Effectiveness of a probiotic combination on the neurodevelopment of the very premature infant.

Probiotics have shown a benefit in reducing necrotising enterocolitis in the premature infant, however the study of their effect on premature neonates' neurodevelopment is limited. The aim of our study was to elucidate whether the effect of Bifidobacterium bifidum NCDO 2203 combined with Lactobacillus acidophilus NCDO 1748 could positively impact the neurodevelopment of the preterm neonates. Quasi-experimental comparative study with a combined treatment of probiotics in premature infants < 32 weeks and < 1500 g birth weight, cared for at a level III neonatal unit. The probiotic combination was administered orally to neonates surviving beyond 7 days of life, until 34 weeks postmenstrual age or discharge. Globally, neurodevelopment was evaluated at 24 months corrected age. A total of 233 neonates were recruited, 109 in the probiotic group and 124 in the non-probiotic group. In those neonates receiving probiotics, there was a significant reduction in neurodevelopment impairment at 2 years of age RR 0.30 [0.16-0.58], and a reduction in the degree of impairment (normal-mild vs moderate-severe, RR 0.22 [0.07-0.73]). Additionally, there was a significant reduction in late-onset sepsis (RR 0.45 [0.21-0.99]). The prophylactic use of this probiotic combination contributed to improving neurodevelopmental outcome and reduced sepsis in neonates born at < 32 weeks and < 1500 g.Per style, a structured abstract is not allowed so we have changed the structured abstract to an unstructured abstract. Please check and confirm.Accepted.

Effects of Antioxidant Intake on Fetal Development and Maternal/Neonatal Health during Pregnancy.

During pregnancy, cycles of hypoxia and oxidative stress play a key role in the proper development of the fetus. Hypoxia during the first weeks is crucial for placental development, while the increase in oxygen due to the influx of maternal blood stimulates endothelial growth and angiogenesis. However, an imbalance in the number of oxidative molecules due to endogenous or exogenous factors can overwhelm defense systems and lead to excessive production of reactive oxygen species (ROS). Many pregnancy complications, generated by systemic inflammation and placental vasoconstriction, such as preeclampsia (PE), fetal growth restriction (FGR) and preterm birth (PTB), are related to this increase of ROS. Antioxidants may be a promising tool in this population. However, clinical evidence on their use, especially those of natural origin, is scarce and controversial. Following PRISMA methodology, the current review addresses the use of natural antioxidants, such as epigallocatechin gallate (EGCG), melatonin and resveratrol (RESV), as well as other classical antioxidants (vitamin C and E) during the prenatal period as treatment of the above-mentioned complications. We review the effect of antioxidant supplementation on breast milk in lactating mothers.

Early Identification of Prolonged QT Interval for Prevention of Sudden Infant Death.

Introduction: Long QT syndrome is the main arrhythmogenic disease responsible for sudden death in infants, especially in the first days of life. Performing an electrocardiogram in newborns could enable early diagnosis and adoption of therapeutic measures focused on preventing lethal arrhythmogenic events. However, the inclusion of an electrocardiogram in neonatal screening protocols still remains a matter of discussion. To comprehensively analyse the potential clinical value of performing an electrocardiogram and subsequent follow-up in a cohort of newborns. Methods: Electrocardiograms were performed in 685 neonates within the first week of life. One year follow-up was performed if QTc > 450 ms identified. Comprehensive genetic analysis using massive sequencing was performed in all cases with QTc > 470 ms. Results: We identified 54 neonates with QTc > 450 ms/ <470 ms; all normalized QTc values within 6 months. Eight cases had QTc > 480 ms at birth and, if persistent, pharmacological treatment was administrated during follow-up. A rare variant was identified as the potential cause of long QT syndrome in five cases. Three cases showed a family history of sudden arrhythmogenic death. Conclusions: Our prospective study identifies 0.14% of cases with a definite long QT, supporting implementation of electrocardiograms in routine pediatric protocols. It is an effective, simple and non-invasive approach that can help prevent sudden death in neonates and their relatives. Genetic analyses help to unravel the cause of arrhythmogenic disease in diagnosing neonates. Further, clinical assessment and genetic analysis of relatives allowed early identification of family members at risk of arrhythmias helping to adopt preventive personalized measures.

