Low Birth Weight Girls Research Articles

The effect of metformin on low birth weight girls with precocious puberty: A protocol for systematic review and meta-analysis.

Background:In recent years, the role of metformin in girls with precocious puberty (PP) has been increasingly frequently studied. The objective of this present study is to assess the effect of metformin on low birth weight girls with precocious puberty (LBW-PP girls).Methods:We search the confirmed studies about circulating metformin and PP from the databases of EMBASE, PubMed, and Web of Science. Data were reported as weighted mean difference (WMD) and associated 95% confidence intervals (CIs). Analysis was performed by Review Manager 5.3 and Stata version 12.0.Results:A total of 205 cases (metformin group n = 102, untreated group n = 103) were included in this study. The meta-analysis of randomized controlled trials (RCTs) suggested that metformin had statistically significant effects on testosterone (P = .001), androstenedione (P = .022), bone mineral density (BMD; P = .151), triglycerides (P ≤ .001), body mass index Z score (BMI Z score; P ≤ .001), dehydroepiandrosterone-sulfate (DHEAS; P = .053), sex hormone-binding globulin (SHBG; P = .049), high-density lipoprotein (HDL) cholesterol (P ≤ .001), low-density lipoprotein (LDL) cholesterol (P = .021), fat mass (P ≤ .001), lean mass (P = .025), and fasting insulin (P = .002).Conclusion:This meta-analysis provided evidence of the efficacy of metformin in girls with LBW-PP girls, which proved that metformin could improve metabolism and reduce weight. Metformin had a positive effect on preventing LBW-PP girls from developing into obesity and polycystic ovarian syndrome. In addition, this meta-analysis provided important reference opinions and directions for the treatment of LBW-PP girls.

Maternal selenium deficiency during gestation is positively associated with the risks for LBW and SGA newborns in a Chinese population.

Maternal selenium (Se) deficiency is associated with some adverse pregnant outcomes. However, it remains controversial whether maternal Se deficiency during gestation enhances the risks for low-birth-weight (LBW) and small-for-gestational-age (SGA) newborns. For our cohort study, total 3133 mother-and-infant pairs were selected. Maternal serum Se concentration was detected by graphite furnace atomic absorption spectrometry. According to international references for maternal serum Se concentration, subjects were divided into Se deficiency (<45.0 μg/L), Se insufficiency (45.0-94.9 μg/L) and Se sufficiency (≥95.0 μg/L). There was a positive relation of maternal serum Se concentration in gestation and neonatal birth weight. Further analysis showed that the risks for LBW and SGA in SD group were significantly higher than that in SI and SS group, the adjusted ORs for LBW and SGA newborns were 1.87 (95%CI: 1.02, 3.45; P = 0.04) and 1.47 (95%CI: 1.07, 2.02; P = 0.02) in SI group, and 3.92 (95%CI: 2.03, 7.57; P < 0.001) and 2.77 (95%CI: 1.92, 4.02; P < 0.001) in SD group compared to SS group. In different gender subgroup, positive relations were observed between maternal Se deficiency and the risk for LBW girls, as well as the risks for both SGA girls and boys. Maternal Se deficiency in gestation was positively associated with the risk for LBW girls, as well as the risks for both SGA girls and boys.

Low Birthweight Is Associated with Higher Risk of High Blood Pressure in Chinese Girls: Results from a National Cross-Sectional Study in China.

Objective: To investigate the relationship between low birthweight (LBW) and blood pressure and to assess whether LBW leads to a higher risk of high blood pressure (HBP) by gender in Chinese students aged 6–18 years. Also, to investigate whether the association was affected by childhood obesity. Methods: Data was obtained from a baseline dataset of a national school-based program. Anthropometric parameters, including height, weight, and blood pressure, were measured, while birthweight and other characteristics were obtained from questionnaires. Stratified chi-squared tests were used to compare the prevalence of HBP between LBW and normal birthweight (NBW) groups in each age and sex category. Multivariable logistic regressions were conducted to estimate the HBP risks in each birthweight group. Results: Both systolic and diastolic blood pressure showed a U-shaped relationship with increased birthweight. Compared to NBW groups, LBW girls showed a higher HBP risk, with an odds ratio of 1.29 (95% confidence interval (CI): 1.02, 1.64, p = 0.033), regardless of their current body mass index status, while no significant association in boys was found. Conclusions: Low birthweight is associated with higher HBP risk in adolescent girls, regardless of their childhood BMI status.

