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Background: Adaptive 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., Objective: The 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., Design: In a cohort of 132 pregnant women, serial blood samples were obtained and ultrasound scans were performed throughout pregnancy., Methods: Serum levels of TSH, free and total thyroxine (T(4)), free and total triiodothyronine (T(3)) as well as autoantibodies against thyroid peroxidase and thyroglobulin were measured in 979 serum samples., Results: Intra-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 T(4) (FT(4)) (b=0.003; P=0.031) and pre-pregnancy body mass index with T(3) and free T(3) (b=0.017; <0.001 and b=0.007; P<0.001). Smoking was positively associated with T(4) and FT(4), but it was modulated by gestational age. Gestation-specific reference intervals for thyroid function variables from autoantibody-negative participants are presented., Conclusions: In 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.

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.

The exposure levels of placenta and paired breast milk samples to selected organochlorine compounds and pesticides from Danish and Finnish samples have been investigated. p,p'-DDE is the dominant pollutant, beta-HCH, hexachlorobenzene, endosulfan-I, dieldrin, oxychlordane, cis-heptachlor epoxide and p,p'-DDT being the other major constituents. Their concentrations are linearly correlated between milk and placenta in similar patterns for Danish and Finnish samples. Milk samples have higher levels of these pollutants than placenta on lipid base. However, the apparently not correlated compounds, such as alpha-HCH, pentachlorobenzene, pentachloroanisole and methoxychlor, are generally accumulated more in placenta, which may suggest a tissue specific metabolic activity. Thus, depending on the compound of interest, biomonitoring may be done in placenta only or in both matrices.

Context: Concern has been raised about the safety of assisted reproduction techniques for the offspring., Objectives: The objective of the study was to investigate postnatal growth and growth factors in children born after intra-cytoplasmatic sperm injection (ICSI) and in vitro fertilization (IVF)., Design: The study had two cohorts: a population-based longitudinal infant cohort 0-36 months [236 ICSI, 173 IVF, 1530 naturally conceived (NC)], and a cross-sectional child cohort at 5 yr (68 ICSI, 67 IVF, 70 NC)., Intervention: Anthropometrical measurements were made at birth, 3, 18, 36 (infant cohort), and 60 months (child cohort), and blood samples were collected at 3 or 60 months., Main Outcome Measures: Serum IGF-I, IGFBP-3, height, weight, head and abdominal circumference, body mass index, and fat folds were the main outcome measures., Results: Anthropometrical measurements showed no significant differences between ICSI and IVF children and controls in either cohort. However, singleton ICSI girls [3.4 (0.6) kg, P = 0.008] had a slightly lower birth weight than IVF [3.5 (0.5) kg] and NC girls [3.5 (0.5) kg]. Birth weights of singleton boys [3.6 (0.5) kg], twin boys [2.6 (0.6) kg], and twin girls [2.4 (0.5) kg] did not differ between types of conception. In the infant cohort in 3-month-old singletons, serum IGF-I was lower in ICSI [78 (26) ng/ml] than NC boys [94 (27) ng/ml, P < 0.001] and IVF [74 (34) ng/ml], compared with NC girls [93 (43) ng/ml, P = 0.011]. ICSI children were also smaller than their target height (sd score) at 3 yr of age [mean -0.91 (1.2)], compared with NC children [-0.61 (0.9), P = 0.033]. In the child cohort, target height attainment (sd score) and growth factors did not differ among the three groups., Conclusions: The overall growth pattern of ICSI and IVF children in both cohorts was normal. Our findings of subtle differences in target height attainment and serum IGF-I levels between infants born after assisted reproduction techniques and controls may not be clinically significant. However, these observations indicate that further systematic follow-up of growth and puberty in these children is needed.

Context: Recent studies showed that male reproductive health problems, such as cryptorchidism, hypospadias, testicular cancer, and low sperm quality, are more prevalent in Denmark than in Finland., Objectives: We hypothesized that, if fetal testicular dysgenesis contributed to these observations, differences in gonadal development and the hypothalamus-pituitary-testis axis would already be detectable perinatally. Thus, we investigated healthy newborn boys in both countries., Design: This was a prospective, longitudinal population-based study., Setting: Two primary obstetric centers were included at the University Hospitals of Copenhagen, Denmark, and Turku, Finland., Participants: The participants of the study included 633 Danish and 1044 Finnish boys, born at term with appropriate weight for gestational age., Interventions: Ultrasound determination of testis size at 0, 3, and 18 months and blood sampling (n = 727) at 3 months were analyzed., Main Outcome Measures: Testicular volume and reproductive hormones were measured., Results: Testis volume was significantly higher at all ages in Finnish than in Danish boys (medians, 98 vs. 95, 185 vs. 119, and 188 vs. 136 mm(3), respectively; P < 0.00001). Testis growth from birth to 3 months was larger in Finnish than in Danish boys (mean, 75 vs. 26 mm(3); P < 0.0001). Serum hormone levels were higher in Finnish than Danish boys for inhibin B (median, 456 vs. 385 pg/ml; P < 0.0001), FSH (1.33 vs. 1.21 IU/liter; P < 0.036), and SHBG (143 vs. 136 nmol/liter; P < 0.022). Inhibin B was significantly positively correlated to testicular volume (r = 0.25; P < 0.006)., Conclusions: The larger testes and higher inhibin B levels most likely represent a bigger volume of seminiferous tubules in Finnish compared with Danish boys. Although this phenomenon may be attributable to a genetic difference between the two countries, it may also reflect environmental factors influencing testicular development.