Therapeutic Effects of Catechins in Less Common Neurological and Neurodegenerative Disorders.

In recent years, neurological and neurodegenerative disorders research has focused on altered molecular mechanisms in search of potential pharmacological targets, e.g., imbalances in mechanisms of response to oxidative stress, inflammation, apoptosis, autophagy, proliferation, differentiation, migration, and neuronal plasticity, which occur in less common neurological and neurodegenerative pathologies (Huntington disease, multiple sclerosis, fetal alcohol spectrum disorders, and Down syndrome). Here, we assess the effects of different catechins (particularly of epigalocatechin-3-gallate, EGCG) on these disorders, as well as their use in attenuating age-related cognitive decline in healthy individuals. Antioxidant and free radical scavenging properties of EGCG -due to their phenolic hydroxyl groups-, as well as its immunomodulatory, neuritogenic, and autophagic characteristics, makes this catechin a promising tool against neuroinflammation and microglia activation, common in these pathologies. Although EGCG promotes the inhibition of protein aggregation in experimental Huntington disease studies and improves the clinical severity in multiple sclerosis in animal models, its efficacy in humans remains controversial. EGCG may normalize DYRK1A (involved in neural plasticity) overproduction in Down syndrome, improving behavioral and neural phenotypes. In neurological pathologies caused by environmental agents, such as FASD, EGCG enhances antioxidant defense and regulates placental angiogenesis and neurodevelopmental processes. As demonstrated in animal models, catechins attenuate age-related cognitive decline, which results in improvements in long-term outcomes and working memory, reduction of hippocampal neuroinflammation, and enhancement of neuronal plasticity; however, further studies are needed. Catechins are valuable compounds for treating and preventing certain neurodegenerative and neurological diseases of genetic and environmental origin. However, the use of different doses of green tea extracts and EGCG makes it difficult to reach consistent conclusions for different populations.

Toxic Elements in Traditional Kohl-Based Eye Cosmetics in Spanish and German Markets.

Kohl is a traditional cosmetic widely used in Asia and Africa. In recent years, demand for kohl-based eyelids and lipsticks has increased in Europe, linked to migratory phenomena of populations from these continents. Although the European legislation prohibits the use of heavy metals in cosmetics due to the harmful effects to human health, particularly to pregnant women and children, these elements are still present in certain products. The European Union recommended levels are Pb < 20 ppm, As < 5 ppm, Cd < 5 ppm, Sb < 100 ppm, and Ni < 200 ppm. In Germany, levels are more restrictive: Pb < 2 ppm, As < 0.5 ppm, Cd < 0.1 ppm, Sb < 0.5 ppm, and Ni < 10 ppm. Here, we analyzed 12 kohl-based cosmetics in different presentations (powder, paste, and pencil) that were purchased in Spanish and German local shops. An inductively coupled plasma optical emission spectrophotometer was used to identify toxic elements and heavy metals. Levels of Pb ranged between 1.7 and 410,000 ppm in six of the study samples, four of which had levels above the recommended limit of at least two heavy metals. Arsenic (a carcinogenic element) values were within the range allowed by the EU in only 58% of the studied samples. Moreover, two products doubled this limit, reaching levels of 9.2 and 12.6 ppm. In one of the products, cadmium, related to toxic keratitis, was four times higher (20.7 ppm) than that allowed, while in two other products, these limits were doubled (11.8 and 12.7 ppm). Our results indicate the need to supervise the manufacture of kohl-based traditional products and the analysis of their composition prior distribution in European countries.

Environmental Exposure during Pregnancy: Influence on Prenatal Development and Early Life: A Comprehensive Review.

