Puberty in girls with Prader-Willi syndrome: cohort evaluation and clinical recommendations in a Latin American tertiary center.

Introduction: Prader-Willi syndrome (PWS) is a genetic disorder characterized by hypothalamic-pituitary deficiencies including hypogonadism. In girls with PWS, hypogonadism can present early in childhood, leading to genital hypoplasia, delayed puberty, incomplete pubertal development, and infertility. In contrast, girls can present with premature activation of the adrenal axis leading to early pubarche and advanced bone age. We aim to evaluate the progression of puberty and adrenarche signals in girls with PWS. Methodology: A longitudinal retrospective cohort study included girls with PWS followed at a Pediatric Endocrinology Outpatient Clinic in a Tertiary University Hospital in Sao Paulo, Brazil from 2002 to 2022. Data collected via chart review included clinical information on birth history, breast and pubic hair Tanner stages, presence of genital hypoplasia, age at menarche, regularity of menstrual cycles, body mass index (BMI) z-score, final height, age of initiation of estrogen replacement and growth hormone replacement, as well as results for PWS genetic subtype; biochemical investigation (LH, FSH, estradiol, DHEA-S); radiographic bone age and pelvic ultrasound. Results: A total of 69 girls were included in the study and the mean age of puberty onset was 10.2 years in those who started puberty after the age of 8 years. Breast Tanner stage IV was reached by 29.1% girls at a mean age of 14.9 years. Spontaneous menarche was present in 13.8% and only one patient had regular menstrual cycles. Early adrenarche was seen in 40.4% of cases. Conclusion: Our study demonstrated in a large sample that girls with PWS often present with delayed onset of puberty despite frequent premature adrenarche. Based on our results, we suggest an estrogen replacement protocol for girls with PWS to be started at the chronological age or bone age of 12-13 years, taking into consideration the uterus size. Further prospective studies are needed.

Differential methylation pattern in pubertal girls associated with biochemical premature adrenarche.

Biochemical premature adrenarche is defined by elevated serum DHEAS [≥40 µg/dL] before age 8 y in girls. This condition is receiving more attention due to its association with obesity, hyperinsulinemia, dyslipidemia, and polycystic ovary syndrome. Nevertheless, the link between early androgen excess and these risk factors remains unknown. Epigenetic modifications, and specifically DNA methylation, have been associated with the initiation and progression of numerous disorders, including obesity and insulin resistance. The aim of this study was to determine if prepubertal androgen exposure is associated with a different methylation profile in pubertal girls. Eighty-six healthy girls were studied. At age 7 y, anthropometric measurements were begun and DHEAS levels were determined. Girls were classified into Low DHEAS (LD) [<42 µg/dL] and High DHEAS (HD) [≥42 µg/dL] groups. At Tanner stages 2 and 4 a DNA methylation microarray was performed to identify differentially methylated CpG positions (DMPs) between HD and LD groups. We observed a differential methylation pattern between pubertal girls with and without biochemical PA. Moreover, a set of DNA methylation markers, selected by the LASSO method, successfully distinguished between HD and LD girls regardless of Tanner stage. Additionally, a subset of these markers were significantly associated with glucose-related measures such as insulin level, HOMA-IR, and glycaemia. This pilot study provides evidence consistent with the hypothesis that high DHEAS concentration, or its hormonally active metabolites, may induce a unique blood methylation signature in pubertal girls, and that this methylation pattern is associated with altered glucose metabolism.

High DHEAS in girls and metabolic features throughout pubertal maturation.

CONTEXT: An association between premature adrenarche and metabolic syndrome at presentation has been described. Our aim was to assess whether the presence of high dehydroepiandrosterone sulphate (DHEAS [HD]) at the adrenarche determines the risk of metabolic syndrome during puberty, taking into account body mass index (BMI) and birth weight. DESIGN: Prospective observational. PATIENTS: Five hundred four girls from the Growth and Obesity Chilean Cohort Study were followed from birth through puberty. At age ~7, subjects were classified by DHEAS concentrations into the HD (>75th percentile) or normal DHEAS (ND, ≤75th percentile) subgroups. MEASUREMENTS: Anthropometrics, semiannual clinical pubertal staging and hormonal and metabolic levels. The relationships among DHEAS at age ~7, metabolic syndrome, and each of its components independently, were analyzed by linear and logistic regression models during puberty and 1-year postmenarche, adjusted by confounders. RESULTS: Girls with HD at 7 years exhibited higher BMI, more central fat and higher serum androgen and insulin like growth factor (IGF)-I levels throughout puberty. Also, girls with HD had a greater prevalence of hyperglycemia at B2 and B4 breast stages, and of low HDL at B4. At 1 year after menarche, HD girls had a higher prevalence of metabolic syndrome, and those with BMI > 1 SD score had a higher metabolic score and insulin levels than ND girls with similar BMI. CONCLUSIONS: Our observations suggest that girls with HD at the age of adrenarche may be at greater risk for metabolic syndrome at adolescence, especially in those who are overweight or obese. Our results emphasize the importance of lifestyle interventions for childhood overweight and obesity among girls with HD.

