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Lourdes Ibáñez

Publications and source records attributed to Lourdes Ibáñez.

At least 19 recordsLinked to original sources
PubMed2006

Puberty and prenatal growth.

There is increasing evidence for a link between puberty and prenatal growth. Here we highlight a selection of pubertal characteristics in children who were born small-for-gestational-age (SGA). Boys born SGA are at risk for high FSH and low inhibin B levels, and a small testicular volume in adolescence. In girls born SGA, the age at pubertal onset and the age at menarche are advanced by about 5-10 months; prenatal growth restraint may be associated with higher FSH levels and with small internal genitalia in adolescence. The ovulation rate was found to be low in SGA adolescents, and an insulin-sensitizing therapy was capable of raising this low ovulation rate. Menarche is definitely advanced in SGA girls with precocious pubarche. Current evidence suggests that insulin resistance is a key mechanism linking a post-SGA state to early menarche; hence, insulin sensitization may become a valid approach to prevent early menarche and early growth arrest in SGA girls.

Age Factors↗
PubMed2006

Metformin treatment to prevent early puberty in girls with precocious pubarche.

CONTEXT AND OBJECTIVE: 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. SETTING, DESIGN, AND PATIENTS: 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. MAIN OUTCOME MEASURES: 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. RESULTS: 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. CONCLUSION: 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.

Adrenarche↗
PubMed2006

Hirsutism.

Explore the source record for details and available documents.

Androgen Antagonists↗
PubMed2006

Early development of adiposity and insulin resistance after catch-up weight gain in small-for-gestational-age children.

CONTEXT AND OBJECTIVE: Low birth weight followed by rapid postnatal weight gain is associated with long-term risks for central obesity and insulin resistance. However, the timing of these changes is unclear. SETTING, DESIGN, AND PATIENTS: This was a longitudinal cohort study in low birth weight (SGA; birth weight < -2 sd; n = 29) and normal birth weight (AGA; n = 22) children from Barcelona. MAIN OUTCOME MEASURES: Body composition, by dual-energy x-ray absorptiometry scan, and insulin sensitivity, assessed longitudinally at ages 2, 3, and 4 yr, were measured. RESULTS: Mean height, weight, and body mass index at ages 2, 3, and 4 yr were not different between SGA and AGA children. At age 2 yr, SGA children had similar body composition but were more insulin sensitive than AGA children and had lower serum IGF-I levels and lower neutrophil counts. Between ages 2 and 4 yr, despite similar gains in weight and body mass index, SGA children gained more abdominal fat and body adiposity and less lean mass than AGA children; by age 4 yr, SGA children had greater adiposity, insulin resistance, and higher neutrophil counts than AGA children (P = 0.01-0.0004). In SGA children, total and abdominal fat mass at 4 yr was more closely related to rate of weight gain between 0 and 2 yr (P = 0.002-0.0003) than between 2 and 4 yr (P = 0.04-0.1). CONCLUSION: Consequent to catch-up weight gain between birth and 2 yr, SGA children showed a dramatic transition toward central adiposity and insulin resistance between ages 2 and 4 yr. Understanding the mechanisms underlying this predisposition to adverse future health could lead to specific preventive interventions during early childhood.

Adiposity↗
PubMed2006

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.

CONTEXT AND OBJECTIVE: 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. SETTING, DESIGN, AND PATIENTS: 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. MAIN OUTCOME MEASURES: 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. RESULTS: 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. CONCLUSION: 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.

Body Composition↗
PubMed2006

Associations between common variation in the aromatase gene promoter region and testosterone concentrations in two young female populations.

