[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.

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and Aggression (ADA scores, indicative for attention deficit hyperactivity syndrome, ADHD), and scores regarding Withdrawn, Anxious, Social, and Thought problems (WAST scores, indicative for autism) to the occurrence of over- and undertreatment in five age periods.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.

INSL3 and AMH in patients with previously congenital or acquired undescended testes.

BACKGROUND: In previous reports no differences in Leydig and Sertoli cell function were found between congenital undescended testis (CUDT) and acquired UDT (AUDT) on the basis of serum levels of LH, testosterone, FSH or inhibin B. This study tried to detect differences in Leydig and Sertoli cell function between CUDT and AUDT using insulin-like peptide 3 (INSL3) and anti-Müllerian hormone (AMH). METHOD: 118 men with a history of UDT (CUDT N=55 (6/55 bilateral), AUDT N=63 (15/63 bilateral)) were investigated. Differences between CUDT and AUDT, influence of age at surgery in CUDT, and effect of spontaneous descent or orchiopexy in AUDT were evaluated. RESULTS: For INSL3, no significant differences were found. AMH levels in bilateral CUDT were significantly lower compared with bilateral AUDT (6.4 (1.7-11.4) vs 13.2 (6.1-30.1) µg/l, p=0.02). AMH levels in unilateral CUDT were significantly higher than in bilateral CUDT (12.1 (2.4-43.7) vs. 6.4 (1.7-11.4) µg/l, p=0.02). CONCLUSION: No differences in Leydig cell function on the basis of INSL3 levels between the different UDT groups were found. Sertoli cell function evaluated by AMH, was more negatively affected in bilateral CUDT in comparison with bilateral AUDT and unilateral CUDT. LEVEL OF EVIDENCE RATING: Level III Treatment Study.

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.

A human vitamin D receptor mutation causes rickets and impaired Th1/Th17 responses.

We present a brother and sister with severe rickets, alopecia and highly elevated serum levels of 1,25-dihydroxyvitamin D (1,25-(OH)2D3). Genomic sequencing showed a homozygous point mutation (A133G) in the vitamin D receptor gene, leading to an amino acid change in the DNA binding domain (K45E), which was described previously. Hereditary vitamin D resistant rickets (HVDRR) was diagnosed. Functional studies in skin biopsy fibroblasts confirmed this. 1,25-(OH)2D3 reduced T helper (Th) cell population-specific cytokine expression of interferon γ (Th1), interleukins IL-17A (Th17) and IL-22 (Th17/Th22) in peripheral blood mononuclear cells (PBMCs) from the patient's parents, whereas IL-4 (Th2) levels were higher, reflecting an immunosuppressive condition. None of these factors were regulated by 1,25-(OH)2D3 in PBMCs from the boy. At present, both patients (boy is 23 years of age, girl is 7) have not experienced any major immune-related disorders. Although both children developed alopecia, the girl did so earlier than the boy. The boy showed complete recovery from the rickets at the age of 17 and does not require any vitamin D supplementations to date. In conclusion, we characterized two siblings with HVDRR, due to a mutation in the DNA binding domain of VDR. Despite a defective T cell response to vitamin D, no signs of any inflammatory-related abnormalities were seen, thus questioning an essential role of vitamin D in the immune system. Despite the fact that currently medicine is not required, close monitoring in the future of these patients is warranted for potential recurrence of vitamin D dependence and diagnosis of (chronic) inflammatory-related diseases.

Maternal early-pregnancy thyroid function is associated with subsequent hypertensive disorders of pregnancy: the generation R study.

CONTEXT: Hypertensive disorders during pregnancy are associated with a wide range of maternal and fetal complications, and only a few risk factors are known for the development of these disorders during pregnancy. Conflicting and limited data are available on the relationship between thyroid (dys)function and the risk of hypertensive disorders of pregnancy. OBJECTIVE: The objective of the investigation was to study the associations between early-pregnancy thyroid dysfunction, thyroid function within the normal range, and the risk of hypertensive disorders. DESIGN, SETTING, AND PARTICIPANTS: In early pregnancy, serum TSH, free T4 (FT4), and thyroperoxidase antibody (TPOAb) levels were determined in 5153 pregnant women. No interventions were done. The associations of thyroid function with the risk of hypertensive disorders were studied. MAIN OUTCOME MEASURES: Mean blood pressures and hypertensive disorders, including pregnancy-induced hypertension (n = 209) and preeclampsia (n = 136), were measured. RESULTS: Hyperthyroid mothers had a higher risk of hypertensive disorders [odds ratio (OR) 3.40 [95% confidence interval (CI) 1.46-7.91], P = .005], which was mainly due to an increased risk of pregnancy-induced hypertension [OR 4.18 (95% CI 1.57-11.1), P = .004]. Hypothyroidism and hypothyroxinemia were not associated with hypertensive disorders. Within the normal range, the high-normal FT4 levels were associated with an increased risk of hypertensive disorders [OR 1.62 (95% CI 1.06-2.47), P = .03], which was mainly due to an increased risk of preeclampsia [OR 2.06 (95% CI 1.04-4.08), P = .04]. The TPOAb status was not associated with hypertensive disorders. CONCLUSIONS: We show that biochemical hyperthyroidism and also high-normal FT4 levels during early pregnancy are associated with an increased risk of hypertensive disorders. These data demonstrate that these associations are even seen for a mild variation in thyroid function within the normal range.