Context: Hormonal dysregulation has been suggested to be one of many etiological factors of cryptorchidism., Objectives: The objective of this study was to assess the hypothalamic-pituitary-testicular axis in cryptorchid boys during the postnatal hormonal surge., Design: This was a prospective, longitudinal, population-based study., Setting: The study was performed at two primary obstetric centers., Participants: Study participants included 388 Finnish and 433 Danish boys (88 and 34 with cryptorchidism, respectively)., Interventions: Clinical examinations were performed at 0 and 3 months. Blood samples were taken at 3 months., Main Outcome Measures: The main outcome measures were testis position and reproductive hormone levels., Results: Finnish cryptorchid boys had significantly higher FSH [1.59 (0.50-3.53) vs. 1.30 (0.49-2.92) IU/liter; P < 0.0001] and lower inhibin B [426 (254-770) vs. 459 (266-742) pg/ml; P < 0.015] levels than Finnish control boys [median (2.5th-97.5th percentiles)]. Danish cryptorchid boys had higher FSH levels than controls [1.47 (0.54-3.89) vs. 1.18 (0.41-3.04) IU/liter; P = 0.018]. Inhibin B levels in healthy Danish boys were lower than those in Finnish boys [380 (233-637) pg/ml; P < 0.0001] and were not reduced in Danish crypt-orchid boys [392 (236-672) pg/ml; P = 0.851]. Changes in hormone levels were strongest in boys with severe, persistent cryptorchidism, but were also detectable in mild and transient cryptorchidism. Effects on Leydig cell function were subtle, with an increase in LH in Finnish (but not Danish) cryptorchid boys vs. controls [1.97 (0.77-5.91) vs. 1.75 (0.58-4.04) IU/liter; P < 0.021], but testosterone levels remained within the normal range., Conclusions: Our results support the hypothesis that cryptorchidism is associated with a primary testicular disorder, which could be a cause or a consequence of cryptorchidism. This malfunction is reflected by low inhibin B production in the Finnish cohort and high gonadotropin drive in both the Finnish and Danish cohorts.

Unlabelled: Phthalates adversely affect the male reproductive system in animals. We investigated whether phthalate monoester contamination of human breast milk had any influence on the postnatal surge of reproductive hormones in newborn boys as a sign of testicular dysgenesis., Design: We obtained biologic samples from a prospective Danish-Finnish cohort study on cryptorchidism from 1997 to 2001. We analyzed individual breast milk samples collected as additive aliquots 1-3 months postnatally (n = 130; 62 cryptorchid/68 healthy boys) for phthalate monoesters [mono-methyl phthalate (mMP), mono-ethyl phthalate (mEP), mono-n-butyl phthalate (mBP), mono-benzyl phthalate (mBzP), mono-2-ethylhexyl phthalate (mEHP), mono-isononyl phthalate (miNP)]. We analyzed serum samples (obtained in 74% of all boys) for gonadotropins, sex-hormone binding globulin (SHBG), testosterone, and inhibin B., Results: All phthalate monoesters were found in breast milk with large variations [medians (minimum-maximum)]: mMP 0.10 (< 0.01-5.53 microg/L), mEP 0.95 (0.07-41.4 microg/L), mBP 9.6 (0.6-10,900 microg/L), mBzP 1.2 (0.2-26 microg/L), mEHP 11 (1.5-1,410 microg/L), miNP 95 (27-469 microg/L). Finnish breast milk had higher concentrations of mBP, mBzP, mEHP, and Danish breast milk had higher values for miNP (p = 0.0001-0.056). No association was found between phthalate monoester levels and cryptorchidism. However, mEP and mBP showed positive correlations with SHBG (r = 0.323, p = 0.002 and r = 0.272, p = 0.01, respectively); mMP, mEP, and mBP with LH:free testosterone ratio (r = 0.21-0.323, p = 0.002-0.044) and miNP with luteinizing hormone (r = 0.243, p = 0.019). mBP was negatively correlated with free testosterone (r = -0.22, p = 0.033). Other phthalate monoesters showed similar but nonsignificant tendencies., Conclusions: Our data on reproductive hormone profiles and phthalate exposures in newborn boys are in accordance with rodent data and suggest that human Leydig cell development and function may also be vulnerable to perinatal exposure to some phthalates. Our findings are also in line with other recent human data showing incomplete virilization in infant boys exposed to phthalates prenatally.