We recently reported association between a coding-region single nucleotide polymorphism (SNP50) in the aromatase gene that encodes a key enzyme in testosterone metabolism, with risk for the development of precocious pubarche and circulating testosterone concentrations in two independent female populations. We have now explored further association with variation in the promoter-region of the aromatase gene. We genotyped six promoter-region haplotype-tag SNPs in young women from Oxford, UK (n = 109), and in girls with precocious pubarche (n = 186) and controls (n = 71) from Barcelona, Spain. Aromatase distal promoter-region variation was associated with plasma testosterone concentrations in both Oxford (r(2) = 18.3%, p = 0.01) and Barcelona (r(2) = 8.5%, p = 0.03) females. These associations were independent of SNP50, but appeared to be dependent on different SNPs in Oxford (r(2) = 13.7%, p = 0.006 with SNPs 11 (p = 0.009), 28 (p = 0.02) and 39 (p = 0.06)) and Barcelona (r(2) = 5.9%, p = 0.002 with SNP43 (p = 0.002)) populations. Aromatase distal promoter-region variation was also associated with PCOS symptom score in Oxford women (r(2) = 14.5%, p = 0.048), but, unlike SNP50, was not associated with precocious pubarche risk in Barcelona girls. In conclusion, aromatase distal promoter-region variation appears to have functional consequences for plasma testosterone concentrations in females. The variable associations with androgen-related clinical features could possibly reflect the tissue-specific promoters of the aromatase gene.

Adolescent↗
PubMed2006

Low-dose flutamide-metformin therapy for hyperinsulinemic hyperandrogenism in non-obese adolescents and women.

Polycystic ovary syndrome (PCOS) is a variable disorder that is characterized in adolescents and young women by a broad spectrum of anomalies, including hyperandrogenemia, insulin resistance, dyslipidemia, body adiposity and low-grade inflammation. At present, there is no approved therapy for PCOS. Recent studies indicate that a low-dose combination of flutamide (Flu; a generic androgen-receptor blocker) and metformin (Met; a generic insulin-sensitizer) normalizes the adolescent PCOS spectrum more than an oral contraceptive (OC); in young women, the PCOS spectrum was found to be more normalized by OC plus Flu-Met than by OC alone. Within the pathophysiological cascade of PCOS, Flu-Met seems to counter upstream anomalies like hyperinsulinemia or hyperandrogenism, thereby preventing or reversing downstream effects. In contrast, an OC essentially masks downstream symptoms like hirsutism, acne or irregular menses, whereas the upstream aberrations remain unaltered or may even be worsened. The available experience with Flu-Met is limited but promising. We emphasize that Flu-Met may (as part of its efficacy) induce ovulation but is contra-indicated post-conception because of potential embryotoxicity; therefore, it seems wise to combine Flu-Met with an oral or a transdermal oestro-progestagen or with a non-endocrine method of contraception. May this update prompt further research into Flu-Met's therapeutic potential in patients with PCOS. Until the abovementioned effects have been broadly confirmed, Flu-Met should not be regarded as a standard therapy for widespread clinical practice.

Adolescent↗
PubMed2006

Cerebral folate deficiency and leukoencephalopathy caused by a mitochondrial DNA deletion.

OBJECTIVE: Our aim was to describe a child with an incomplete form of Kearns-Sayre syndrome who presented profound cerebrospinal fluid (CSF) folate deficiency and his response to folinic acid supplementation METHODS: CSF 5-methyltetrahydrofolate was analyzed by HPLC with fluorescence detection and mitochondrial DNA deletions by southern blot hybridization. RESULTS: Cranial magnetic resonance imaging showed a leukoencephalopathy. Profound CSF 5-methyltetrahydrofolate deficiency was observed with normal blood folate values and decreased CSF/serum folate ratio, suggesting a transport defect across the blood-brain barrier. Folinic acid treatment was established, and after 1 year clinical response to folinic supplementation was remarkable, with almost normal white matter image. INTERPRETATION: The clinical response after folinic therapy highlights the need for the study of cerebral folate deficiency in patients with mitochondrial disorders and white matter lesions.

Brain Chemistry↗
PubMed2006

Low-dose flutamide-metformin therapy for hyperinsulinemic hyperandrogenism in nonobese adolescents and women.