Karyotype-specific ear and hearing problems in young adults with Turner syndrome and the effect of oxandrolone treatment.

OBJECTIVE: To evaluate karyotype-specific ear and hearing problems in young-adult patients with Turner syndrome (TS) and assess the effects of previous treatment with oxandrolone (Ox). STUDY DESIGN: Double-blind follow-up study. SETTING: University hospital. PATIENTS: Sixty-five TS patients (mean age, 24.3 yr) previously treated with growth hormone combined with placebo, Ox 0.03 mg/kg per day, or Ox 0.06 mg/kg per day from the age of 8 years and estrogen from the age of 12 years. INTERVENTION: Ear examination was performed according to standard clinical practice. Air- and bone conduction thresholds were measured in decibel hearing level. MAIN OUTCOME MEASURES: We compared patients with total monosomy of the short arm of the X chromosome (Xp), monosomy 45,X and isochromosome 46,X,i(Xq), with patients with a partial monosomy Xp, mosaicism or other structural X chromosomal anomalies. We assessed the effect of previous Ox treatment. RESULTS: Sixty-six percent of the patients had a history of recurrent otitis media. We found hearing loss in 66% of the ears, including pure sensorineural hearing loss in 32%. Hearing thresholds in patients with a complete monosomy Xp were about 10 dB worse compared with those in patients with a partial monosomy Xp. Air- and bone conduction thresholds were not different between the placebo and Ox treatment groups. CONCLUSION: Young-adult TS individuals frequently have structural ear pathology, and many suffer from hearing loss. This indicates that careful follow-up to detect ear and hearing problems is necessary, especially for those with a monosomy 45,X or isochromosome 46,X,i(Xq). Ox does not seem to have an effect on hearing.

Soluble Flt1 and placental growth factor are novel determinants of newborn thyroid (dys)function: the generation R study.

CONTEXT: Adequate thyroid hormone availability during fetal and early life is crucial for normal child growth and development. Fetal growth heavily depends on angiogenesis. Placental growth factor (PlGF) is a proangiogenic factor sharing high homology with vascular endothelial growth factor, whereas soluble FMS-like tyrosine kinase-1 (sFlt1) is a potent antagonist of vascular endothelial growth factor and PlGF signaling. Because the thyroid is a highly vascularized organ, we hypothesized that fetal angiogenic factors influence in utero thyrogenesis and impair newborn thyroid function. Therefore, we investigated the association between sFlt1 and PlGF on newborn thyroid function. DESIGN, SETTING, AND PARTICIPANTS: sFlt1, PlGF, TSH, and free T4 (FT4) were determined in cord serum of 3525 newborns from a large prospective cohort study. Analyses were adjusted for relevant maternal and child covariates. RESULTS: sFlt1 levels were positively associated with TSH (ß 0.07 ± 0.02 mU/L; P < .001) and inversely with FT4 (ß -0.58 ± 0.11; P < .001). PlGF showed a positive association with FT4 (ß 0.19 ± 0.02; P < .001). Elevated levels of sFlt1 were associated with a 2.8-fold increased risk of hypothyroxinemia (P = .04). Decreased levels of PlGF were associated with a 6.7-fold increased risk of hypothyroxinemia (P < .001). Within the normal range, a dose-dependent effect of sFlt1 on thyroid dysfunction was observed: high-normal sFlt1 levels were associated with a 17.7-fold increased risk of hypothyroxinemia (P < .001) and a 2.7-fold increased risk of hyperthyrotropinemia (P = .01). CONCLUSION: Fetal angiogenic factors sFlt1 and PlGF are associated with newborn thyroid function. Possible effects are most likely mediated through effects on in utero thyrogenesis. Abnormal as well as normal-range fetal sFlt1 and PlGF levels influence the risk of impaired newborn thyroid function, which has been associated with adverse neurodevelopmental effects. These data provide important novel insights into the physiology of thyrogenesis and into the etiology of newborn thyroid (dys)function.