Prevalence of under nutrition and associated factors among female higher secondary students in the schools of costal block panchayat in Kerala

Introduction: The health status of an adolescent determines the health status in her adulthood. Adolescent girls in the age group 15-19 years are closer to their mother hood and thus the low birth weight girls become the next generation of stunted mothers thus, perpetuating the vicious cycle of malnutrition. Objectives: 1) To determine the prevalence of under nutrition among female higher secondary students in the schools of Ambalapuzha block. 2) To determine the factors associated with under nutrition. Methods: Cross- sectional study was conducted among higher secondary female students in the schools of Ambalapuzha Block. Sample size was calculated using the formula Zα2PQ/L2 (Zα -1.96, P -33, Q -67 L -12% of P). Considering design effect (1.5) and 10% non-response, 559 adolescents were studied. Stratified and cluster sampling method was used. Information was collected using semi structured questionnaire. Weights and heights were measured and body mass index calculated and compared with Tim Cole anthropometric standards. Results: Prevalence of under nutrition was found to be 45.8%. Factors associated with undernutrition were Hindu religion, nuclear family, father manual laborer or fisher man and absence of media influence on nutrition. Father being a manual laborer or fisherman was found to be an independent predictor of under nutrition. Conclusion: Prevalence of under nutrition was found to be high among female higher secondary students in Ambalappuzha Block

The molecular and genetic aspects of adolescent girls anomalous uterine bleeding: the role of endothelial dysfunction syndrome

The objective of the study is to assess NOS3 and ESR1 gene polymorphism in adolescent girls born with low birth weight (LBW) and suffered by anomalous uterine bleeding (AUB). A total 95 adolescent girls were studied including 32 born with LBW and AUB; 36 girls with normal birth weight and AUB; and 27 healthy girls. Single allele gene polymorphism NOS3 786T > C, 894G > T, ESR1 351A > G and 397T > C was studied. The existence of polymorphous allele С gene NOS3 786Т > С (for homozygote OR = 2.03; 95% CI: 1.12–3.68; p = 0.04; for heterozygote OR = 1.68; 95% CI: 1.09–2.60; p = 0.046) and genotype Pvull-CC ESR1 (OR = 4.58; 95% CI: 0.97–21.68; p = 0.04) was detected in LBW girls with AUB. It was suggested that intrauterine programming of endothelial dysfunction syndrome could play a significant role in the development of AUB in adolescent girls born with LBW.

IS-062 Endocrine And Metabolic Consequences Of Low Weight At Birth

About 3% of human fetuses are born small for gestational age (SGA). More than 90% of those SGA infants catch-up growth and normalise their body size by the age of 2 yr. Longitudinal studies have disclosed that SGA-catch-up children tend to become hyperinsulinemic, viscerally adipose and to show an abnormal adipokine profile by 4–6 years of age, even if not obese. Between 6 and 8 years, their circulating levels of sex hormone binding globulin (SHBG) start to be low, and those of dehydroepiandrosterone-sulphate (DHEAS) start to be high; in girls, precocious pubarche (pubic hair < 8 yr) may emerge as clinical marker. A mismatch between early adipogenesis and later lipogenesis, accounting for lipotoxicity, dys-adipokinemia and insulin resistance, seems to encompass this sequence; postnatal overweight amplify these risks. Beyond the age of 8 years, such SGA children tend to experience an early onset of puberty with rapid progression, that may lead to a lower adult stature; low birthweight girls with precocious pubarche are also at increased risk for developing hyperinsulinemic androgen excess in adolescence. In these girls, insulin sensitisation with metformin started in prepuberty and maintained throughout puberty appears to decrease visceral and hepatic adiposity, and to have normalising effects on serum insulin, lipids, leptin and adipokines, on the tempo of puberty, on final stature, and on the prevalence of androgen excess in adolescence.

