Neus Potau

Reduced Uterine and Ovarian Size in Adolescent Girls Born Small for Gestational Age

Reduced fetal growth is known to be associated with a reduced ovarian fraction of primordial follicles, with ovarian hyperandrogenism and anovulation in late adolescence. In this study, we examined whether adolescent girls born small for gestational age also present an abnormality in uterine or ovarian size. Standardized ultrasound measurements of the internal genitalia were performed in 36 healthy post-menarcheal girls (mean age 14 y) born with a size that was either appropriate for gestational age (AGA) or small (SGA), birth weight averaging 0.1 and −3.0 SD, respectively; clinical and endocrine characteristics were documented concomitantly. Compared with AGA girls, the SGA girls had a smaller uterus (mean difference of 20%;p < 0.006) and a reduced ovarian volume (mean difference of 38%;p < 0.0002). In conclusion, the gynecological correlates of prenatal growth restriction are herewith extended to include a reduced size of the uterus and the ovaries.

Polycystic ovary syndrome after precocious pubarche: ontogeny of the low-birthweight effect

OBJECTIVE Young girls with precocious pubarche (PP) are at increased risk of developing polycystic ovary syndrome (PCOS), including hyperinsulinism, dyslipidaemia and ovarian hyperandrogenism, particularly if PP itself was preceded by a low birthweight. Resistance to insulin is thought to be a key factor in the pathogenesis of this sequence. We aimed to elucidate the peripubertal ontogeny of the low birthweight effect on hyperinsulinism, dyslipidaemia and ovarian dysfunction after PP.

Premature pubarche, ovarian hyperandrogenism, hyperinsulinism and the polycystic ovary syndrome: From a complex constellation to a simple sequence of prenatal onset

Adolescent girls with a history of premature pubarche have an increased incidence of functional ovarian hyperandrogenism [a form of polycystic ovary syndrome (PCOS)] at adolescence, which is usually associated with hyperinsulinemia and dyslipemia. The hyperinsulinemia and lipid disturbances can often be detected in the prepubertal period and throughout puberty, and are associated with an exaggerated ovarian androgen synthesis. Birthweight SD scores are lower in premature pubarche girls than in control girls, and particularly so in those girls who show hyperinsulinemia and subsequently develop ovarian hyperandrogenism. Therefore, although the mechanisms interlinking the triad of premature pubarche, hyperinsulinism and ovarian hyperandrogenism remain enigmatic, these data indicate that the triad may result, at least in part, from a common early origin, rather than from a direct interrelationship later in life.

Girls diagnosed with premature pubarche show an exaggerated ovarian androgen synthesis from the early stages of puberty: evidence from gonadotropin-releasing hormone agonist testing☆☆☆

OBJECTIVE To assess the gonadotropin and ovarian steroid responses to the GnRH agonist (GnRH-a) leuprolide acetate (LA) in premature pubarche girls and in Tanner stage- and bone age-matched controls to ascertain whether the ovarian 17-hydroxyprogesterone (17-OHP) hyper-response to GnRH-a challenge present in some subsets of adolescent premature pubarche girls is detectable during puberty and whether these patients have a distinct pattern of pituitary-ovarian maturation. DESIGN Cross-sectional study. SETTING A university teaching hospital. PATIENT(S) Seventy-six premature pubarche girls (early pubertal [B2; n = 31], midpubertal [B3; n = 15], late pubertal [B4; n = 12], and postmenarcheal [B5; n = 18]) and 45 controls. INTERVENTION(S) Gonadotropins and plasma steroid hormones (17-OHP, 17-OH-pregnenolone [17-Preg], androstenedione [A], T, DHEA, DHEAS, E2, and cortisol) were measured before and 3 and 24 hours, respectively, after LA challenge (500 micrograms SC). MAIN OUTCOME MEASURE(S) Ovarian-steroidogenic responses to GnRH-a challenge. RESULT(S) Luteinizing hormone responsiveness increased significantly during puberty in all subjects whereas FSH levels changed less consistently. Peak E2 levels differed among pubertal stages and were significantly higher in premature pubarche girls than in controls at B4 and at B5. Both peak and incremental increases of 17-Preg and DHEA throughout puberty and of 17-OHP and A at B4 were significantly higher in premature pubarche girls than in controls. This pattern of ovarian-steroidogenic response was most evident during midpuberty and late puberty and resembled the adrenal hyper-response to ACTH of exaggerated adrenarche, suggestive of increased ovarian activity of both the 17 alpha-hydroxylase and the 17,20 lyase functions of cytochrome P450c17 alpha. CONCLUSION(S) Pubertal girls with a history of premature pubarche show a distinct pattern of ovarian maturation characterized by an exaggerated ovarian androgen synthesis throughout puberty.