Comparison of body surface area versus weight-based growth hormone dosing for girls with Turner syndrome.

BACKGROUND/AIMS: Growth Hormone (GH) dosage in childhood is adjusted for body size, but there is no consensus whether body weight (BW) or body surface area (BSA) should be used. We aimed at comparing the biological effect and cost-effectiveness of GH treatment dosed per m2 BSA in comparison with dosing per kg BW in girls with Turner syndrome (TS). METHODS: Serum IGF-I, GH dose, and adult height gain (AHG) from girls participating in two Dutch and five Swedish studies on the efficacy of GH were analyzed, and the cumulative GH dose and costs were calculated for both dose adjustment methods. Additional medication included estrogens (if no spontaneous puberty occurred) and oxandrolone in some studies. RESULTS: At each GH dose, the serum IGF-I standard deviation score remained stable over time after an initial increase after the start of treatment. On a high dose (at 1 m2 equivalent to 0.056-0.067 mg/kg/day), AHG was at least equal on GH dosed per m2 BSA compared with dosing per kg BW. The cumulative dose and cost were significantly lower if the GH dose was adjusted for m2 BSA. CONCLUSION: Dosing GH per m2 BSA is at least as efficacious as dosing per kg BW, and is more cost-effective.

Fertility potential in a cohort of 65 men with previously acquired undescended testes.

PURPOSE: To evaluate testicular function in men with previously acquired undescended testes (AUDT) in whom spontaneous descent was awaited until puberty followed by orchiopexy in case of nondescent. METHODS: Andrological evaluation including paternity, scrotal ultrasound, reproductive hormones, and semen analysis was performed in three groups: men with AUDT, healthy controls, and men with previously congenital undescended testes (CUDT). RESULTS: In comparison with controls, men with AUDT more often had significantly abnormal testicular consistency, smaller testes, lower sperm concentration, and less motile sperm. Except for more often a normal testicular consistency in men with AUDT, no differences were found between men with AUDT and men with CUDT. Also, no differences were found between men with AUDT which had spontaneously descended and men who underwent orchiopexy. CONCLUSIONS: Fertility potential in men with AUDT is compromised in comparison with healthy controls, but comparable with men with CUDT. This suggests that congenital and acquired UDT share the same etiology. No significant difference was found between men who had spontaneous descent and men needing orchiopexy. However, fertility potential is unknown for men after immediate surgery at diagnosis, and this should be a subject for future studies.

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.

Hypothyroxinemia and TPO-antibody positivity are risk factors for premature delivery: the generation R study.

CONTEXT: Premature delivery is an important risk factor for child mortality and psychiatric, metabolic, and cardiovascular disease later in life. In the majority of cases, the cause of prematurity cannot be identified. Currently, it remains controversial whether abnormal maternal thyroid function during pregnancy increases the risk of premature delivery. Therefore, we investigated the relation between maternal serum thyroid parameters and the risk of premature delivery in a large prospective population-based study. DESIGN: Serum TSH, free T4 (FT4), T4, and TPO antibodies (TPOAbs) were determined during early pregnancy in 5971 pregnant women from the Generation R study. Data were available on maternal age, parity, smoking, socioeconomic status, ethnicity, maternal anthropometrics, and urinary iodine levels. RESULTS: Of all women, 5.0% had a premature delivery (<37 weeks), 4.4% had a spontaneous premature delivery, and 1.4% had a very premature delivery (<34 weeks). High TSH levels and subclinical hypothyroidism were associated with premature delivery but not with spontaneous premature delivery. Maternal hypothyroxinemia was associated with a 2.5-fold increased risk of premature delivery, a 3.4-fold increased risk of spontaneous premature delivery, and a 3.6-fold increased risk of very premature delivery (all P < .01). TPOAb positivity was associated with a 1.7-fold increased risk of premature delivery (P = .01), a 2.1-fold increased risk of spontaneous premature delivery (P = .02), and a 2.5-fold increased risk of very premature delivery (P = .04). These effects remained similar after correction for TSH and FT4 levels. CONCLUSIONS: Hypothyroxinemia and TPOAb positivity are associated with an increased risk of premature delivery. The increased risk in TPOAb-positive women seems to be independent of thyroid function.