Accelerated early pubertal progression, ovarian morphology, and ovarian function in prospectively followed low birth weight (LBW) girls

To compare pubertal development in age-matched healthy girls born with low birth weight (LBW) or appropriate birth weight for gestational age (AGA). Girls with breast in Tanner stage II and normal body mass index were followed for 3 years with a complete physical exam, bone age, pelvic ultrasound, and measurement of gonadal hormones using a leuprolide test. Forty-one girls (AGA 25/LBW 16) were followed up for 3 years. By 3 years, they had similar bone age, adjusted height, and body composition. In LBW girls, breast Tanner stage advanced faster during the first 2 years of follow-up, which was associated with higher serum androgens. Hirsutism score, ovarian volume, and number of follicles between AGA and LBW were not different nor was age of menarche. By the third year, basal and poststimulated levels of gonadotropins and androgens anti-Müllerian hormone and inhibin B were similar in both groups and did not show differences related to birth weight or degree of catch-up growth. LBW recruits showed a slightly faster breast development but no differences in androgen excess signs, internal genitalia, and gonadal hormonal patterns.

Management of Adolescents with Polycystic Ovary Syndrome

Polycysticovarysyndrome(PCOS)isadisorderofmetabolic as well as reproductive function; common (although not universal) comorbidities include insulin resistance, hyperinsulinemia,hypoadiponectinemia,dyslipidemia,hepatic steatosis, carotid intimal medial thickening, impaired glucose tolerance, and a predisposition to type 2 diabetes and cardiovascular disease (1, 2). Studies in monozygotic and dizygotic twins (3) suggest that PCOS emerges from the interaction of genetic and environmental factors; the latter may include intrauterine as well as nutritional determinants (1). High-risk groups include low birth weight girls who develop precocious adrenarche and children with family histories of PCOS (4). Sixty percent of patients with PCOS are overweight or obese, and even “normal-weight” subjects have relative visceral adiposity and heightened production of inflammatory adipocytokines (5, 6). Obesity itself causes insulin resistance and may promote free testosterone excess and oligomenorrhea/anovulation throughup-regulationofovarian and adipose tissue 17-hydroxysteroid dehydrogenase 5 expression and down-regulation of hepatic SHBG (1, 7); thus, it is not entirely clear which, and to what extent, the clinical features of PCOS derive from excess adiposity (1, 7–9). Some studies find that insulin resistance and metabolic dysfunction are more severe in adolescents and women with PCOS than in body mass index (BMI)-matched subjects without hirsutism and menstrual irregularity (1, 9). Yet the hyperandrogenism and metabolic defects of PCOS are clearly aggravated by excess weight gain and visceral fat accumulation (1, 5–9). Thus, control of body weight and white adipose storage remains a primary goal in the management of all patients with PCOS. What is the best way to achieve reductions in total body and visceral fat while countering androgen excess, restoring menstrual function, and preventing or reversing the metabolic comorbidities of PCOS? Studies in adults with PCOS show that loss of 5–10% of body weight through diet and exercise counseling can reduce androgen levels and improve menstrual function in approximately 50% of cases (1, 10). Thus, lifestyle intervention is considered by many to be the first line of treatment for PCOS in adults. However, simple weight loss may fail to normalize insulin secretion, glucose tolerance, or dyslipidemia in adults with PCOS and does not always restore menstrual cyclicity or reduce hirsutism scores. Are lifestyle approaches effective for the treatment of PCOS in adolescence? The study by Lass et al. (11) in this issue of JCEM suggests that a lifestyle program consisting of nutrition education (using a generic “traffic light” diet that focused on reducing caloric density), exercise training, and behavior therapy can provide reproductive and metabolic benefits in some obese teenage girls with PCOS. Among 59 patients who completed the 12-month program, the 26 who lost weight (minimum BMI change, 0.2 SD; mean BMI, 3.9 kg/m; mean BMI z-score, 0.63) had significant reductions in blood pressure ( 9 mm Hg systolic, 8 mm Hg diastolic), plasma insulin ( 6 U/ml), and serum triglycerides ( 26 mg%); an 8 mg% rise in high-density lipoprotein levels; and an 18% reduction in carotid intimal medial thickness (CIMT). Testosterone levels fell, SHBG levels rose, and menstrual cycles normalized in 61% of the weight responders. In contrast, there was no recovery of menstrual function and no change in metabolic comorbidities in subjects who failed to lose (or gained) weight. These findings are similar to those of Hoeger et al. (12), who showed that modest weight loss (BMI, 1.1 kg/m) can reduce free androgen index by 59% and increase SHBG by 122% in teenage