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.

Background: Low birth weight is an important risk factor for hypertension and unfavorable prognoses of a number of renal diseases. It is also associated with reduced kidney size and nephron number. A differentiation between the effects of low birth weight versus being born premature or small for gestational age has, however, not been addressed., Methods: The influence of weight for gestational age (percentage deviation from expected mean), gestational age, birth weight, and early diet on kidney growth was studied in 178 children born pre- or postmature and/or small or large for gestational age, comparing them to 717 mature children, birth weight appropriate for gestational age. Kidney size was determined by bilateral ultrasonography measuring length, width and depth, using the equation of an ellipsoid for volume calculation. The examinations were performed at 0, 3, and 18 months of age together with measurements of body weight, height, and skinfold thickness., Results: Weight for gestational age had a significant, positive effect on combined kidney volume at all three ages (0 months, P < 0.001; 3 months, P < 0.001; and 18 months, P < 0.001). A slight catch-up growth in kidney size was seen in the most growth-retarded infants (<10th percentile) between 0 and 18 months of age (mean Deltaz score(0-18 mo)=+0.22 SD) (P= 0.037). Premature children had smaller kidneys compared to mature at all ages (0 months, P= 0.001; 3 months, P= 0.007; and 18 months, P= 0.042), without any significant catch-up with age. Relative kidney volume was inversely correlated with weight for gestational age at birth (P= 0.007) but positively at 18 months (P= 0.008). Relative kidney growth 0 to 18 months was positively correlated to weight for gestational age (P= 0.013). Low birth weight was associated with impaired relative kidney growth in response to formula feeding., Conclusion: Being small for gestational age is associated with small kidneys at birth and impaired kidney growth in early childhood. The present data suggest that intrauterine growth has a regulatory influence on nephron formation and renal function in humans reaching beyond the neonatal period.

A high protein intake results in increased kidney growth and glomerular filtration rate in human adults and young rats. It is unknown whether kidney size in young infants is influenced by increased protein intake in formula-fed compared with breast-fed infants. We investigated the effect of formula versus breast feeding on kidney growth in a cohort of 631 healthy children examined at birth, and at 3 and 18 months of age. Kidney size was determined by ultrasonography and related to gender, age, body size, and feeding category (fully breast fed, partially breast fed, or fully formula fed at 3 months). Serum urea nitrogen, serum creatinine, and estimated creatinine clearance were measured at 3 months of age. Kidney growth and serum urea nitrogen were significantly increased in partially or fully formula-fed 3-month-old infants. This effect was more pronounced in boys than in girls. The changes in relative kidney size were temporary, as they did not persist at 18 months of age, when all children received a normal mixed diet. The immediate renal effects of formula feeding should be taken into consideration for recommendations concerning infant feeding. Whether there are any long-term effects of early increased protein intake on later kidney function remains to be seen.

Kidney size is an important parameter in the evaluation of children with renal disease. However, reference materials for kidney size in healthy children have been limited beyond the neonatal period. We performed a longitudinal cohort study of 717 healthy children born at term with normal birth weight. Kidney size and shape were determined by ultrasonography and related to gender, age, and body size (weight, length, body surface area, skinfold thickness) at 0, 3, and 18 months of age. Gender-differentiated reference charts were established. Boys had significantly larger kidney volumes than girls ( P<0.001) and larger relative volumes (kidney volume/weight) at 0 and 3 months ( P<0.001), but not at 18 months of age. The best single predictor of gender-differentiated kidney volume was weight. Relative kidney volume changed with increasing age and height in a two-phase pattern: an initial decrease until a height of 65-70 cm was reached followed by a stable level. In conclusion, kidney size was significantly influenced by gender, age, and body composition. Relative kidney volume decreased with increasing age and height in a two-phase pattern. These characteristic changes in kidney volume indicated that infant kidney growth might be influenced by sex steroids and growth hormone in addition to body composition.