Variantes de la pubertad precoz en las niñas / Variants of precocious puberty in girls

Introducción: El inicio de la pubertad está determinado por la interacción entre factores genéticos y reguladores. En las niñas ocurre alrededor de los ocho años. Puede afectarse cuando existe una pubertad adelantada, pubertad precoz o una variante de la pubertad. Para su diferenciación los estudios imagenológicos se han convertido en una herramienta vital. Objetivo: Describir aspectos fisiopatológicos, clínico-epidemiológicos y del diagnóstico por imágenes de la pubertad precoz y de sus variantes puberales en las niñas. Métodos: Se realizó una revisión sistemática a través de términos de búsqueda según descriptores en ciencias de la salud. Se utilizaron artículos de libre acceso en las bases de datos de PubMed, SciELO y Google Académico. De un total de 125 artículos, se utilizaron 45 de mayor interés: 34 en idioma español y nueve en inglés, que incluyeron libros y revistas. Análisis e integración de la información: Constituye un desafío distinguir la pubertad precoz de la telarquia, pubarquia, adrenarquia o menarquia aislada de aparición precoz, ya que son variantes del desarrollo puberal. Para su diagnóstico es importante descartar una causa tratable subyacente. El examen físico, análisis de laboratorio y estudios por imágenes, permiten diferenciar las formas completas de sus variantes y las posibles causas que determinan la estimulación de la producción hormonal. Conclusiones: El conocimiento del desarrollo normal de la pubertad y la aparición de sus variantes en las niñas resultan de gran utilidad. Su detección temprana ayudaría a recibir atención médica y descartar mediante métodos de imágenes sus causas secundarias(AU)

Introduction: The start of puberty is determined by the interaction between genetic and regulatory factors. Among girls this occurs around the age of eight years. However, the process may be affected by the presence of early puberty, precocious puberty or a variant of puberty. Imaging studies have become a vital tool for their differentiation. Objective: Describe the pathophysiological, clinical-epidemiological and imaging diagnostic aspects of precocious puberty and its pubertal variants in girls. Methods: A systematic review was conducted using search terms obtained from health sciences descriptors. The documents reviewed were open access papers from the databases PubMed, SciELO and Google Scholar. Of a total 125 papers retrieved, a selection was made of the 45 of greatest interest: 34 in Spanish and 9 in English, including books and journals. Data analysis and integration: Distinguishing precocious puberty from thelarche, pubarche, adrenarche or isolated premature menarche is a challenge, for these are variants of pubertal development. Ruling out an underlying treatable cause is important for diagnosis. Physical examination, laboratory analysis and imaging studies make it possible to differentiate complete forms from their variants and the possible causes determining the stimulation of hormone production. Conclusions: Knowledge about the normal development of puberty and the emergence of its variants in girls is very useful. Early detection would pave the way for medical care, including imaging studies to rule out its secondary causes(AU)

The timing of adrenarche in Maya girls, Merida, Mexico.

BACKGROUND: Adrenarche involves maturation of the hypothalamic-pituitary-adrenal axis and increased production of dehydroepiandrosterone and its sulfate ester, dehydroepiandrosterone-sulfate (DHEA-S). It occurs at ages 6 to 8 in industrialized populations, marking the transition from childhood to juvenility and cognitive development at middle childhood. Studies in subsistence level populations indicate a later age (8-9) for adrenarche, but only two such studies currently exist for comparison. AIMS: To investigate adrenarcheal age among Maya girls and its association with body composition and dietary variables. We hypothesized adrenarche would occur earlier given the current dual burden of nutrition in Mexico. MATERIALS AND METHODS: 25 Maya girls aged 7 to 9 from Merida, Mexico using ELISAs to measure salivary DHEA-S, standard anthropometry for height, weight, and skinfolds, bioelectrical impedance for body composition variables, as well as a food frequency questionnaire for dietary information. RESULTS: Our hypothesis was rejected-adrenarche occurred close to 9 years. While no measures of body composition were significantly associated with adrenarcheal status, girls eating meat and dairy products more frequently had significantly higher DHEA-S levels. DISCUSSION: Like other populations living in ecologically challenging environments, adrenarche occurred relatively late among Maya girls. Adrenarche has been linked to measures of body composition, particularly, the adiposity or body mass index rebound, but no relevant anthropometric measures were associated, possibly because of the small sample. CONCLUSION: Further studies are required to illuminate how adrenarcheal variation relates to developmental plasticity, body composition, pubertal progression, and animal product consumption in other transitional populations.