Pubertal Metformin Therapy to Reduce Total, Visceral, and Hepatic Adiposity

Puberty is part of a critical window in which adiposity and its correlates can be fine-tuned toward reproduction, which implies that puberty provides an opportunity to reprogram a misprogramming that occurred in early life. We tested this hypothesis in low-birthweight (LBW) girls with precocious pubarche (PP), who are at risk for hyperinsulinemic body adiposity during and beyond puberty. LBW girls with PP (n = 38; mean age 8 years) were randomized to remain untreated or to receive metformin across puberty (425 mg/d for 2 years, then 850 mg/d for 2 years); subsequently, all girls were monitored for 1 year without intervention. Here we report on the latter year. The benefits of metformin were mostly maintained during the posttreatment year so that, after 5 years, metformin therapy was associated with more lean mass; with less total, visceral, and hepatic fat; with lower circulating levels of androgens and leptin; and with elevated levels of high-molecular-weight adiponectin and undercarboxylated osteocalcin. In LBW girls with PP, pubertal metformin therapy was followed by a favorable adipokine profile and by a reduction of total, visceral, and hepatic adiposity beyond puberty.

Birth Weight and Gestational Age Characteristics of Children With Autism, Including a Comparison With Other Developmental Disabilities

The objectives of this study were to compare the birth weight and gestational age distributions and prevalence rates of autism with those of other developmental disabilities and to estimate the birth weight-and gestational age-specific risks for autism. For the first objective, a retrospective cohort of children born in Atlanta, Georgia, in 1981-1993 who survived to 3 years of age was identified through vital records. Children in the cohort who had developmental disabilities (autism, mental retardation, cerebral palsy, hearing loss, or vision impairment) and were still residing in metropolitan Atlanta at 3 to 10 years of age were identified through the Metropolitan Atlanta Developmental Disabilities Surveillance Program. A nested case-control sample from the cohort was used for the second objective; all cohort children identified with autism were case participants, and control participants were cohort children who were not identified as having developmental disabilities or receiving special education services. The prevalence of autism in low birth weight or preterm children was markedly lower than those of other developmental disabilities. In multivariate analyses, birth weight of <2500 g and preterm birth at <33 weeks' gestation were associated with an approximately twofold increased risk for autism, although the magnitude of risk from these factors varied according to gender (higher in girls) and autism subgroup (higher for autism accompanied by other developmental disabilities). For example, a significant fourfold increased risk was observed in low birth weight girls for autism accompanied by mental retardation, whereas there was no significantly increased risk observed in low birth weight boys for autism alone. Gender and autism subgroup differences in birth weight and gestational age, resulting in lower gender ratios with declining birth weight or gestational age across all autism subgroups, might be markers for etiologic heterogeneity in autism.

Pubertal adiposity after fetal growth restraint: toward a calorie restriction mimetic approach

Randomized studies in early-maturing (P2 <8 years, B2 between 8 and 9 years), low–birth weight girls (N = 60) show that calorie restriction mimetic therapy with metformin for 3 years is accompanied by a strikingly leaner body composition (on average, 5.2 kg less gain of fat; 1.6 kg more gain of lean mass; P < .0001).

Eating attitudes and weight concerns in female low birth weight adolescents

Studies of clinically referred patients have implicated low birth weight (LBW) as a possible risk factor for eating disorders. This study examines eating attitudes and weight concerns in nonreferred LBW female adolescents. 274 LBW girls (mean age 15.9) belonging to a prospective regional LBW birth cohort completed the Eating Attitudes Test (EAT-26) and items from the Eating Symptoms Inventory on weight perception and weight dissatisfaction. Only 2.3% scored above threshold for eating disorder risk on the EAT-26. A total of 25% perceived themselves as overweight and 18.7% perceived themselves as underweight, while 63.4% desired to lose and 17.7% desired to gain weight. Girls who perceived themselves as overweight or desired to lose weight had higher mean EAT scores than those who did not. Nonreferred adolescent girls born at LBW are not, as a whole, at risk for abnormal eating attitudes and negative perceptions of their weight.