Preconception and prenatal exposure to environmental contaminants may affect future health. Pregnancy and early life are critical sensitive windows of susceptibility. The aim of this review was to summarize current evidence on the toxic effects of environment exposure during pregnancy, the neonatal period, and childhood. Alcohol use is related to foetal alcohol spectrum disorders, foetal alcohol syndrome being its most extreme form. Smoking is associated with placental abnormalities, preterm birth, stillbirth, or impaired growth and development, as well as with intellectual impairment, obesity, and cardiovascular diseases later in life. Negative birth outcomes have been linked to the use of drugs of abuse. Pregnant and lactating women are exposed to endocrine-disrupting chemicals and heavy metals present in foodstuffs, which may alter hormones in the body. Prenatal exposure to these compounds has been associated with pre-eclampsia and intrauterine growth restriction, preterm birth, and thyroid function. Metals can accumulate in the placenta, causing foetal growth restriction. Evidence on the effects of air pollutants on pregnancy is constantly growing, for example, preterm birth, foetal growth restriction, increased uterine vascular resistance, impaired placental vascularization, increased gestational diabetes, and reduced telomere length. The advantages of breastfeeding outweigh any risks from contaminants. However, it is important to assess health outcomes of toxic exposures via breastfeeding. Initial studies suggest an association between pre-eclampsia and environmental noise, particularly with early-onset pre-eclampsia. There is rising evidence of the negative effects of environmental contaminants following exposure during pregnancy and breastfeeding, which should be considered a major public health issue.

Effects of Microbiota Imbalance in Anxiety and Eating Disorders: Probiotics as Novel Therapeutic Approaches.

Anxiety and eating disorders produce a physiological imbalance that triggers alterations in the abundance and composition of gut microbiota. Moreover, the gut-brain axis can be altered by several factors such as diet, lifestyle, infections, and antibiotic treatment. Diet alterations generate gut dysbiosis, which affects immune system responses, inflammation mechanisms, the intestinal permeability, as well as the production of short chain fatty acids and neurotransmitters by gut microbiota, which are essential to the correct function of neurological processes. Recent studies indicated that patients with generalized anxiety or eating disorders (anorexia nervosa, bulimia nervosa, and binge-eating disorders) show a specific profile of gut microbiota, and this imbalance can be partially restored after a single or multi-strain probiotic supplementation. Following the PRISMA methodology, the current review addresses the main microbial signatures observed in patients with generalized anxiety and/or eating disorders as well as the importance of probiotics as a preventive or a therapeutic tool in these pathologies.

Eating Disorders During Gestation: Implications for Mother's Health, Fetal Outcomes, and Epigenetic Changes.

Introduction: Eating disorders (EDs) have increased globally in women of childbearing age, related to the concern for body shape promoted in industrialized countries. Pregnancy may exacerbate a previous ED or conversely may be a chance for improving eating patterns due to the mother's concern for the unborn baby. EDs may impact pregnancy evolution and increase the risk of adverse outcomes such as miscarriage, preterm delivery, poor fetal growth, or malformations, but the knowledge on this topic is limited. Methods: We performed a systematic review of studies on humans in order to clarify the mechanisms underpinning the adverse pregnancy outcomes in patients with EDs. Results: Although unfavorable fetal development could be multifactorial, maternal malnutrition, altered hormonal pathways, low pre-pregnancy body mass index, and poor gestational weight gain, combined with maternal psychopathology and stress, may impair the evolution of pregnancy. Environmental factors such as malnutrition or substance of abuse may also induce epigenetic changes in the fetal epigenome, which mark lifelong health concerns in offspring. Conclusions: The precocious detection of dysfunctional eating behaviors in the pre-pregnancy period and an early multidisciplinary approach comprised of nutritional support, psychotherapeutic techniques, and the use of psychotropics if necessary, would prevent lifelong morbidity for both mother and fetus. Further prospective studies with large sample sizes are needed in order to design a structured intervention during every stage of pregnancy and in the postpartum period.