Objective: The purpose of this study was to evaluate placental growth hormone levels in maternal circulation throughout pregnancy in normal and growth hormone-deficient women with the use of a specific assay and to determine the clearance of placental growth hormone from maternal circulation after birth., Study Design: Seventeen healthy pregnant women and 1 patient with growth hormone deficiency substituted with recombinant growth hormone during pregnancy participated in a longitudinal study from early pregnancy until birth with repetitive blood sampling and measurement of placental growth hormone levels throughout pregnancy. Furthermore, serial blood samples were drawn before, during, and after elective caesarean deliveries in 5 healthy women to calculate the half-life of placental growth hormone. Placental growth hormone was measured with the use of two monoclonal antibodies in a commercially available solid-phase iodine 125-labeled immunoradiometric assay (Biocode, Liège, Belgium)., Results: Placental growth hormone levels were detectable from as early as 8 weeks of gestation in some of the women and increased throughout gestation, with a maximum at approximately 35 to 36 weeks of gestation (13.7 ng/mL; range, 5.9-24.4 ng/mL) and large interindividual variations. Placental growth hormone levels did not correlate with birth weight or placental weight. In the patient with isolated growth hormone deficiency, placental growth hormone levels were detectable from 11 weeks of gestation (3.4 ng/mL) and increased throughout pregnancy to 13.9 ng/mL, which is similar to values that are obtained in the healthy pregnant women. Substitution therapy with recombinant human growth hormone did not suppress the increase in placental growth hormone. We found a mean half-life of placental growth hormone of 13.8 minutes (range, 11.5-15.2 minutes) in healthy pregnant women and an apparently similar half-life of placental growth hormone (15.8 minutes) in the growth hormone-deficient patient, assuming a monoexponential disappearance of placental growth hormone during the first 30 minutes after the delivery. After the initial 30 minutes, approximately 75% (range, 65%-89%) of the placental growth hormone had been cleared from the maternal circulation., Conclusion: Levels of placental growth hormone in maternal circulation increase throughout pregnancy from as early as 8 weeks of pregnancy, with maximum levels around the week 35 of gestation. The pregnancy-induced rise in placental growth hormone levels in the growth hormone-deficient patient was comparable to the rise seen during normal pregnancies and was not suppressed by the concurrent human growth hormone treatment. We speculate that maternal serum levels of placental growth hormone reflect placental function and fetal growth. However, further studies are needed to evaluate the potential clinical use of placental growth hormone determinations.

Breast tissue in newborn infants is considered to be physiologic and mainly related to exposure to maternal hormones in utero or through breast-feeding. However, controversy exists as to whether breast tissue in later infancy is under the influence of endogenous hormones. Children at 2-4 mo of age have a surge of reproductive hormones, including estradiol, which may affect the mammary gland. In a prospective cohort study of 1126 healthy, 3-mo-old infants, breast tissue size and reproductive hormones were measured. We found that palpable breast tissue (diameter >or=3 mm) is a common physiologic condition present in 78.9% of children, significantly more frequent (p < 0.001) and larger (p < 0.001) in girls than in boys. Girls had significantly higher median estradiol levels than boys (30.0 versus 21.0 pmol/L, p < 0.001). In a multiple regression model including breast tissue size given as quartiles as the dependent variable and weight for gestational age, subscapular skinfold, weight at 3 mo of age and serum estradiol as independent variables, a gender difference was shown. In girls, the estradiol level was positively (p < 0.03) correlated to breast quartile. In boys, no correlations were found. Whether the stimulation of the mammary gland in infancy represents a developmental window that is of biologic significance for breast development and pathology in adulthood remains to be defined.

Placental GH is thought to be responsible for the rise in maternal IGF-I during pregnancy and is considered to be important for fetal growth. In this prospective longitudinal study of healthy pregnant women, we investigated determinants of placental GH in maternal serum. Serum was obtained from 455 women with normal singleton pregnancies at approximately 19 and 28 wk gestation. Serum placental GH concentrations were measured by a highly specific immunoradiometric assay, and fetal size was measured by ultrasound. Data on birth weight, gender, prepregnancy body mass index (BMI), parity, and smoking habits were obtained from medical records. Serum placental GH concentrations were detectable in serum from all women as early as 14 wk gestation and increased during pregnancy in all individuals (P < 0.001). Placental GH levels at second examination were found to be higher in women carrying female fetuses [median, 9.0 ng/ml; 95% confidence interval (CI), 4.7-23.0] compared with women carrying male fetuses (median, 8.2 ng/ml; 95% CI, 3.96-19.4; P = 0.004). Similarly, the increase in placental GH between 19 and 28 wk gestation was significantly larger in female fetus bearers than in male fetus bearers (P = 0.002). Placental GH at second examination was positively correlated with gestational age (P = 0.002) and negatively correlated with prepregnancy BMI (P = 0.039). Placental GH correlated with fetal weight at approximately 28 wk gestation (P = 0.002) but did not predict birth weight at term. Our study supports the role of maternal placental GH in the regulation of fetal growth. In conclusion, we found that 1) placental GH levels correlated significantly with fetal size at 28 wk gestation; 2) GH levels were measurable in serum from all women as early as 14 wk gestation; 3) maternal prepregnancy BMI and smoking were determinants of placental GH levels, although their specific effects on the serum maternal levels of placental GH remain to be seen; and 4) women carrying female fetuses have significantly higher placental GH levels compared with women carrying male fetuses at 28 wk gestation.