Metformin Treatment for Four Years to Reduce Total and Visceral Fat in Low Birth Weight Girls with Precocious Pubarche

A low birth weight (LBW) tends to be followed by overweight due to an excess of fat, including visceral fat. LBW girls with precocious pubarche (PP) (pubic hair < 8 yr) are at high risk for developing an adipose state of hyperinsulinemic androgen excess that leads toward early menarche. We explored the effects of insulin sensitization with metformin in LBW-PP girls. SETTING, DESIGN, PATIENTS, INTERVENTION: Prepubertal LBW girls with PP (mean body weight 2.4 kg; age 7.9 yr; body mass index 18.4 kg/m(2)) were studied. Girls were randomly assigned to remain untreated (n=19) or receive metformin for 4 yr (n = 19; 425 mg/d for 2 yr, then 850 mg/d for 2 yr). At the start and after 4 yr, height, weight, fasting insulin, glucose, IGF-I, testosterone, lipids, leptin, high molecular weight adiponectin, body composition by absorptiometry, abdominal fat partitioning (only 4 yr) by magnetic resonance imaging, and menarcheal status were determined. Metformin-treated girls gained on average 5.5 kg (or approximately 50%) less fat, after 4 yr were less insulin resistant and less hyperandrogenic, had lower IGF-I levels and a less atherogenic lipid profile, and were less likely to be post-menarcheal than untreated girls, whereas their gain in height, lean mass, and bone mineral density were similar. After 4 yr, untreated girls had more visceral fat, a higher ratio of visceral-to-sc fat, and a higher leptin-to-high molecular weight adiponectin ratio (all approximately 50% higher) than metformin-treated girls. Long-term metformin treatment appears to reduce total and visceral fat in LBW-PP girls, and to delay menarche without attenuating linear growth, thereby opening the perspective that adult height may be increased.

Persisting benefits 12–18 months after discontinuation of pubertal metformin therapy in low birthweight girls

Persisting benefits 12–18 months after discontinuation of pubertal metformin therapy in low birthweight girls

Persisting benefits 12–18 months after discontinuation of pubertal metformin therapy in low birthweight girls

BackgroundDiscontinuation of metformin therapy, if started beyond menarche in adolescents or young women with hyperinsulinaemia following low birthweight, is rapidly followed by rebound deteriorations in body fat, insulin resistance and blood lipid profile.ObjectiveWe hypothesized that early commencement of metformin and its continuation throughout puberty might have more persisting benefits.Patients and measurementsWe followed up on a previously reported randomized study cohort at 12 months and 18 months after treatment discontinuation, including body composition by absorptiometry, fasting insulin, glucose and blood lipids. In that open-labelled, prospective study, 22 low birthweight girls with early normal puberty (Stage 2 breast development at age 8–9 years) were randomized to remain untreated (N = 12]) or to receive metformin (850 mg/day; N = 10) for 36 months (between time –36 months to 0 month).ResultsThe significant improvements previously reported at the end of the 36-month active treatment period in per cent body fat, abdominal fat mass, fasting insulin sensitivity, high density lipoprotein (HDL) cholesterol and triglyceride levels all persisted at follow-up 12 months after treatment discontinuation. Further anthropometry at 18 months off therapy confirmed the persistence of benefits in height, body mass index (BMI) and waist circumference in the previously metformin-exposed girls.ConclusionIn low birth weight girls with early normal onset of puberty, metformin treatment for 3 years across puberty resulted in auxological, endocrine and metabolic benefits that persisted for at least 1 year after metformin withdrawal. Further follow-up and longer-term studies are needed to explore the possibility that insulin sensitization therapy during puberty might reprogramme predisposition to metabolic disease.

