biventricular size and function in TS at least 6 months after discontinuation of GH treatment. METHODS: TS patients and healthy women prospectively underwent cardiac magnetic resonance imaging. Ventricular two-dimensional tomographic cine data were acquired to obtain biventricular volume, mass, and ejection fraction. Atrioventricular valve flow measurements were performed using a two-dimensional flow-sensitized sequence. Flow velocity curves were calculated and indices of biventricular diastolic filling were derived. RESULTS: Thirty-one patients [mean (sd) age 20 (2) yr, body surface area 1.75 (0.15) m(2), 5 (2) yr after GH discontinuation] and 23 normal control women [age 21 (2) yr, body surface area 1.80 (0.13) m(2)] were included. Compared with controls, patients had smaller mean end-diastolic volumes [right ventricle (RV), 84 (11) ml/m(2) vs. 79 (10), P = 0.02; left ventricle (LV), 81 (10) vs. 72 (9), P < 0.001], end-systolic volumes [RV 38 (7) ml/m(2) vs. 36 (6), P = 0.04; LV 34 (5) vs. 29 (4), P < 0.001], and stroke volumes [RV 46 (6) ml/m(2) vs. 43 (6), P = 0.03; LV, 47 (7) vs. 44 (4), P = 0.02]. Patients had a higher mean heart rate [79 (13) beats/min vs. 71 (10), P < 0.05]. Biventricular ejection fraction, mass, cardiac output, and diastolic filling pattern were comparable. CONCLUSION: After discontinuation of GH treatment TS patients showed no myocardial hypertrophy and well-preserved biventricular function. Ventricular volumes were smaller in Turner patients, compared with controls, whereas mean heart rate was higher. These last observations may be part of the natural development in TS and not linked to GH treatment, which at this point we consider safe.

Successful long-term growth hormone therapy in a girl with haploinsufficiency of the insulin-like growth factor-I receptor due to a terminal 15q26.2->qter deletion detected by multiplex ligation probe amplification.

CONTEXT: Microscopically visible heterozygous terminal 15q deletions encompassing the IGF1R gene are rare and usually associated with intrauterine growth retardation and short stature. The incidence of submicroscopic deletions is unknown, as is the effect of GH therapy in this condition. OBJECTIVE: The objective of the study was to describe the use of a novel genetic technique [multiplex ligation probe amplification (MLPA)] to detect haploinsufficiency of the IGF1R gene in a patient suspected of an IGF1R gene defect and evaluate the effect of long-term GH therapy. PATIENT: A 15-yr-old adolescent, born small for gestational age, showed persistent postnatal growth retardation, microcephaly, and elevated IGF-I levels. She had been treated with GH since the age of 5 yr. METHODS: MLPA and array comparative genomic hybridization (aCGH) were performed to examine gene copy number changes. Dermal fibroblast cultures were used for functional analysis. RESULTS: With MLPA, a deletion of one copy of the IGF1R gene was detected, defined by aCGH as a loss of 15q26.2->qter. IGF1R mRNA expression was decreased in fibroblasts. IGF-I binding and type 1 IGF receptor protein expression as well as activation of type 1 IGF receptor autophosphorylation and protein kinase B/Akt by IGF-I tended to be lower, but this did not reach statistical significance. GH treatment resulted in a good growth response and a normal adult height. CONCLUSIONS: MLPA and aCGH are useful tools to detect submicroscopic deletions of the IGF1R gene in patients born small for gestational age with persistent growth failure. The phenotype resembles that of a heterozygous inactivating IGF1R mutation. Long-term GH therapy causes growth acceleration in childhood and a normal adult height.

Relation between Early Over- and Undertreatment and Behavioural Problems in Preadolescent Children with Congenital Hypothyroidism.