Hyperinsulinemic hyperandrogenism is the core of polycystic ovary syndrome (PCOS), and, accordingly, low-dose flutamide-metformin proved so far to be a most effective approach to normalize the broad spectrum of PCOS anomalies in nonobese adolescents and young women. For safety reasons, it is wise to combine flutamide-metformin with a contraceptive, for example, an oral or transdermal estroprogestagen.

Adolescent↗
PubMed2006

Prenatal growth restraint followed by catch-up of weight: a hyperinsulinemic pathway to polycystic ovary syndrome.

One of the pathways to polycystic ovary syndrome (PCOS) starts with an early-life sequence of prenatal growth restraint followed by catch-up of weight during infancy. This sequence results by mid-childhood in a pre-PCOS state including hyperinsulinemia, a low-grade proinflammatory state, an amplified adrenarche (with or without precocious pubarche), and an adipose body composition even in the absence of obesity. This variant of pre-PCOS and PCOS responds well to intervention with metformin.

Aging↗
PubMed2006

The tumour necrosis factor (TNF)-alpha-308GA promoter polymorphism is related to prenatal growth and postnatal insulin resistance.

OBJECTIVE: Variation in the tumour necrosis factor gene, (TNF) has been associated with insulin resistance traits. We questioned whether the TNF-308G/A polymorphism is associated with birthweight and insulin resistance in children born small for gestational age (SGA), a patient population known to be at risk for insulin resistance. DESIGN: A cross-sectional, hospital-based study assessing insulin sensitivity in SGA children. PATIENTS: One hundred and ninety-eight school-age children born either SGA (n=90, age 7.4+/- 4.5 years) or appropriate for gestational age (AGA, n=108, age 8.7+/- 4.0 years). MEASUREMENTS: All children were genotyped for the TNF-308G/A polymorphism; a biochemical profile was also performed in prepubertal SGA (n=58) and AGA (n=57) subjects. RESULTS: Genotype frequencies for the TNF-308G/A single nucleotide polymorphisms (SNPs) (GG and GA/AA) differed between SGA and AGA children (86%vs. 72% and 14%vs. 28%, respectively; P=0.025). The GG genotype was associated with lower birthweight and birth length (2747.0+/- 23.3 g vs. 2851.0+/- 45.7 g, P=0.045, and 47.0+/- 0.2 cm vs. 48.2+/- 0.4 cm, P=0.011, respectively) and, in AGA but not in SGA children, with higher systolic blood pressure [103.3 (95% confidence interval (CI) 96.4-110.2) mmHg vs. 92.8 (84.9-100.7) mmHg; P=0.028], higher blood glucose [4.8 (4.7-5.0) mmol/l vs. 4.5 (4.3-4.8) mmol/l; P=0.042] and higher homeostasis model assessment for insulin resistance (HOMA-IR) index [1.4 (1.1-1.7) vs. 0.9 (0.4-1.3); P=0.005]. In multivariate analysis, the TNF-308GG genotype was an independent predictor of HOMA-IR during childhood, explaining 8% of its variance. CONCLUSION: SGA children show increased frequency of the TNF-308G allele, an allele that is associated with prenatal growth and with postnatal insulin resistance. The TNF-308G/A polymorphism may have implications in the growth and metabolic abnormalities that characterise SGA children.

Birth Weight↗
PubMed2006

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 (approximately 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 (approximately 75% vs approximately 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.

17-alpha-Hydroxyprogesterone↗
PubMed2005

Discontinuous low-dose flutamide-metformin plus an oral or a transdermal contraceptive in patients with hyperinsulinaemic hyperandrogenism: normalizing effects on CRP, TNF-alpha and the neutrophil/lymphocyte ratio.