Ovarian Volume and Uterine Length in Neonatal Girls

This study was undertaken to establish reference values for the size of the uterus and ovaries in newborns. We also studied the frequency and follow-up of functional ovarian cysts in healthy neonatal girls. Pelvic ultrasonography was performed on 55 normal newborns. Right and left ovarian volumes positively correlated with birth weight and length, but there was no correlation between uterine length and any of the parameters studied. In a total of 55 newborns, 16 ovarian cysts were detected by transabdominal ultrasound: six neonates (10.9%) had cysts on the left side, ten (18.2%) on the right side, and two (3.6%) had bilateral cysts. All were uncomplicated homogeneous cysts and resolved spontaneously. A higher percentage of cysts was found in the 26 infants weighing 2,500-2,999 g, ten (38.4%) of whom had cysts, than in the 29 infants weighing 3,000 g or more, four (13.7%) of whom had cysts (p < 0.05). Newborns with cysts were followed up, and the cysts resolved spontaneously within 3 months in all but three patients in whom resolution took almost 6 months. Right and left ovarian volumes were positively correlated with birth weight and length, but no significant correlation was found between uterine length and any parameter. In conclusion, ovarian volume was found to be reduced in newborns with relatively low birth weight as well as intra-uterine growth retardation. Functional cysts were more prevalent among low birth weight girls. We suggest that small ovaries and ovarian dysfunction may have a prenatal origin, and further studies on normal and growth-retarded newborns are needed.

Emotional, Behavioral, Social, and Academic Outcomes in Adolescents Born With Very Low Birth Weight

Very low birth weight survivors are at increased risk of developing emotional and behavioral problems and low social and academic competencies. Information on such problems in very low birth weight adolescents is still sparse. Our purpose for this work was to study gender-specific emotional and behavioral problems and social and academic competencies in a cohort of very low birth weight adolescents in north Norway. Families with very low birth weight adolescents aged 13 to 18 years, born between 1978 and 1989 (n = 162) were addressed by mail and asked to complete the Child Behavior Check List and the Youth Self-Report. Data were compared with 2 normative adolescent populations (Child Behavior Check List, n = 540; Youth Self-Report, n = 2522). Scores given by very low birth weight adolescents and their parents on identical items in Child Behavior Check List and Youth Self-Report (cross-informant syndrome constructs) were compared in pairs. To explore predictive effects, demographic and early medical characteristics were entered into a hierarchical multiple regression analysis. There were 156 eligible families, and 99 (63.5%) responded. All completed the Child Behavior Check List, and 82 (52.6%) completed the Youth Self-Report. Very low birth weight boys reported less externalizing and internalizing behaviors and thought and attention problems and higher activity score, whereas very low birth weight girls reported less externalizing behavior and less social, thought, and attention problems and higher activity score compared with normative adolescents. Very low birth weight parents, however, reported more social and attention problems and less social and school competence in boys and more internalizing behavior and social and attention problems and less school competence in girls compared with normative parents. They scored high proportions of both genders within the borderline/clinical range on all of the scales, except for externalizing behavior and social problems in girls. Female very low birth weight adolescents, in contrast to males, reported more problems than parents when compared in pairs, and externalizing problems in particular were not recognized by parents. From parents' point of view, significant proportions of very low birth weight adolescents experience more emotional and behavioral problems and less competence than normative adolescents. In contrast, very low birth weight adolescents state less problems and similar or higher competence than normative adolescents. Very low birth weight adolescent girls report more emotional and behavioral problems compared with their parents than very low birth weight adolescent boys do. Externalizing problems in very low birth weight adolescent girls are often not recognized by parents. To better understand these seemingly paradoxical findings and to develop adequate intervention programs, there is a need for prospective longitudinal studies.