Probiotic Supplementation During the Perinatal and Infant Period: Effects on Gut Dysbiosis and Disease.

The perinatal period is crucial to the establishment of lifelong gut microbiota. The abundance and composition of microbiota can be altered by several factors such as preterm delivery, formula feeding, infections, antibiotic treatment, and lifestyle during pregnancy. Gut dysbiosis affects the development of innate and adaptive immune responses and resistance to pathogens, promoting atopic diseases, food sensitization, and infections such as necrotizing enterocolitis (NEC). Recent studies have indicated that the gut microbiota imbalance can be restored after a single or multi-strain probiotic supplementation, especially mixtures of Lactobacillus and Bifidobacterium strains. Following the systematic search methodology, the current review addresses the importance of probiotics as a preventive or therapeutic tool for dysbiosis produced during the perinatal and infant period. We also discuss the safety of the use of probiotics in pregnant women, preterm neonates, or infants for the treatment of atopic diseases and infections.

Impact of Nicotine Replacement and Electronic Nicotine Delivery Systems on Fetal Brain Development.

Maternal tobacco smoking during pregnancy remains a major public health issue. The neurotoxic properties of nicotine are associated with fetal neurodevelopmental disorders and perinatal morbimortality. Recent research has demonstrated the effects of nicotine toxicity on genetic and epigenetic alterations. Smoking cessation strategies including nicotine replacement therapy (NRT) and electronic nicotine delivery systems (ENDS) show lack of clear evidence of effectiveness and safety in pregnant women. Limited trials using randomized controls concluded that the intermittent use formulation of NRT (gum, sprays, inhaler) in pregnant women is safe because the total dose of nicotine delivered to the fetus is less than continuous-use formulations (transdermal patch). Electronic nicotine delivery systems (ENDS) were hyped as a safer alternative during pregnancy. However, refill liquids of ENDS are suspected to be cytotoxic for the fetus. Animal studies revealed the impact of ENDS on neural stem cells, showing a similar risk of pre- and postnatal neurobiological and neurobehavioral disorders to that associated with the exposure to traditional tobacco smoking during early life. There is currently no clear evidence of impact on fetal brain development, but recent research suggests that the current guidelines should be reconsidered. The safety of NRT and ENDS is increasingly being called into question. In this review, we discuss the special features (pharmacodynamics, pharmacokinetics, and metabolism) of nicotine, NRT, and ENDS during pregnancy and postnatal environmental exposure. Further, we assess their impact on pre- and postnatal neurodevelopment.

The Effects of Vegetarian and Vegan Diet during Pregnancy on the Health of Mothers and Offspring.

Vegetarian and vegan diets have increased worldwide in the last decades, according to the knowledge that they might prevent coronary heart disease, cancer, and type 2 diabetes. Althought plant-based diets are at risk of nutritional deficiencies such as proteins, iron, vitamin D, calcium, iodine, omega-3, and vitamin B12, the available evidence shows that well planned vegetarian and vegan diets may be considered safe during pregnancy and lactation, but they require a strong awareness for a balanced intake of key nutrients. A review of the scientific literature in this field was performed, focusing specifically on observational studies in humans, in order to investigate protective effects elicited by maternal diets enriched in plant-derived foods and possible unfavorable outcomes related to micronutrients deficiencies and their impact on fetal development. A design of pregestational nutrition intervention is required in order to avoid maternal undernutrition and consequent impaired fetal growth.

Gain-of-function DNMT3A mutations cause microcephalic dwarfism and hypermethylation of Polycomb-regulated regions.

