Deborah Sloboda

Prenatal exposure to glucocorticoids is associated with alterations in fetal growth and endocrine function. However, few studies have examined the effects of clinically relevant doses of glucocorticoids on postnatal hypothalamic-pituitary-adrenal (HPA) function. To determine the effects of maternal or fetal betamethasone administration (0.5 mg/kg maternal or estimated fetal weight) on postnatal HPA function at 6 months and 1 year postnatal age, pregnant ewes were randomized into the following treatment groups: no treatment (n=6); maternal saline (n=6); single maternal betamethasone (M1) (n=6); repeated maternal betamethasone (M4) (n=6); fetal saline (n=5); single fetal betamethasone (n=6) and repeated fetal betamethasone (F4) (n=6). Single injections were given at 104 days of gestation and repeated injections at 104, 111, 118 and 125 days. Lambs were born spontaneously and the ACTH and cortisol responses to i.v. corticotropin-releasing hormone (CRH) (0.5 microg/kg) plus arginine vas...

Prenatal glucocorticoid exposure has been associated with a reduction in birth weight and postnatal alterations in glucose homeostasis and hypothalamic-pituitary-adrenal (HPA) axis function. The mechanisms underlying these responses are unknown, although changes in fetal hepatic development may play an important role. The fetal liver produces key regulators of fuel metabolism and of the developing HPA axis that are altered by glucocorticoids. The local availability of glucocorticoids is regulated, in part, by corticosteroid-binding protein (CBG), glucocorticoid receptors (GR) and by the enzyme 11beta-hydroxysteroid dehydrogenase (11betaHSD), but the effects of maternal glucocorticoid administration on the expression of these genes in the fetal liver are unknown. 11betaHSD1 is the predominant form of this enzyme present in the liver and is responsible for the conversion of cortisone to cortisol. To determine if prenatal glucocorticoid exposure alters fetal hepatic regulation of CBG, ...

Background / Purpose: Maternal obesity results in obese offspring with metabolic and reproductive dysfunction. Taurine ameliorates adverse metabolic outcomes in offspring of protein-malnourished mothers and improves insulin sensitivity in diet-induced obesity. We hypothesised that supplementing a maternal obesogenic diet with taurine will reverse metabolic compromise in male offspring. Main conclusion: Taurine supplementation reduced maternal weight gain in late pregnancy and prevented elevations in TNF-alpha, glutamate and leptin but not HcY or insulin in obese dams. Taurine modified metabolic dysfunction in the offspring of obese mothers in the presence of a postnatal obesogenic diet.

Diagnosing polycystic ovary syndrome (PCOS) in adolescence is clinically challenging. The prevalence of clinical, ultrasound and biochemical features of PCOS in a community-based adolescent population using current diagnostic criteria has not previously been described. This was a prospective cohort study with 244 unselected post-menarchal girls, mean age 15.2 years, of whom 91% were Caucasian. Subjects were recruited from a large population-based birth cohort (the Raine cohort). Clinical hyperandrogenism (HA) was quantified using Ferriman-Gallwey scores. In the early follicular phase (Day 2-6), we measured circulating androgens and sex hormone-binding globulin by immunoassay, and ovarian morphology was assessed by transabdominal ultrasound examination. BMI and waist-hip ratio were measured. Normal ranges for early follicular phase androgens in adolescence were derived for this population. The top 5 and 10% of circulating free testosterone levels were 45.6 and 34.5 pmol/l, respective...

Excessive fructose consumption is associated with insulin resistance (IR) and nonalcoholic fatty liver disease (NAFLD), and high fructose intake during pregnancy can lead to compromised fetal development in the rat. Evidence suggests that the amino acid taurine can ameliorate fructose-induced IR and NAFLD in nonpregnant animals. This study investigated the efficacy of taurine supplementation on maternal fructose-induced metabolic dysfunction and neonatal health. Time-mated Wistar rats were randomized to four groups during pregnancy and lactation: (a) control diet (CON), (b) CON supplemented with 1.5% taurine in drinking water (CT), (c) CON supplemented with fructose solution (F) and (d) F supplemented with taurine (FT). Maternal and neonatal weights, plasma cytokines and hepatic gene expression were analyzed. Maternal hyperinsulinemia, increased homeostasis model assessment of IR indices and elevated proinflammatory cytokines were observed in F group and normalized in FT group. Mate...