Cognitive development in congenital hypothyroidism: is overtreatment a greater threat than undertreatment?

BACKGROUND: Optimal treatment of children with congenital hypothyroidism (CHT) is still debated. Our objective was to evaluate whether early undertreatment (UT) and overtreatment (OT) influence cognitive development at age 11 years. METHODS: Sixty-one patients (27 severe CHT, 34 mild CHT) were psychologically tested at ages 1.8 (Mental Development Index), 6 [intelligence quotient (IQ) 6], and 11 years (IQ11). Scores for cognitive development were related to initial levels of TSH normalization (fast, moderate, or slow) and to total durations of the UT and OT episodes within the first 2 years of life (no, short, or long UT/OT). UT and OT were defined as a free T4 (fT4) concentration below or above the individual fT4 steady-state concentration range (±2 SD). RESULTS: Patients with fast and moderate TSH normalization had higher Mental Development Index scores than patients with slow TSH normalization; 14.2 and 7.7 points higher, respectively (P = .001). TSH normalization had no significant effect on IQ11. Patients with long and short overtreatment had IQ11s that were -17.8 and -13.4 points lower, respectively, than the IQ11s of patients with no overtreatment (P = .014). UT without OT was associated with normal development scores, but UT with OT was associated with -14.7 points lower IQ11s than UT without OT (P = .005). CONCLUSIONS: Our study suggests that CHT overtreatment during the first 2 years leads to lowered cognitive outcomes at 11 years, whereas undertreatment, if not complicated by overtreatment, results in a normal cognitive development. Fast TSH normalization at initial treatment leads to above-normal development scores at a young age but does not affect IQ at age 11 years.

Ethnic differences in maternal thyroid parameters during pregnancy: the Generation R study.

CONTEXT: Abnormal maternal thyroid function during pregnancy is associated with various complications. International guidelines advocate the use of population-based trimester-specific reference ranges for thyroid function tests. When unavailable, an upper TSH limit of 2.5 for the first trimester and 3.0 mU/L for the second and third trimesters is recommended. Although interindividual differences in thyroid function tests can partially be explained by ethnicity, data on the influence of ethnicity on TSH and free T4 reference ranges during pregnancy are sparse. DESIGN: Serum TSH, free T4, T4, and TPO-antibody levels were determined during early pregnancy in 3944 women from the Generation R study, Rotterdam, The Netherlands. RESULTS: The study population consisted of 2765 Dutch, 308 Moroccan, 421 Turkish, and 450 Surinamese women. Mean TSH levels were higher in Dutch and Turkish women than in Moroccan or Surinamese women (1.50-1.48 vs 1.29-1.33 mU/L; P < .01). Although no differences in free T4 were seen, T4 was lowest in Dutch women (142 vs 150-156 nmol/L; P < .01). Turkish women had the highest frequency of TPO-antibody positivity (9.3% vs 5.0-5.8%; P < .05) and of elevated TSH levels in the second trimester (11.0% vs 3.8-7.3%; P < .01). A comparison of disease prevalence between a population-based vs an ethnicity-specific reference range changed the diagnosis for 18% of women who were initially found to have abnormal thyroid function test results. CONCLUSIONS: We show ethnic differences in serum TSH, T4, and TPO-antibody positivity and found significant diagnostic discrepancies depending on whether population or ethnicity-specific reference ranges were used to diagnose thyroid disease.

Long-term effects of previous oxandrolone treatment in adult women with Turner syndrome.

OBJECTIVE: Short stature is a prominent feature of Turner syndrome (TS), which is partially overcome by GH treatment. We have previously reported the results of a trial on the effect of oxandrolone (Ox) in girls with TS. Ox in a dose of 0.03 mg/kg per day (Ox 0.03) significantly increased adult height gain, whereas Ox mg/kg per day (0.06) did not, at the cost of deceleration of breast development and mild virilization. The aim of this follow-up study in adult participants of the pediatric trial was to investigate the long-term effects of previous Ox treatment. DESIGN AND METHODS: During the previous randomized controlled trial, 133 girls were treated with GH combined with placebo (Pl), Ox 0.03, or Ox 0.06 from 8 years of age and estrogen from 12 years. Sixty-eight women (Pl, n=23; Ox 0.03, n=27; and Ox 0.06, n=18) participated in the double-blind follow-up study (mean age, 24.0 years; mean time since stopping GH, 8.7 years; and mean time of Ox/Pl use, 4.9 years). We assessed height, body proportions, breast size, virilization, and body composition. RESULTS: Height gain (final minus predicted adult height) was maintained at follow-up (Ox 0.03 10.2±4.9 cm, Ox 0.06 9.7±4.4 cm vs Pl 8.0±4.6 cm). Breast size, Tanner breast stage, and body composition were not different between groups. Ox-treated women reported more subjective virilization and had a lower voice frequency. CONCLUSION: Ox 0.03 mg/kg per day has a beneficial effect on adult height gain in TS patients. Despite previously reported deceleration of breast development during Ox 0.03 treatment, adult breast size is not affected. Mild virilization persists in only a small minority of patients. The long-term evaluation indicates that Ox 0.03 treatment is effective and safe.