Pubertal Changes in Insulin Secretion and Peripheral Insulin Sensitivity

Using a simple and standardized method we estimated both insulin secretion and insulin sensitivity in peripheral tissues in relation to Tanner pubertal stages. Early insulin response, mean blood glucose (MBG), mean serum insulin (MSI), glucose uptake rate in peripheral tissues and insulin sensitivity index (SI) in response to the standard oral glucose tolerance test were evaluated in 73 normal girls. Study subjects were divided into 4 groups: group 1 (Tanner stage I, n = 20); group 2 (Tanner stage II, n = 14); group 3 (Tanner stages III and IV, n = 15), and group 4 (Tanner stage V, n = 24). Steroid levels and insulin-like growth factors were determined to characterize clinical pubertal development. MBG was similar in all groups but MSI increased at stage II and retained similar values throughout puberty, with those of group I being statistically lower than in the other groups (p < 0.001). When MSI values were adjusted per kilogram of body weight, a significant increase was observed in group II (p < 0.05). The MSI adjusted values were: group 1, 1.0 +/- 0.4; group 2, 1.4 +/- 0.4; group 3, 1.0 +/- 0.3, and group 4, 1.0 +/- 0.4 mU/l/kg. SI values were similar in groups 1 and 2 and significantly lower than in groups 3 and 4 (p < 0.001). Our results confirm both that insulin secretion is related to age and that an insulin-resistant state occurs during puberty. Thus, the insulin-resistant state coincides with Tanner stage II. In conclusion, this mathematical approach is considered to be a simple and reliable method for analyzing the possible alterations in insulin secretion and action in children and adolescents in whom more sophisticated procedures must be limited in this early period of life for ethical reasons.

Leptin Values in Placental Cord Blood of Human Newborns with Normal Intrauterine Growth after 30–42 Weeks of Gestation

Objective: To evaluate leptin values in placental cord blood of newborns with normal intrauterine growth after 30–42 weeks of gestation. Design: Leptin, a protein encoded by the ob gene, plays an important role in the regulation of feeding behaviour and energy balance in rodents, primates and humans. The presence of leptin in human amniotic fluid and cord blood has recently been reported in human gestations at term and the possible role of leptin in human fetal growth suggested. However, little is known of leptin synthesis during human foetal development. Thus, the aim of our work was to measure leptin (RIA, Linco Research, Inc.) in placental cord blood of human newborns at different fetal ages. Patients: One hundred and twenty-six healthy newborns with normal intrauterine growth were studied. Twenty-nine were preterm (15 males and 14 females; gestational age: 30–36 weeks) and 99 were at term (49 males and 48 females; gestational age: 37–42 weeks). Results: Leptin values increase progressively throughout gestation from 1.30 ± 0.53 ng/ml at 30 weeks of gestation to 7.98 ± 4.96 ng/ml (mean ± SD) at term, and correlate positively with birth weight (r = 0.56, p < 0.005, n = 126), length (r = 0.37, p < 0.005, n = 126), BMI (r = 0.57, p < 0.005, n = 126), head circumference (r = 0.37, p < 0.005, n = 126), gestational age (r = 0.48, p < 0.005, n = 126) and placental weight (r = 0.38, p < 0.003, n = 59). Leptin values are statistically significantly lower (p < 0.005) preterm (median: 2.05 ng/ml; range: 0.7–8.3 ng/ml) than at term (median: 7.0 ng/ml; range: 1.1–28.1 ng/ml). Leptin values are also significantly (p < 0.005) higher in females (median: 7.2 ng/ml; range: 0.9–23.6 ng/ml, n = 62) than in males (median: 4.8 ng/ml; range: 0.7–28.1 ng/ml, n = 64), although there are no differences in weight (2,864 ± 536 g in females vs. 2,937 ± 744 g in males). Multiple regression analysis shows weight to be a positive sex-independent predictor of serum leptin values (p < 0.0005). Sex also proves to be a predictor of leptin, independently of weight and is higher in females than in males (p < 0.003). Conclusion: Leptin is present in placental human cord blood after 30–42 weeks of gestation. Newborn weight and sex are independent predictors of leptin values.