OBJECTIVE: Congenital hypothyroidism (CH) per se, when not treated or undertreated, may lead to severe behavioural problems (cretinism), whereas overtreatment of CH seems associated with attention problems. DESIGN AND METHODS: For 55 CH patients, prospectively followed from birth until 11 years, parents rated the Child Behaviour Checklist and teachers the Teacher's Report Form at children's ages 6 and 11 years. We related scores regarding Attention, Delinquency, and Aggression (ADA scores, indicative for attention deficit hyperactivity syndrome, ADHD), and scores regarding Withdrawn, Anxious, Social, and Thought problems (WAST scores, indicative for autism) to the occurrence of over- and undertreatment in five age periods. Over- and undertreatment were defined as free thyroxine (fT4) concentrations above/below the range of the patient's individual fT4 steady state concentration. RESULTS: ADA scores at 6 and 11 years for patients overtreated in the period 1-3 months postnatally were higher than those for patients who were not overtreated. Patients with severe CH undertreated in the period 3-6 months postnatally had higher WAST scores at 6 and 11 years than all other patients. CONCLUSIONS: This is the first study suggesting that permanent ADHD as well as autism in CH patients at ages 6 and 11 years are the result of early overtreatment and undertreatment, respectively.

Anti-Mullerian hormone is a sensitive serum marker for gonadal function in women treated for Hodgkin's lymphoma during childhood.

PURPOSE: The aim of this study was to evaluate the long-term effects of combination chemotherapy treatment for girls with Hodgkin's lymphoma (HL) on gonadal function using anti-Müllerian hormone (AMH) and inhibin B as ovarian reserve parameters. PATIENTS AND METHODS: LH, FSH, inhibin B, and AMH were measured in 32 women treated from 1974 to 1998 for pediatric HL with chemotherapy, with the intention to avoid radiotherapy. All patients [median age 25.0 yr (range 19.2-40.4 yr)] were in complete remission with a median follow-up time of 14.0 yr (range 5.7-24.5 yr) after therapy. All patients were treated with combination chemotherapy doxorubicin, bleomycin, vinblastine and dacarbazine (ABVD) or EBVD with or without mechlorethamine, vincristine, procarbazine, and prednisone (MOPP). Because of incomplete remission or relapse, involved field radiotherapy was needed in seven of 32 women. Results were compared with a healthy control group. RESULTS: Patients treated with six or more cycles of MOPP combination chemotherapy had significantly higher levels of FSH and lower serum levels of inhibin B and AMH, compared with healthy women [FSH, 17.0 vs. 6.0 U/liter (P < 0.05); inhibin B, 23.0 vs. 112.5 ng/liter (P < 0.01); AMH, 0.39 vs. 2.10 microg/liter (P < 0.01)]. AMH was also significantly lower, compared with women treated without MOPP (median 0.39 vs. 1.40 microg/liter; P = 0.01). CONCLUSIONS: Women treated during childhood for HL with MOPP seem to have a distinctly lower ovarian reserve as measured by lower AMH values at early adulthood, compared with healthy women. Moreover, AMH seems to be the only predictor that is sufficiently sensitive to detect this decrease in ovarian reserve.

Final height outcome after three years of growth hormone and gonadotropin-releasing hormone agonist treatment in short adolescents with relatively early puberty.

OBJECTIVE: Our objective was to assess final height (FH) and adverse effects of combined GH and GnRH agonist (GnRHa) treatment in short adolescents born small for gestational age or with normal birth size (idiopathic short stature). DESIGN AND PATIENTS: Thirty-two adolescents with Tanner stage 2-3, age and bone age (BA) less than 12 yr for girls or less than 13 yr for boys, height sd score (SDS) less than -2.0 SDS or between -1.0 and -2.0 SDS plus a predicted adult height (PAH0) less than -2.0 SDS were randomly allocated to receive GH plus GnRHa (n=17) or no treatment (n=15) for 3 yr. FH was assessed at the age of 18 yr or older in girls or 19 yr or older in boys. RESULTS: FH was not different between treatment and control groups. Treated children had a larger height gain (FH-PAH0) than controls: 4.4 (4.9) and -0.5 (6.4) cm, respectively (P<0.05). FH was higher than PAH0 in 76 and 60% of treated and control subjects, respectively. During follow-up, 50% of the predicted height gain at treatment withdrawal was lost, resulting in a mean gain of 4.9 cm (range, -4.0 to 12.3 cm) compared with controls. Treatment did not affect body mass index or hip bone mineral density. Mean lumbar spine bone mineral density and bone mineral apparent density tended to be lower in treated boys, albeit statistically not significant. CONCLUSION: Given the expensive and intensive treatment regimen, its modest height gain results, and the possible adverse effect on peak bone mineralization in males, GH plus GnRHa cannot be considered routine treatment for children with idiopathic short stature or persistent short stature after being born small for gestational age.