Experience in treating congenital hypothyroidism: implications regarding free thyroxine and thyrotropin steady-state concentrations during optimal levothyroxine treatment.

BACKGROUND: A major problem in the treatment of patients with congenital hypothyroidism (CHT) is that the optimal individual target values of thyrotropin (TSH) and free thyroxine (fT(4)) are unknown. We investigated whether patients with CHT have during treatment considered optimal stable fT(4) and TSH steady-state concentrations (SSCs) that can be used as target values, and whether TSH or fT(4) is more useful in guiding decisions regarding therapy. METHODS: From 60 early-treated patients with CHT, TSH and fT(4) follow-up samples within the age interval 1.5-132 months (postinitial period) and within TSH interval 0.5-10 mU/L were selected. TSH and fT(4) SSCs were estimated by taking the individual mean values of a series of determinations, under the most euthyroid conditions possible (n=1257), for the whole age and TSH intervals, as well as for the age intervals 1.5-24, 25-72, and 73-132 months, as well as, for fT(4), for the two split TSH intervals 0.5-4.49 and 4.5-10 mU/L. For all SSCs, the within-subject coefficient of variation (CV(w)) was determined. Further, fT(4) SSCs were assessed for the first 6 weeks after therapy initiation. RESULTS: For both TSH and fT(4), individual SSCs differed significantly (p<0.001). The 95% confidence interval for TSH SSCs was 1.1-5.7 mU/L and for fT(4) SSCs 16.6-28.7 pmol/L. Mean CV(w) values for TSH and fT(4) SSCs were 60.9% and 13.1%, respectively. Individual fT(4) and TSH SSCs were reproducible when assessed for the three age intervals, both slightly decreasing with age (p≤0.033), and fT(4) SSCs were reproducible for the two split TSH intervals, with a slight fT(4) difference (p<0.001). fT(4) SSCs were largely independent of the administered LT(4) dosage (range 2.4-6.1 µg/kg). fT(4) SSCs of the initial period were comparable to those of postinitial period with a mean±SD difference of 1.0±3.5 pmol/L, p=0.07. CONCLUSIONS: Our study suggests that in CHT during therapy considered optimal, stable TSH and fT(4) SSCs can be found slightly decreasing with age and largely independent of the administered LT(4) dosage (range 2.4-6.1 µg/kg). In clinical follow-up, fT(4) SSCs may be more valuable as individual target values than TSH SSCs.

Maternal thyroid hormone parameters during early pregnancy and birth weight: the Generation R Study.

CONTEXT: Maternal hyperthyroidism during pregnancy is associated with an increased risk of low birth weight, predisposing to neonatal morbidity and mortality. However, the effects of variation in maternal serum thyroid parameters within the normal range on birth weight are largely unknown. OBJECTIVE: The aim was to study the effects of early pregnancy maternal serum thyroid parameters within the normal range on birth weight, as well as the relation between umbilical cord thyroid parameters and birth weight. DESIGN, SETTING, AND PARTICIPANTS: In early pregnancy, serum TSH, FT4 (free T(4)), and thyroid peroxidase antibody levels were determined in 4464 pregnant women. Cord serum TSH and FT4 levels were determined in 2724 newborns. Small size for gestational age at birth (SGA) was defined as a gestational age-adjusted birth weight below the 2.5th percentile. The associations between normal-range maternal and cord thyroid parameters, birth weight, and SGA were studied using regression analyses. RESULTS: In mothers with normal-range FT4 and TSH levels, higher maternal FT4 levels were associated with lower birth weight [ß = -15.4 (3.6) g/pmol · liter, mean (SE); P = 1.6 × 10(-5)], as well as with an increased risk of SGA newborns [odds ratio (95% confidence interval) = 1.09 (1.01-1.17); P = 0.03]. Birth weight was positively associated with both cord TSH [ß = 4.1 (1.4) g/mU · liter; P = 0.007] and FT4 levels [ß = 23.0 (3.2) g/pmol · liter; P = 9.2 × 10(-13)]. CONCLUSIONS: We show that maternal high-normal FT4 levels in early pregnancy are associated with lower birth weight and an increased risk of SGA newborns. Additionally, birth weight is positively associated with cord TSH and FT4 levels. These data demonstrate that even mild variation in thyroid function within the normal range can have important fetal consequences.