The effects of endogenous cortisol on binucleate cells (BNCs), which promote fetal growth, may be mediated by glucocorticoid receptors (GRs), and exposure to dexamethasone (DEX) in early pregnancy stages of placental development might modify this response. In this article, we have investigated the expression of GR as a determinant of these responses. Pregnant ewes carrying singleton fetuses (n = 119) were randomized to control (2 mL saline/ewe) or DEX-treated groups (intramuscular injections of 0.14 mg/kg ewe weight per 12 hours) at 40 to 41 days of gestation (dG). Placental tissue was collected at 50, 100, 125, and 140 dG. Total glucocorticoid receptor protein (GRt) was increased significantly by DEX at 50 and 125 dG in females only, but decreased in males at 125 dG as compared to controls. Glucocorticoid receptor α (GRα) protein was not changed after DEX treatment. Three BNC phenotypes were detected regarding GRα expression (++, +-, --), DEX increased the proportion of (++) and de...

Our aim was to determine the postnatal effects of single and repeated glucocorticoid injections during late gestation. Repeated (104, 111, 118, 125 days) or single (104 days) injections of betamethasone or saline were given to the ewe or by ultrasound guided injection to the fetus (term 150 days). Lambs were born spontaneously and studied at 3 and 6 mo and 1 yr of age. Arterial pressure was measured at each age, and we performed intravenous glucose tolerance tests at 6 mo and 1 yr. Repeated maternal, but not single maternal or fetal, betamethasone injections prolonged gestation, reduced weight at birth and 3 mo, and was associated with low arterial pressure at 3 mo but not at 6 mo and 1 yr. Glucose metabolism was altered in all betamethasone treatment groups, regardless of the number or route of injections. Our data demonstrate that glucocorticoid-induced fetal growth restriction is associated with a transient reduction in postnatal arterial pressure, but glucocorticoid exposure wit...

Prenatal exposure to testosterone has been shown to affect fetal brain maturation as well as postnatal cognition and behavior in animal studies. Although there are well-established sex-differences in the use of social communication (or 'pragmatic language') in humans, there has been limited investigation of the association between fetal testosterone exposure and postnatal pragmatic language ability. In this prospective study, pragmatic language skills, assessed using a pragmatic language score (PLS), were measured in 78 girls aged 10 years and correlated with testosterone levels in umbilical cord blood. A measure of the biologically active, 'free' fraction of testosterone, the free androgen index (FAI), was positively correlated with the PLS (R=.3). Regression analyses showed that the FAI was a significant, positive predictor of pragmatic language difficulties in girls after controlling for maternal and infant-health variables (B=0.02, 95% confidence interval=0.01-0.04, p=0.02). This is the first prospective study to identify an association between early life testosterone exposure and pragmatic language difficulties in girls. These novel findings are discussed with reference to the 'extreme male-brain' theory of autism.

Antenatal corticosteroids are used to augment fetal lung maturity in human pregnancy. Dexamethasone (DEX) is also used to treat congenital adrenal hyperplasia of the fetus in early pregnancy. We previously reported effects of synthetic corticosteroids given to sheep in early or late gestation on pregnancy length and fetal cortisol levels and glucocorticoids alter plasma insulin-like growth factor (IGF) and insulin-like growth factor binding protein (IGFBP) concentrations in late pregnancy and reduce fetal weight. The effects of administering DEX in early pregnancy on fetal organ weights and betamethasone (BET) given in late gestation on weights of fetal brain regions or organ development have not been reported. We hypothesized that BET or DEX administration at either stage of pregnancy would have deleterious effects on fetal development and associated hormones. In early pregnancy, DEX was administered as four injections at 12-hourly intervals over 48 h commencing at 40-42 days of gestation (dG). There was no consistent effect on fetal weight, or individual fetal organ weights, except in females at 7 months postnatal age. When BET was administered at 104, 111 and 118 dG, the previously reported reduction in total fetal weight was associated with significant reductions in weights of fetal brain, cerebellum, heart, kidney and liver. Fetal plasma insulin, leptin and triiodothyronine were also reduced at different times in fetal and postnatal life. We conclude that at the amounts given, the sheep fetus is sensitive to maternal administration of synthetic glucocorticoid in late gestation, with effects on growth and metabolic hormones that may persist into postnatal life.