Precocious Pubarche, Dyslipidemia, and Low IGF Binding Protein-1 in Girls: Relation to Reduced Prenatal Growth

An increasing series of pediatric endocrinopathies and metabolic anomalies has been recognized as related to reduced prenatal growth. We have tested whether the association of precocious pubarche (PP), dyslipidemia, and low serum IGF binding protein-1 in girls is also related to reduced prenatal growth. Fasting serum lipids, lipoproteins, and IGFBP-1 concentrations were measured in 187 girls (83 without PP and 104 with PP; mean age, 11.8 y; range, 5-18 y) with known birthweight and gestational age, the latter being transformed into birthweight SD scores. Birthweight SD scores of girls with PP were lower than those of girls without PP. Within the group of PP girls, those with dyslipidemia and low IGFBP-1 had lower (p < 0.0001) birthweight SD scores (-2.02 ± 0.23; mean ± SEM) than those with normal lipids, lipoproteins, and IGFBP-1 (-0.37 ± 0.15), whereas girls with an intermediate number of abnormalities had intermediate birthweight SD scores (-0.80 ± 0.18). In conclusion, dyslipidemia and low serum IGFBP-1 in girls with PP were found to be related to reduced prenatal growth, an observation pointing to the prenatal origin of these metabolic abnormalities.

A lesser postprandial suppression of plasma ghrelin in Prader-Willi syndrome is associated with low fasting and a blunted postprandial PYY response.

Objective  Ghrelin and polipeptide YY (PYY) are involved in the regulation of food intake. We evaluated these two peptides and their possible relationship in adult patients with Prader–Willi syndrome (PWS).

Increased bone mineral density and serum leptin in non-obese girls with precocious pubarche: relation to low birthweight and hyperinsulinism.

Background: Hyperinsulinism and hyperandrogenism have the capacity to increase bone mineral density (BMD) and serum leptin, independently of body fat mass. We therefore assessed lumbar BMD and serum leptin in girls with the sequence of a low birthweight and precocious pubarche (PP) in childhood, in whom hyperinsulinism and hyperandrogenism have been described. Methods: Fifty-two non-obese PP girls were studied (age range 6.9–14.9 years). Serum leptin was also measured in 42 control girls, matched for age, body mass index and pubertal stage. Results: BMD SDS, measured by dual-energy X-ray absorptiometry, was elevated in PP girls compared to the population reference (0.39 ± 0.18 SDS; p = 0.03) and bone age, assessed from hand radiographs, was significantly advanced compared to chronological age (1.2 ± 0.1 years; p < 0.0005). Conclusion: Compared to control girls, PP girls had higher leptin levels for degree of body mass index (PP girls: 9.4 ± 0.6 ng/ml; controls: 7.8 ± 0.6 ng/ml; p = 0.01). In PP girls, serum leptin was inversely related to birthweight (r = –0.32, p = 0.01) and positively related to free androgen index (FAI) (r = 0.71, p < 0.0005). BMD SDS was also inversely related to birthweight (r = –0.26, p < 0.05) and positively related to serum leptin (r = 0.42, p < 0.05), FAI (r = 0.45, p < 0.05) and mean serum insulin during oral glucose tolerance testing (MSI) (r = 0.59, p < 0.0005). In multiple regression, MSI was the strongest determinant of BMD SDS (β = 0.50, p = 0.002). In conclusion, elevated BMD and serum leptin in non-obese PP girls were related to degrees of low birthweight, hyperinsulinism and hyperandrogenism. The characteristic hyperinsulinism of PP girls is proposed to be the key variable in this constellation.

Adrenal hyperandrogenism in adolescent girls with a history of low birthweight and precocious pubarche

Girls with precocious pubarche (PP) are at increased risk for ovarian dysfunction, hyperinsulinism and dyslipidaemia in adolescence, in particular when PP is preceded by reduced fetal growth. However, it is not known whether PP girls still have adrenal hyperandrogenism after puberty and if so, which fraction of PP girls develops so‐called functional adrenal hyperandrogenism (FAH), an entity characterized by ACTH‐dependent 17‐ketosteroid excess.