DNA methylation and Polycomb are key factors in the establishment of vertebrate cellular identity and fate. Here we report de novo missense mutations in DNMT3A, which encodes the DNA methyltransferase DNMT3A. These mutations cause microcephalic dwarfism, a hypocellular disorder of extreme global growth failure. Substitutions in the PWWP domain abrogate binding to the histone modifications H3K36me2 and H3K36me3, and alter DNA methylation in patient cells. Polycomb-associated DNA methylation valleys, hypomethylated domains encompassing developmental genes, become methylated with concomitant depletion of H3K27me3 and H3K4me3 bivalent marks. Such de novo DNA methylation occurs during differentiation of Dnmt3aW326R pluripotent cells in vitro, and is also evident in Dnmt3aW326R/+ dwarf mice. We therefore propose that the interaction of the DNMT3A PWWP domain with H3K36me2 and H3K36me3 normally limits DNA methylation of Polycomb-marked regions. Our findings implicate the interplay between DNA methylation and Polycomb at key developmental regulators as a determinant of organism size in mammals.

Brown adipose tissue in prepubertal children: associations with sex, birthweight, and metabolic profile.

BACKGROUND/OBJECTIVES: Individuals born small-for-gestational age (SGA), especially those who experience postnatal catch-up growth, are at increased risk for developing endocrine-metabolic abnormalities before puberty. In adults, brown adipose tissue (BAT) has been associated with protection against metabolic disorders, such as obesity, type 2 diabetes, and dyslipidaemia. Here, we assessed for the first time whether BAT activation differs between prepubertal children born SGA or appropriate-for-gestational age (AGA). SUBJECTS/METHODS: The study population consisted of 86 prepubertal children [41 AGA and 45 SGA; age (mean ± SEM), 8.5 ± 0.1 years], recruited into two prospective longitudinal studies assessing endocrine-metabolic status and body composition in infancy and childhood. The temperature at the supraclavicular region (SCR) before and after a cold stimulus was measured by infrared thermal imaging, and the area of thermally active SCR (increase after cold challenge, ΔAreaSCR) was calculated as a surrogate index of BAT activation. The results were correlated with clinical, endocrine-metabolic, and inflammation variables, and with visceral and hepatic adiposity (assessed by Magnetic Resonance Imaging). RESULTS: No differences in BAT activation index, as judged by ΔAreaSCR, were found between AGA and SGA children. However, girls showed higher baseline and post-cold induction AreaSCR than boys (both p ≤ 0.01). An interaction between gender and birth weight subgroup was observed for BAT activation; AGA girls increased significantly the ΔAreaSCR as compared to AGA boys; this increase did not occur in SGA girls vs SGA boys. Cold-induced ΔAreaSCR negatively correlated with HOMA-IR, us-CRP, liver volume, and liver fat. CONCLUSIONS: Prepubertal AGA girls had significantly greater BAT activation index as compared to AGA boys; this difference was not observed in SGA subjects. Higher BAT activation associated with a lower amount of visceral fat and with a favorable metabolic profile. Long-term follow-up is needed to determine whether those differences relate to pubertal timing, and to the development of obesity and metabolic disorders.

The Effects of Alcohol and Drugs of Abuse on Maternal Nutritional Profile during Pregnancy.

The consumption of alcohol and drugs of abuse among pregnant women has experienced a significant increase in the last decades. Suitable maternal nutritional status is crucial to maintain the optimal environment for fetal development but if consumption of alcohol or drugs of abuse disrupt the intake of nutrients, the potential teratogenic effects of these substances increase. Despite evidence of the importance of nutrition in addicted pregnant women, there is a lack of information on the effects of alcohol and drugs of abuse on maternal nutritional status; so, the focus of this review was to provide an overview on the nutritional status of addicted mothers and fetuses. Alcohol and drugs consumption can interfere with the absorption of nutrients, impairing the quality and quantity of proper nutrient and energy intake, resulting in malnutrition especially of micronutrients (vitamins, omega⁻3, folic acid, zinc, choline, iron, copper, selenium). When maternal nutritional status is compromised by alcohol and drugs of abuse the supply of essential nutrients are not available for the fetus; this can result in fetal abnormalities like Intrauterine Growth Restriction (IUGR) or Fetal Alcohol Spectrum Disorder (FASD). It is critical to find a strategy to reduce fetal physical and neurological impairment as a result of prenatal alcohol and drugs of abuse exposure combined with poor maternal nutrition. Prenatal nutrition interventions and target therapy are required that may reverse the development of such abnormalities.