BACKGROUND: Low-dose flutamide-metformin (Flu-Met) with an oral contraceptive is a therapeutic option for women with hyperinsulinaemic hyperandrogenism. We questioned (i) whether Flu-Met maintains efficacy if given discontinuously; (ii) how the efficacy of discontinuous Flu-Met plus a transdermal contraceptive compares with Flu-Met plus oral contraceptive; and (iii) whether these treatments also lower circulating C-reactive protein (CRP) and tumour necrosis factor alpha (TNF-alpha) and the high neutrophil/lymphocyte ratio. METHODS: Non-obese, young patients (n = 31) with hyperinsulinaemic hyperandrogenism were started on Flu-Met (21/28 days) and randomized to receive in addition either a drospirenone oral contraceptive or a transdermal contraceptive for 6 months. RESULTS: The effects of Flu-Met were similar whether combined with oral or transdermal contraceptive. In both groups, CRP and TNF-alpha levels fell and the high neutrophil/lymphocyte ratio normalized (P < 0.001). Lean body mass increased (P < 0.001) in both groups but, in contrast to earlier experience with continuous Flu-Met, fat mass failed to decrease in either group. CONCLUSIONS: Flu-Met seems less lipolytic, if given for only 21 days in every 28-day period. The efficacy of Flu-Met is comparable when combined with an oral contraceptive or a transdermal contraceptive. The range of Flu-Met effects may henceforth include lower levels of CRP and TNF-alpha, and a normalization of the neutrophil/lymphocyte ratio.

Administration, Cutaneous↗
PubMed2005

Absent or delayed adrenarche in Pit-1/POU1F1 deficiency.

Mutations of the PIT1/POU1F1 gene are responsible for a rare variant of anterior hypopituitarism, including deficiency of growth hormone, prolactin and thyrotropin. In 8 ethnically diverse POU1F1-deficient patients (4 different mutations) with normal circulating levels of cortisol and adrenocorticotropic hormone, and with spontaneous onset and progression of puberty, we observed an absence or delay of adrenarche (median circulating dehydroepiandrosterone-sulfate -6.2 SD); in each of the 4 postmenarcheal females, pubarche (i.e. appearance of pubic hair) was also absent or delayed. The absence/delay of adrenarche in POU1F1-deficient patients and the absence/delay of pubarche in POU1F1-deficient females suggest that a POU1F1-dependent factor contributes to the normal development of adrenarche and female pubarche.

Adolescent↗
PubMed2005

High neutrophil count in girls and women with hyperinsulinaemic hyperandrogenism: normalization with metformin and flutamide overcomes the aggravation by oral contraception.

BACKGROUND: The endocrine hallmark of polycystic ovary syndrome (PCOS) is hyperinsulinaemic hyperandrogenism; another facet of PCOS is low-grade inflammation. METHODS: In adolescents and young women with hyperinsulinaemic hyperandrogenism (n = 118; mean age 16 years, body mass index 22 kg/m(2)), we analysed whether the PCOS-associated rise in leukocyte count is already detectable at young age and, if so, whether such elevation is lowered by metformin, flutamide-metformin, oral contraception (OC), or their combination. RESULTS: Leukocyte count (x 1000/mm(3)) in patients was high versus controls (7.5 +/- 0.1 versus 6.4 +/- 0.1; P < 0.001) due to a rise in neutrophils (4.2 +/- 0.1 versus 3.0 +/- 0.1; P < 0.001). Randomized studies at mean ages of 12.5 years (n = 24) and 15.2 years (n = 33) demonstrated normalizing effects of metformin (850 mg/day; P < 0.001) and, respectively, metformin plus flutamide (62.5 mg/day) on neutrophil counts; in young women (18.3 years; n = 41), the neutrophil count rose further on OC monotherapy (P = 0.003), but normalized on the same OC plus flutamide-metformin (P < 0.001 versus OC alone). CONCLUSIONS: (i) A high leukocyte count is already present in girls with hyperinsulinaemic hyperandrogenism, and this is due to a raised neutrophil count; (ii) this hyperneutrophilia is attenuated by metformin or flutamide-metformin, and is amplified by OC monotherapy; (iii) if these treatments are combined, the normalizing effect of flutamide-metformin overcomes the OC effect on neutrophil count.

