Lourdes Ibáñez

Early Puberty: Rapid Progression and Reduced Final Height in Girls With Low Birth Weight

Objective. To assess whether, in girls with early onset of puberty, low birth weight is a risk factor for rapid progression to menarche and for short adult stature. Design. Longitudinal clinical assessment of 54 Catalan (Northern Spanish) girls followed from early onset of puberty (onset of breast development between 8.0 and 9.0 years of age) to final height. The timing of menarche and the final height were analyzed a posteriori according to birth weight, the cutoff level between normal and low birth weight subgroups being −1.5 standard deviation (SD; ∼2.7 kg at term birth). Results. Normal and low birth weight girls had similar target heights and characteristics at diagnosis of early puberty. However, menarche occurred on average 1.6 years earlier in low versus normal birth weight girls (11.3 ± .3 years vs 12.9 ± .2 years), and final height was >5 cm shorter in low birth weight girls (parental adjusted height SD: −.6 ± .2 cm vs .3 ± .2 cm). Conclusion. The timing of menarche and the level of final height in Catalan girls with early onset of puberty was found to depend on prenatal growth. Girls with normal birth weight tend to progress slowly through puberty with a normal timing of menarche and normal final height. In contrast, girls with low birth weight tend to progress relatively rapidly to an early menarche and to a reduced final height. If these findings are confirmed in other ethnic and/or larger groups, then a subgroup has been identified that will most likely benefit from any therapeutic intervention aiming at a delay of pubertal development and/or an increase of final height.

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.

Early Puberty-Menarche After Precocious Pubarche: Relation to Prenatal Growth

OBJECTIVE. Girls with precocious pubarche (PP; pubic hair at <8 years of age) as a result of an early or amplified adrenarche (high dehydroepiandrosterone-sulfate [DHEAS]) tend to be hyperinsulinemic, in particular when born with low birth weight (LBW). The objective of this study was to assess the interrelationship among prenatal growth, PP, the timing of puberty-menarche, and adult stature. METHODS. We studied 187 PP girls longitudinally: (1) at birth, (2) in prepuberty, (3) at onset of puberty, (4) at menarche, and (5) on reaching adult stature. This PP cohort was divided into subgroups of higher birth weight (>0 SD), intermediate birth weight (0 to −2 SD), and lower birth weight (less than −2 SD). RESULTS. At the time of PP diagnosis, age, bone age, and BMI were similar across birth weight subgroups; circulating sex hormone–binding globulin and body height were reduced in PP girls with lower birth weight, and these remained so throughout pubertal development. Onset of puberty occurred earlier in PP girls with lower birth weight; so did menarche. Adult height differed by an average of 6.5 cm (∼1 SD) between the upper and lower birth weight subgroups; this difference was essentially achieved before puberty and even before PP. Menarche before age 12.0 years was twofold more prevalent in PP girls than in control subjects. Among PP girls, age at menarche was advanced by 8 to 10 months in lower versus higher birth weight girls. Menarche before age 12.0 years was threefold more prevalent among LBW-PP girls than in control subjects (∼75% vs ∼25%). CONCLUSIONS. The link between prenatal growth restraint and early menarche is herewith extended to PP girls. In particular LBW-PP girls may become a target group for interventions directed toward normalization of pubertal onset and progression.

Visceral Adiposity without Overweight in Children Born Small for Gestational Age

CONTEXT Children born small for gestational age (SGA) tend to develop catch-up growth in infancy and become overweight by the age of 6 yr. Weight control is advocated as a preventive measure, but it is unknown whether such control suffices to prevent visceral fat excess and hypoadiponectinemia. SETTING The study was performed at a university hospital. STUDY POPULATION AND DESIGN A total of 64 children (32 matched pairs) aged 6 yr, of whom 32 were born appropriate for gestational age and 32 were born SGA, and had subsequently developed spontaneous catch-up growth were included in the study; matching was performed for gender, height, weight, and, thus, body mass index. MAIN OUTCOMES Fasting insulin, IGF-I, high molecular weight adiponectin, leptin, visfatin, and lean and fat mass were calculated by absorptiometry, and abdominally sc and visceral fat by magnetic resonance imaging. RESULTS After strict matching, SGA children had a total lean mass, total fat mass, leptinemia, and visfatinemia comparable to those in the appropriate for gestational age children, but they still had higher fasting insulin and IGF-I levels (P < 0.01), much lower high molecular weight adiponectin levels (P < 0.0001), and a striking shift from abdominally sc to visceral fat (P < 0.0001). Fasting insulin (r = 0.52; P < 0.00001) was a major determinant of visceral fat in boys and girls, explaining 28% of its variance. CONCLUSIONS SGA children tend to be viscerally adipose and hypo-adiponectinemic, even if they are not overweight. Therefore, measures beyond weight control seem to be needed to allow most SGA children to normalize their body composition and endocrine-metabolic homeostasis.