Nerve Growth Factor Levels in Term Human Infants: Relationship to Prenatal Growth and Early Postnatal Feeding.

BACKGROUND: Nerve growth factor (NGF) plays a key role in neuroprotection and developmental maturity. We assessed longitudinally the circulating concentrations of NGF in term healthy human newborns and infants as well as their association with prenatal growth and early postnatal feeding patterns. METHODS: Circulating NGF and anthropometric measures (weight, length, body mass index, and ponderal index) were assessed longitudinally-at birth and at age 4 months-in 86 term infants born appropriate (AGA), small (SGA), or large for gestational age (LGA). RESULTS: Cord blood NGF levels in SGA newborns were higher than those in AGA newborns (1.41 ± 0.2 pg/mL vs. 0.66 ± 0.1 pg/mL; p = 0.02) and not different from those in LGA neonates (0.79 ± 0.2 pg/mL). At age 4 months, SGA-breastfed infants showed the highest NGF concentrations (p = 0.02 and p = 0.01 vs. AGA and SGA-formula-fed infants, respectively), while LGA infants depicted a marginal increase. NGF levels in cord blood correlated negatively with the ponderal index at birth (r = -0.36; p = 0.0008). CONCLUSIONS: Circulating NGF is related to both prenatal growth and early postnatal nutrition. The maintenance of increased NGF concentrations in SGA-breastfed infants at age 4 months might be a potential mechanism to counterbalance potential risks for developing cognitive and psychomotor disadvantages.

Normalizing Ovulation Rate by Preferential Reduction of Hepato-Visceral Fat in Adolescent Girls With Polycystic Ovary Syndrome.

PURPOSE: Polycystic ovary syndrome (PCOS) is an increasingly prevalent disorder in adolescent girls, commonly presenting with hirsutism/oligomenorrhea, commonly treated with an oral contraceptive (OC), and commonly followed by oligoanovulatory subfertility. We tested whether an intervention targeting the reduction of hepato-visceral adiposity is followed by a higher ovulation rate than OC treatment. METHODS: This randomized, open-label, single-center, pilot proof-of-concept study (12 months on treatment, then 12 months off) was performed in adolescent girls with hirsutism and oligomenorrhea (PCOS by National Institutes of Health; no sexual activity; N = 36; mean age 16 years, body mass index 23.5 kg/m2; 94% study completion). Compared treatments were OC (ethinylestradiol-levonorgestrel) versus low-dose combination of spironolactone 50 mg/d, pioglitazone 7.5 mg/d, and metformin 850 mg/d (SPIOMET). Primary outcome was post-treatment ovulation rate inferred from menstrual diaries and salivary progesterone (12 + 12 weeks). Secondary outcomes included body composition (dual X-ray absorptiometry), abdominal fat (magnetic resonance imaging), insulinemia (oral glucose tolerance test), and androgenemia (liquid chromatography - tandem mass spectrometry). RESULTS: SPIOMET was followed by a 2.5-fold higher ovulation rate than OC (p ≤ .001) and by a 6-fold higher normovulatory fraction (71% vs. 12%; p ≤ .001); oligoanovulation risk after SPIOMET was 65% lower (95% confidence interval, 40%-89%) than after OC. Higher post-treatment ovulation rates related to more on-treatment loss of hepatic fat (r2 = .27; p < .005). Visceral fat and insulinemia normalized only with SPIOMET; androgenemia normalized faster with OC but rebounded more thereafter. Body weight, lean mass, and abdominal subcutaneous fat mass remained stable in both groups. CONCLUSIONS: Early SPIOMET treatment for PCOS normalized post-treatment ovulation rates more than OC. Focusing PCOS treatment on early reduction of hepato-visceral fat may prevent part of later oligoanovulatory subfertility.