Metabolic and hormonal assessment of adolescent and young adult women with prior premature adrenarche.

OBJECTIVE: Follow-up studies of girls with premature adrenarche have reported the development of polycystic ovary syndrome, insulin resistance, and dyslipidemia and a propensity to cardiovascular disease. The aim of this study was to analyze the presence of these conditions in patients previously treated at the Universidade Federal do Triângulo Mineiro. METHODS: A total of 130 medical records reported premature adrenarche. One hundred and twenty-two patients were invited to participate, of whom 54 accepted; 34 patients were selected, as they had reached their final height. Anthropometric, blood glucose, insulin, and lipid and hormonal profile (LH, FSH, estradiol, 17α-OH-progesterone, androstenedione, dehydroepiandrosterone sulfate, testosterone) data were obtained, the HOMA-IR index was calculated, and pelvic ultrasonography was performed. To characterize polycystic ovary syndrome and metabolic syndrome, the Rotterdam and International Diabetes Federation criteria, respectively, were used. Data were analyzed according to measures of dispersion, frequency and correlations of interest. RESULTS: The age of the participants ranged from 15.2 to 28.2 years/months; 23.5% of the patients were overweight, 11.8% were obese, 29.4% had a large waist circumference, and 8.8% were hypertensive. None of the patients had altered glucose levels, and insulin levels and HOMA-IR were elevated in 29.4% and 38.2% of the participants, respectively; 14.7% of the patients exhibited acanthosis nigricans. The lipid profiles of the participants were variable, and one patient (2.9%) had metabolic syndrome. Polycystic ovary syndrome was found in 41.2% of patients. CONCLUSION: The percentage of patients with polycystic ovary syndrome who also had overweight, obesity and insulin resistance corroborates the literature data about the need for follow-up aiming at interventions, especially for conditions associated with cardiometabolic risk.

High DHEAS Level in Girls Is Associated with Earlier Pubertal Maturation and Mild Increase in Androgens throughout Puberty without Affecting Postmenarche Ovarian Morphology.

OBJECTIVE: To assess whether the presence of high DHEAS (HD) at 7 years determines different timing, sequence, and rate of pubertal events, and whether it is associated with adrenal and/or ovarian hyperandrogenism and changes in ovarian morphology throughout puberty. METHODS: In a longitudinal study of 504 girls, clinical evaluation was performed every 6 months after 7 years of age to detect Tanner stages; hormonal and anthropometric measurements were conducted at thelarche (B2), breast Tanner 4 (B4), and 1 year after menarche; ultrasonographic evaluation was also performed after menarche. The girls were classified as HD if their DHEAS level was >42.1 µg/dL (>75th percentile) around 7 years. RESULTS: HD around 7 years is associated with a younger age at thelarche, pubarche, and menarche. Girls with HD had higher androstenedione and total testosterone levels, and a higher free androgen index (FAI), and lower levels of antimüllerian hormone (AMH) at B2, and higher levels of androstenedione and FAI at B4 and after menarche. All these results were significant even after adjusting for body mass index, age at first DHEAS determination, and birth weight. One year after menarche, polycystic ovarian morphology was detected in 7.6 and 7.3% of the HD and the normal DHEAS group, respectively. Ovarian volume was correlated with AMH, testosterone, androstenedione, and LH but not with DHEAS around 7 years. CONCLUSION: Prepubertal HD in normal girls was associated with earlier thelarche, pubarche, and menarche, and a mild androgen increase throughout puberty. We believe continuous follow-up of this cohort is important to prospectively address the interrelationships between biochemical adrenarche and early growth as determinants of ovarian function.

Anti-Müllerian Hormone in Girls with Premature Adrenarche: The Impact of Polycystic Ovary Syndrome History in their Mothers.