The objective of this study was to determine the influence of birth weight and postnatal weight gain on age at menarche. This was a prospective cohort study where girls from the West Australian Pregnancy (Raine) Cohort Study were followed prospectively from fetal life (18 wk of pregnancy) to adolescence (12-14 yr). Age at menarche was the main outcome measure. Growth status at birth was judged by expected birth weight ratio (EBW; a ratio of observed infant's birth weight over median birth weight appropriate for maternal age, weight, height, parity, infant sex, and gestational age). Postnatal growth status was judged by body mass index (BMI). Both EBW (P = 0.020) and BMI in childhood (8 yr of age) (P < 0.001) were associated with age at menarche. Menarche occurred earlier in girls with lower EBW and higher BMI. We have demonstrated for the first time that both birth weight and weight gain in childhood are associated with age at menarche. Weight gain before birth and subsequent weight gain up to the age of 8 yr were found to have opposing influences on the timing of menarche. Lower EBW combined with higher BMI during childhood predicted early age at menarche, and this relationship existed across normal birth weight and BMI ranges.

Adequate uterine volume and ovarian reserve are essential for reproductive health. Antenatal events such as restricted fetal growth and maternal tobacco smoking are hypothesized to impact on reproductive function in later life, although not studied in a large prospective normal pregnancy population to date. The objective of the study was to determine the relationship between intrauterine growth, birth weight, and maternal tobacco smoking on uterine volume and ovarian reserve in adolescence. This was a prospective study in which half the cohort underwent intensive ultrasound monitoring in utero. Intrauterine growth was measured using ultrasound at 18, 24, 28, and 34/36 wk gestation (n = 115 girls). Maternal smoking data were prospectively collected at 18 and 34/36 wk from the whole cohort. Uterine (n = 229) and early follicular ovarian volume and antral follicle count (n = 225) were measured using transabdominal ultrasound (n = 230). Ovarian reserve was estimated using early follicular phase anti-Mullerian hormone, inhibin B, and FSH (n = 213). The relationship between maternal tobacco smoking, intrauterine growth trajectories, and markers of ovarian reserve and uterine size in adolescence was measured. Linear regression showed that daughters of mothers who smoked had a significantly smaller uterus compared with nonsmokers (P = 0.019). No significant relationship between maternal tobacco smoking and ovarian volume (P = 0.164) or markers of ovarian reserve (antral follicle count, plasma FSH, anti-Mullerian hormone, and inhibin B) in adolescence was determined. Our findings indicate that maternal smoking, but not variations in fetal growth, may lead to a reduction in uterine volume and does not appear to impact ovarian reserve.

The prenatal antecedents of polycystic ovary syndrome (PCOS) are not known, but prenatal androgen exposure is thought to contribute. This has not previously been investigated in large prospective studies of normal human pregnancy. The aim of the study was to establish the prospective relationship between early life androgen exposure and PCOS in adolescence. A prospective cohort study was conducted in the general community. A total of 2900 pregnant women were recruited at 18 wk gestation. Prenatal androgen exposure was measured from maternal blood samples (at 18 and 34-36 wk) and umbilical cord blood. Timed (d 2-5 menstrual cycle) blood samples were collected, clinical hyperandrogenism was assessed, and transabdominal ultrasound examination of ovarian morphology was performed in 244 unselected girls from the Raine cohort aged 14-17 yr. We examined the relationship between early life androgen exposure and PCOS in adolescence. We did not observe a statistically significant relationship between early life androgen exposure and PCOS in adolescence. This is the first prospective study to evaluate the relationship between prenatal androgen exposure and PCOS in adolescence in normal pregnancy. Our findings do not support the hypothesis that maternal androgens, within the normal range for pregnancy, directly program PCOS in the offspring.

We investigated the relationship between autistic-like traits in early childhood and age at menarche in typically developing girls. Autistic-like symptoms were measured at age 2 years using the Child Behaviour Checklist, and age at menarche (AAM) was determined prospectively using self-report questionnaires at age 8, 10, 14 and 17 years. Girls with 'high' autistic-like symptoms at age 2 years demonstrated significantly later AAM (n = 70; M = 13.07 years; SD = 1 year) than girls reported to show 'typical' (n = 216; M = 12.72 years; SD = 1.1) or 'low' (n = 47; M = 12.66 years; SD = 1.13 years) levels of these behaviors. These data further establish a link between the autism phenotype and later AAM and may provide insights into the etiology of the condition.