The Association between the FTO Gene and Fat Mass in Humans Develops by the Postnatal Age of Two Weeks

OBJECTIVE Little is known about the genetic determinants of fat mass around birth. We hypothesized that the common rs9939609 single-nucleotide polymorphism (SNP) in FTO is associated with fat mass and metabolic parameters in neonates. DESIGN We conducted a cross-sectional, hospital-based study. PATIENTS Patients included 234 full-term, healthy newborns [122 girls and 112 boys; gestational age (mean, range), 39.0 (37.0-42.0) wk; birth weight, 3.2 (1.9-4.2) kg]. METHODS Cord-blood insulin, IGF-I, IGF-binding protein-1, adiponectin, and visfatin were measured by specific immunoassays. Body composition was assessed by dual-energy x-ray absorptiometry at about 13 d (range, 9-20 d). Genotyping of rs9939609 was achieved by restriction fragment length polymorphism analysis. RESULTS The rs9939609 SNP in FTO was not associated with birth weight; however, it was associated with serum visfatin (P < 0.001), with weight and ponderal index at age 2 wk (P < 0.05), and with total, truncal, and abdominal fat (P < 0.05 to P = 0.01), so that AA homozygotes had 37% higher plasma visfatin concentration and 17, 20, and 17% higher total, truncal, and abdominal fat mass, respectively, than T-carrier neonates. CONCLUSION Our findings support a role of the common rs9939609 SNP in FTO gene in the early stages of fat accretion in humans and disclose novel associations between this SNP and both serum visfatin and abdominal fat mass in neonates.

Fat distribution in non‐obese girls with and without precocious pubarche: central adiposity related to insulinaemia and androgenaemia from prepuberty to postmenarche

objective Precocious pubarche (PP) in girls is associated with hyperinsulinaemia and dyslipidaemia of prepubertal onset, and with ovarian hyperandrogenism and ovulatory dysfunction in adolescence, particularly if they also had prenatal growth restraint and postnatal growth acceleration. Hyperinsulinaemia may be the pathogenic key factor, possibly amplified by hyperandrogenaemia. While such PP girls do not have increased body mass index (BMI), we hypothesized that body fat mass and fat distribution may differ between PP girls and matched controls, and may relate to insulin and androgen levels.

Gender specificity of body adiposity and circulating adiponectin, visfatin, insulin, and insulin growth factor-I at term birth: relation to prenatal growth

CONTEXT Fetal development is thought to be gender specific for adiposity and circulating insulin and IGF-I but not adipokinemia, as judged by serum visfatin and adiponectin at term birth. We studied the potential relationship between these gender specificities and fetal growth. SETTING The study was conducted at a university hospital. STUDY POPULATION Subjects included 96 strictly matched neonates born appropriate for gestational age (AGA; 24 girls, 24 boys) or small for gestational age (SGA; 24 girls, 24 boys). MAIN OUTCOMES Outcomes included serum insulin, IGF-I, visfatin, total and high-molecular-weight (HMW) adiponectin, osteocalcin at term birth, and neonatal body composition by absorptiometry. RESULTS Cord insulin and IGF-I levels were higher in girls than boys (P < or = 0.01), in both the AGA and SGA subpopulation. In AGA newborns, fat and lean mass were each gender specific (P < 0.0001), whereas visfatin and total and HMW adiponectin were not. Conversely, in SGA newborns, visfatin and HMW adiponectin were gender specific (higher levels in girls), whereas body adiposity was not. In SGA fetuses, the distribution of adiponectin isoforms was in both genders shifted toward HMW (P < 0.005 vs. AGA). Cord osteocalcin did not differ by either gender or birth weight. CONCLUSION At term birth, the gender specificity of adiposity and circulating visfatin and HMW adiponectin appeared to depend on prenatal growth, whereas the gender specificity of insulin and IGF-I levels did not. The fetal shift in adiponectin isoforms may contribute to explain why SGA newborns tend to be hypersensitive to insulin.

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.

Early Metformin Therapy (Age 8–12 Years) in Girls with Precocious Pubarche to Reduce Hirsutism, Androgen Excess, and Oligomenorrhea in Adolescence

CONTEXT Girls with a combined history of low(-normal) birth weight (LBW) and precocious pubarche (PP) are at high risk to develop polycystic ovary syndrome (PCOS). OBJECTIVE The objective of the study was to compare the capacity of early vs. late metformin treatment to prevent adolescent PCOS. DESIGN This was a randomized, open-label study over 7 yr. SETTING The study was conducted at a university hospital. PATIENTS Thirty-eight LBW-PP girls were followed up from the mean age 8 until age 15 yr. INTERVENTION Early metformin (study yr 1-4; age 8-12 yr) vs. late metformin (yr 6; age 13-14 yr). MAIN OUTCOME MEASURES Measures included height; weight; hirsutism score; menstrual cycle; endocrine-metabolic screening (fasting; follicular phase); C-reactive protein; body composition (absorptiometry); abdominal fat partitioning (magnetic resonance imaging); ovarian morphology (ultrasound); PCOS (National Institutes of Health and Androgen Excess Society definitions) after yr 7 (all girls thus untreated for at least 1 yr). RESULTS None of the girls dropped out of the study. At age 15 yr, early-metformin girls were taller (4 cm), were in a less proinflammatory state, and had less central fat due to reductions in visceral and hepatic fat. Hirsutism, androgen excess, oligomenorrhea, and PCOS were between 2- and 8-fold more prevalent in late- than early-treated girls. Abdominal adiposity was the first variable to diverge (at age 8-10 yr) between girls without vs. with PCOS at age 15 yr. CONCLUSIONS In LBW-PP girls, early metformin therapy was found to prevent or delay the development of hirsutism, androgen excess, oligomenorrhea, and PCOS more effectively than late metformin. The time window of late childhood and early puberty may be more critical for the development, and thus for the prevention, of adolescent PCOS than the first years beyond menarche.