Adolescent↗
PubMed2005

Absence of hepatotoxicity after long-term, low-dose flutamide in hyperandrogenic girls and young women.

BACKGROUND: Flutamide is a pure non-steroidal anti-androgen that may be hepatotoxic, when given in high-dose (750 mg/d). Low- to ultralow-doses (250-62.5 mg/day) have been recently explored in patients with Polycystic Ovary Syndrome (PCOS), and these lower doses were found to confer benefit on multiple PCOS markers. There is a need for evidence on the potential hepatotoxicity of low- and ultralow-dose flutamide therapy. METHODS: We assessed circulating levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) as markers of hepatotoxicity in a total of 190 hyperandrogenic girls and young women receiving low- or ultralow-dose flutamide because of established (n = 150) or incipient (n = 40) PCOS without obesity. Assessments were performed before start of flutamide, after 3 months, and subsequently at least twice yearly. RESULTS: AST and ALT results were normal at baseline, and they remained so on flutamide treatment, including between 3 months and last assessment, which was after a mean time of 19 months on low- or ultralow-dose flutamide (range 3-54 months). None of the AST or ALT levels at any time during flutamide treatment was > or = 45 U/L. CONCLUSION: We found no evidence for hepatotoxicity in 190 hyperandrogenic girls or young women receiving low- or ultralow-dose flutamide for up to 54 months. These results may represent a first step in a long process whereby the status of low- and ultralow-dose flutamide may gradually evolve from 'absence of evidence on toxicity' towards 'evidence of absence of hepatic toxicity'. Ultralow-dose flutamide may become a key component within future therapies for hyperandrogenic states in girls and young women.

Adolescent↗
PubMed2005

Neutrophil count in small-for-gestational age children: contrasting effects of metformin and growth hormone therapy.

A minority of children born small for gestational age (SGA) maintain a slow weight gain and a short stature (SS). At the other end of the spectrum are SGA children who show rapid postnatal weight gain and catch-up growth; these subjects may develop hyperinsulinemia, exaggerated adrenarche with precocious pubarche (PP), and an associated proinflammatory state with raised IL-6 and reduced adiponectin levels. Metformin therapy in SGA-PP girls attenuates the hyperinsulinemia, the adrenal androgen excess, and the proinflammatory state. In contrast, GH therapy in SGA-SS children promotes height gain but may induce hyperinsulinemia. Both groups are associated with increased risk markers for future cardiovascular disease. Therefore, we studied markers of inflammation in both SGA subpopulations at baseline and after their respectively corrective therapies. SGA-PP girls (n = 33; mean age, 8 yr; body mass index, 18.5 kg/m(2)) were randomized to remain untreated or to receive metformin (425 mg/d) for 6 months. SGA-SS children (n = 29; mean age, 7 yr; body mass index, 14.7 kg/m(2)) were randomly assigned to remain untreated or to receive GH (60 mug/kg/d). In SGA-PP girls, the mean neutrophil count (4.0 x 1000/mm(3)) was more than 2 sd above the mean reference level (2.8 x 1000/mm(3), P < 0.001); this remained stable over 6 months in untreated girls but dropped in metformin-treated girls by -1.1 x 1000/mm(3) (P = 0.002). In SGA-SS children, neutrophil counts were also higher at baseline (3.3 x 1000/mm(3), P < 0.01). This remained stable in untreated children but rose in GH-treated children by +1.1 x 1000/mm(3) (P = 0.004). GH-treated children also showed a rise in circulating IL-6 and dehydroepiandrosterone-sulfate levels and a fall in adiponectin levels. In conclusion, neutrophil counts were elevated in SGA children. In SGA girls with PP, the present results corroborate the antiinflammatory benefits of metformin therapy. In contrast, high-dose GH therapy in short SGA children may increase neutrophil counts and lead to a less favorable adipocytokine profile. Future studies with combined GH plus metformin treatment in short SGA children may clarify whether insulin resistance is a mechanism linking GH therapy to markers of inflammation.

Child↗