Low urinary iodine excretion during early pregnancy is associated with alterations in executive functioning in children.

The rare but deleterious effects of severe iodine deficiency during pregnancy on cognitive functioning of children are well known. Reports on possible associations between mild-to-moderate maternal iodine deficiency and child development, however, are scarce. In a population-based cohort we examined the association between maternal urinary iodine during early pregnancy and executive functioning in children at 4 y of age. In addition, we investigated the modification of this association by maternal diet and thyroid function. During pregnancy, we measured urinary iodine and thyroid hormone concentrations in 1156 women. In 692 of their children impairment of executive functioning was assessed by the Behavior Rating Inventory of Executive Function. Five hundred mothers of Dutch national origin completed an FFQ. Analyses were performed by using regression models. The children of mothers with low urinary iodine showed higher scores on the problem scales of inhibition [ß = 0.05 (95% CI: 0.01, 0.10), P = 0.03] and working memory [ß = 0.07 (95% CI: 0.02, 0.12), P = 0.003]. Although maternal dietary intake and thyroid hormone concentration did not significantly modify these associations, the associations between urinary iodine and problems of inhibition were attenuated after adjustment for maternal psychological symptoms. In addition, the consumption of bread [ß = 0.61 (95% CI: 0.27, 0.95), P < 0.001] and eggs (ß = 1.87 (95% CI: 0.13, 3.62), P = 0.04] was associated with higher urinary iodine. Thus, low maternal urinary iodine during pregnancy is associated with impaired executive functioning in children. Because these symptoms were subclinical and occurred at an early age, future studies are needed to show whether these children are more vulnerable to develop later clinical disorders.

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 autoimmunity during pregnancy and the risk of attention deficit/hyperactivity problems in children: the Generation R Study.

BACKGROUND: Maternal thyroid status and autoimmunity during pregnancy have been associated with impaired development of the offspring in animal and human studies. Our objective was to examine whether elevated titers of maternal thyroid peroxidase antibodies (TPOAbs) in early pregnancy increased the risk of cognitive impairment and problem behavior in preschool children. Second, we aimed at exploring to what extent any effect on child behavior was mediated by maternal thyroid parameters during pregnancy. METHODS: In the Generation R Study, a population-based cohort of 3139 children and their mothers, we measured maternal thyroid parameters (thyrotropin [TSH], free Thyroxine, and TPOAbs) at 13.5±1.8 weeks of gestation. Children's verbal and nonverbal cognitive functioning was measured at 2.5 years using the Language Development Survey and the Parent Report of Children Abilities. At 3 years, children's behavior was assessed using the Child Behavior Checklist. RESULTS: Elevated titers of TPOAbs during pregnancy did not predict the verbal and nonverbal cognitive functioning of the children. However, elevated titers of TPOAbs in mothers were associated with externalizing problems in children (odds ratio [OR]=1.64, 95% confidence interval [CI]: 1.17-2.29, p=0.004). In particular, children of TPOAb-positive mothers were at a higher risk of attention deficit/hyperactivity problems (OR=1.77, 95% CI: 1.15-2.72, p=0.01). To explore whether the effect of maternal TPOAbs on child problem behavior was mediated by maternal thyroid parameters, we added maternal TSH to the model. After correcting for TSH, the effect of TPOAbs on externalizing problems was attenuated slightly but remained significant (OR=1.56, 95% CI: 1.14, 2.14, p=0.005). CONCLUSIONS: Our findings imply that the elevated titers of TPOAbs during pregnancy impact children's risk of problem behavior, in particular, attention deficit/hyperactivity. The observed effect is only partially explained by maternal TSH levels. These findings may point to a specific mechanism of Attention Deficit/Hyperactivity Disorder in children. Nevertheless, we can only speculate about public health implication of the study, as there is no specific treatment for TPOAb-positive pregnant women with normal thyroid function. Further investigation is needed to explore whether TPOAb-positive pregnant women and their children can benefit from close monitoring and early detection of developmental delay in populations at risk.