Placental and Cord Blood Methylation of Genes Involved in Energy Homeostasis: Association With Fetal Growth and Neonatal Body Composition.

Low weight at birth is associated with subsequent susceptibility to diabetes. Epigenetic modulation is among the mechanisms potentially mediating this association. We performed a genome-wide DNA methylation analysis in placentas from term infants born appropriate-for-gestational-age (AGA) or small-for-gestational-age (SGA) to identify new genes related to fetal growth and neonatal body composition. Candidate genes were validated by bisulfite pyrosequencing (30 AGA, 21 SGA) and also analyzed in cord blood. Gene expression analyses were performed by RT-PCR. Neonatal body composition was assessed by dual X-ray absorptiometry at age 2 weeks. The ATG2B, NKX6.1, and SLC13A5 genes (respectively related to autophagy, ß-cell development and function, and lipid metabolism) were hypermethylated in placenta and cord blood from SGA newborns, whereas GPR120 (related to free fatty acid regulation) was hypomethylated in placenta and hypermethylated in cord blood. Gene expression levels were opposite to methylation status, and both correlated with birth weight, circulating IGF-I, and total and abdominal fat at age 2 weeks. In conclusion, alterations in methylation and expression of genes involved in the regulation of energy homeostasis were found to relate to fetal growth and neonatal body composition and thus may be among the early mechanisms modulating later susceptibility to diabetes.

Large for Gestational Age Newborns from Mothers Without Diabetes Mellitus Tend to Become Tall and Lean Toddlers.

A longitudinal study with dual x-ray absorptiometry disclosed that infants born large for gestational age from mothers without diabetes mellitus and without excessive gestational weight gain tend to be long with increased adipose tissue as newborns and tall and lean as toddlers.

Oral contraception vs insulin sensitization for 18 months in nonobese adolescents with androgen excess: posttreatment differences in C-reactive protein, intima-media thickness, visceral adiposity, insulin sensitivity, and menstrual regularity.

BACKGROUND: An oral estro-progestagen is the standard medication given to adolescent girls with androgen excess, even when those girls are not at risk of pregnancy. AIM: The aim of this study was to compare on-treatment and post-treatment effects of intervention with an oral contraceptive vs an insulin-sensitizing treatment for androgen excess in nonobese adolescents. DESIGN: This was a randomized, open-label trial. STUDY POPULATION: Subjects were nonobese adolescent girls with hyperinsulinemic androgen excess and without risk of pregnancy (mean age, 16 years; body mass index, 23 kg/m²; n = 34). INTERVENTIONS: The effects of treatment with ethinylestradiol-cyproteroneacetate (EE-CA) vs a low-dose combination of pioglitazone (7.5 mg/d), flutamide (62.5 mg/d), and metformin (850 mg/d) (PioFluMet) for 18 months were studied. Posttreatment follow-up was for 6 months. MAIN OUTCOME MEASURES: Androgen excess (hirsutism and acne scores and serum testosterone), glucose-stimulated insulinemia, circulating C-reactive protein, carotid intima media thickness, body composition (absorptiometry), abdominal fat partitioning (magnetic resonance imaging), and menstrual regularity were measured. RESULTS: EE-CA and PioFluMet attenuated androgen excess similarly but had divergent, and even opposing, effects on other outcomes. Six months posttreatment, the PioFluMet-treated girls had a lower glucose-induced insulinemia, a lower C-reactive protein level, and a thinner intima media than the EE-CA-treated girls, and they were viscerally less adipose, had a higher lean mass, and were more likely to have regular cycles. CONCLUSIONS: The on-treatment and post-treatment effects of PioFluMet compared favorably with those of oral contraception in nonobese adolescents with androgen excess. The intervention whereby androgen excess is reduced in adolescence influences the post-treatment phenotype. PioFluMet-like interventions in adolescence may thus hold the potential to prevent part of the androgen-excess phenotype in adulthood, including adiposity and subfertility.