Metformin Treatment to Prevent Early Puberty in Girls with Precocious Pubarche

Girls with precocious pubarche (PP, pubic hair at < 8 yr of age) are at high risk for early onset and rapid progression of puberty, in particular if their prenatal growth was restrained, i.e. low birth weight (LBW), and followed by rapid postnatal catch-up of weight gain. We postulated that insulin resistance contributes to early onset and rapid progression of puberty in LBW-PP girls and thus explored the puberty-delaying effects of insulin sensitization with metformin initiated shortly after PP diagnosis. The study population consisted of 38 prepubertal LBW girls with PP attributed to exaggerated adrenarche [mean body weight, 2.4 kg; age, 7.9 yr; body mass index (BMI), 18.4 kg/m(2)]. These girls were randomly assigned to remain untreated (n = 19) or to receive metformin (n = 19; 425 mg/d) for 2 yr. Pubertal staging, age at menarche, body composition by absorptiometry, fasting insulin, glucose, lipids, leptin, IGF-I, IGF-binding protein-1, testosterone, dehydroepiandrosterone sulfate, and SHBG were the main outcome measures. Metformin treatment was associated with a less adipose body composition (and lower serum leptin levels) and with a 0.4-yr delay in the clinical onset of puberty (Tanner B2; 9.5 vs. 9.1 yr; P < 0.01). These findings were corroborated by a delay of at least 1 yr in the puberty-associated rise of circulating IGF-I (P < 0.01). Available results also point to a metformin-associated delay of menarche (P < 0.02). Gain in height and lean mass was not divergent between study subgroups. The efficacy of early metformin treatment in PP girls is here extended to include not only a less adipose body composition after 2 yr but also a less advanced onset of puberty, whereas height gain is maintained. These findings open the perspective that, ultimately, metformin treatment may also prove to heighten the short adult stature of LBW-PP girls.

Metformin Therapy during Puberty Delays Menarche, Prolongs Pubertal Growth, and Augments Adult Height: A Randomized Study in Low-Birth-Weight Girls with Early-Normal Onset of Puberty

Low-birth-weight (LBW) girls who enter puberty earlier (around 8-9 yr) tend to have earlier menarche, earlier growth arrest, and a shorter adult stature. At present, there is no therapy for most of these girls. In LBW girls with early puberty, hyperinsulinemic insulin resistance could underpin their rapid transit through puberty and their loss of adult stature. We explored the effects of insulin sensitization with metformin during puberty. In an open-labeled, prospective study, 22 LBW girls (birth weight < -1.5 sd score for gestational age) with early-normal puberty (stage 2 breast development at age 8-9 yr) were randomized to remain untreated (n = 12) or to receive metformin (850 mg/d; n = 10) for 36 months (mean age at start, 9.0 yr). All girls remained untreated between 36 and 42 months. Pubertal growth, body composition by absorptiometry, uterine-ovarian size by ultrasound, fasting insulin, glucose, lipids, leptin, IGF-I, and IGF-binding protein-1 were assessed. Metformin treatment resulted in a longer duration from stage 2 breast development to menarche (P < 0.01; median difference, +1.0 yr), taller near-adult height (P < 0.01), and leaner body composition (P < 0.001). Metformin was also associated with lower insulin resistance and leptin and IGF-I levels and higher SHBG and IGF-binding protein-1 levels and with a more favorable lipid profile. Bone mineral density and uterine-ovarian growth were unaffected. Metformin treatment for 36 months in LBW girls with early-normal puberty normalized their pubertal progression to menarche and increased height gains up to adult stature. These data support the concept that insulin is a major codeterminant of the pubertal tempo and pubertal height gain in girls.

Gender dependent association between perinatal morbidity and estrogen receptor-alpha Pvull polymorphism

Assuming the importance of estrogen in perinatal physiology, we tested the association of an estrogen receptor-alpha (ER-alpha) gene Pvull pP polymorphism with perinatal morbidity in premature infants. The ER-alpha Pp genotype was determined in 69 low-birth weight (LBW) boys and 72 LBW girls, 86 term boys and 81 term girls. The association between risk factors, genotype, gender and perinatal morbidity was tested with binary logistic regression analysis. Boys carrying "p" allele were at lower risk for necrotizing enterocolitis (OR [95% Cl]: 0.24 [0.07-0.83]) and patent ductus arteriosus (OR [95% Cl]: 0.24 [0.05-0.97]). The carrier state of the "p" allele was associated with a 34-h shorter period of oxygen supplementation on average (P=0.0018). Boys with pp genotype were at greater risk for intraventricular hemorrhage (OR [95% Cl]: 4.39 [1.15-16.82]). No association between ER-alpha Pvull polymorphism and morbidity was present in girls. Since homozygocity for any Pvull alleles (i.e. having PP or pp genotype) increases the risk for at least one of the most common perinatal complications, it is likely that the heterozygous carrier state of Pvull genotypes has a protective effect, which is gender-dependent.