Marla Chellakooty

Human breast milk contamination with phthalates and alterations of endogenous reproductive hormones in infants three months of age.

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 μg/L), mEP 0.95 (0.07–41.4 μg/L), mBP 9.6 (0.6–10,900 μg/L), mBzP 1.2 (0.2–26 μg/L), mEHP 11 (1.5–1,410 μg/L), miNP 95 (27–469 μg/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.

Difference in prevalence of congenital cryptorchidism in infants between two Nordic countries.

BACKGROUND Several investigators have shown striking differences in semen quality and testicular cancer rate between Denmark and Finland. Since maldescent of the testis is a shared risk factor for these conditions we undertook a joint prospective study for the prevalence of congenital cryptorchidism. METHODS 1068 Danish (1997-2001) and 1494 Finnish boys (1997-99) were consecutively recruited prenatally. We also established prevalence data for all newborns at Turku University Central Hospital, Finland (1997-99, n=5798). Testicular position was assessed by a standardised technique. All subtypes of congenital cryptorchidism were included, but retractile testes were considered normal. FINDINGS Prevalence of cryptorchidism at birth was 9.0% (95% CI 7.3-10.8) in Denmark and 2.4% (1.7-3.3) in Finland. At 3 months of age, prevalence rates were 1.9% (1.2-3.0) and 1.0% (0.5-1.7), respectively. Significant geographic differences were still present after adjustment for confounding factors (birthweight, gestational age, being small for gestational age, maternal age, parity, mode of delivery); odds ratio (Denmark vs Finland) was 4.4 (2.9-6.7, p<0.0001) at birth and 2.2 (1.0-4.5, p=0.039) at three months. The rate in Denmark was significantly higher than that reported 40 years ago. INTERPRETATION Our findings of increasing and much higher prevalence of congenital cryptorchidism in Denmark than in Finland contribute evidence to the pattern of high frequency of reproductive problems such as testicular cancer and impaired semen quality in Danish men. Although genetic factors could account for the geographic difference, the increase in reproductive health problems in Denmark is more likely explained by environmental factors, including endocrine disrupters and lifestyle.

Intrauterine Growth Retardation and Consequences for Endocrine and Cardiovascular Diseases in Adult Life: Does Insulin-Like Growth Factor-I Play a Role?

Low birth weight has been associated with an increased incidence of ischaemic heart disease (IHD) and type 2 diabetes. Endocrine regulation of fetal growth by growth hormone (GH) and insulin-like growth factor (IGF)-I is complex. Placental GH is detectable in maternal serum from the 8th to the 12th gestational week, and rises gradually during pregnancy where it replaces pituitary GH in the maternal circulation. The rise in placental GH may explain the pregnancy-induced rise in maternal serum IGF-I levels. In the fetal compartment, IGF-I levels increase significantly in normally growing fetuses from 18 to 40 weeks of gestation, but IGF-I levels are four to five times lower than those in the maternal circulation. Thus IGF-I levels in fetal as well as in maternal circulation are thought to regulate fetal growth. Circulating levels of IGF-I are thought to be genetically controlled and several IGF-I gene polymorphisms have been described. IGF-I gene polymorphisms are associated with birth weight in some studies but not in all. Likewise, IGF-I gene polymorphisms are associated with serum IGF-I in healthy adults in some studies, although some controversy exists. Serum IGF-I decreases with increasing age in healthy adults, and this decline could hypothetically be responsible for the increased risk of IHD with ageing. A recent nested case-control study found that adults without IHD, but with low circulating IGF-I levels and high IGF binding protein-3 levels, had a significantly increased risk of developing IHD during a 15-year follow-up period. In summary, the GH/IGF-I axis is involved in the regulation of fetal growth. Furthermore, it has been suggested that low IGF-I may increase the risk of IHD in otherwise healthy subjects. Hypothetically, intrauterine programming of the GH/IGF axis may influence postnatal growth, insulin resistance and consequently the risk of cardiovascular disease. Thus IGF-I may serve as a link between fetal growth and adult-onset disease.

Narrow intra-individual variation of maternal thyroid function in pregnancy based on a longitudinal study on 132 women

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.

Gender difference in breast tissue size in infancy: correlation with serum estradiol.

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 ≥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.