OBJECTIVES: To assess whether the serum levels of anti-Müllerian hormone (AMH) are increased in girls with premature adrenarche because they are at a higher risk of developing polycystic ovary syndrome (PCOS) later in life. STUDY DESIGN: We measured serum levels of AMH, dehydroepiandrosterone sulfate (DHEAS), testosterone, sex hormone binding globulin, androstenedione, and 17-hyroxyprogesterone in 89 girls with premature adrenarche aged 6.98 ± 1.60 years, and in 55 prepubertal normal girls aged 6.78 ± 1.60 years. RESULTS: AMH was significantly higher in girls with premature adrenarche (2.95 ± 1.20 ng/mL) compared with normal prepubertal girls (2.00 ± 0.95 ng/mL; P < .001), whereas their body mass index SD score was similar (P > .05). DHEAS, testosterone, and androstenedione were increased in premature adrenarche, whereas sex hormone binding globulin was decreased in girls with premature adrenarche. Among the 89 girls with premature adrenarche, 33 were daughters of mothers with a positive history of PCOS, whereas the mothers of the remaining 56 girls with premature adrenarche had a negative history of PCOS. The girls with a mother with a positive history of PCOS had significantly higher AMH serum levels compared with girls with a mother with a negative history of PCOS (3.37 ± 1.72 ng/mL vs 2.70 ± 1.25 ng/mL; P < .05) with no differences in testosterone, DHEAS, androstenedione, and sex hormone binding globulin. The serum concentration of AMH was only positively related to androstenedione (r = 0.538; P < .0001). CONCLUSIONS: Girls with premature adrenarche, especially those from mothers with a history of PCOS, could have a higher risk of developing PCOS later in life because they have increased serum AMH.

Metabolic and hormonal assessment of adolescent and young adult women with prior premature adrenarche

OBJECTIVE: Follow-up studies of girls with premature adrenarche have reported the development of polycystic ovary syndrome, insulin resistance, and dyslipidemia and a propensity to cardiovascular disease. The aim of this study was to analyze the presence of these conditions in patients previously treated at the Universidade Federal do Triângulo Mineiro. METHODS: A total of 130 medical records reported premature adrenarche. One hundred and twenty-two patients were invited to participate, of whom 54 accepted; 34 patients were selected, as they had reached their final height. Anthropometric, blood glucose, insulin, and lipid and hormonal profile (LH, FSH, estradiol, 17α-OH-progesterone, androstenedione, dehydroepiandrosterone sulfate, testosterone) data were obtained, the HOMA-IR index was calculated, and pelvic ultrasonography was performed. To characterize polycystic ovary syndrome and metabolic syndrome, the Rotterdam and International Diabetes Federation criteria, respectively, were used. Data were analyzed according to measures of dispersion, frequency and correlations of interest. RESULTS: The age of the participants ranged from 15.2 to 28.2 years/months; 23.5% of the patients were overweight, 11.8% were obese, 29.4% had a large waist circumference, and 8.8% were hypertensive. None of the patients had altered glucose levels, and insulin levels and HOMA-IR were elevated in 29.4% and 38.2% of the participants, respectively; 14.7% of the patients exhibited acanthosis nigricans. The lipid profiles of the participants were variable, and one patient (2.9%) had metabolic syndrome. Polycystic ovary syndrome was found in 41.2% of patients. CONCLUSION: The percentage of patients with polycystic ovary syndrome who also had overweight, obesity and insulin resistance corroborates the literature data about the need for follow-up aiming at interventions, especially for conditions associated with cardiometabolic risk.

Implicancias del polimorfismo de repeticiones de glutamina del receptor de andrógenos en la presentación de eventos peripuberales / Implications of androgen receptor gene glutamine repeat polymorphism in the presentation of peripubertal events

Puberty is a period of transition during which girls and boys acquire secondary sexual characteristics and reproductive capacity. The order of appearance of the pubertal traits accounts for a correct or otherwise incorrect activation of the hypothalamic-pituitary-gonadal axis. The growth of the pubic hair before 8 years in girls and 9 years in boys (precocious pubarche, PP) without any other apparent cause has been largely attributed to the early increase of adrenal androgen levels. Also, premature adrenarche (PA) was traditionally considered an extreme within the normal range, however emerging evidence links early androgen excess with the metabolic syndrome. In this context, it has been suggested that an exacerbated clinical manifestation of androgens may be related to greater sensitivity of the androgen receptor (AR). The purpose of this review is to summarize the current knowledge of the contribution of the CAG repeats polymorphisms of AR in the peripubertal manifestations of androgens with special emphasis on precocious pubarche and body composition

Early Adiposity Rebound and Premature Adrenarche.

OBJECTIVES: To examine differences in the growth pattern and the age at adiposity rebound (AR) between children with premature adrenarche (PA) and their healthy peers (controls). STUDY DESIGN: In this cross-sectional study of 82 prepubertal children with PA and 63 controls, the main outcome measures were height and body mass index SDS progression, from birth to presentation at the clinic, baseline biochemical and hormonal evaluation, bone age determination, and age at AR. RESULTS: Children with PA were significantly taller and more adipose than controls from the first years of life. 33% of children with PA presented the growth pattern of constitutional advancement of growth (ie, early growth acceleration) vs 19% of controls (P = .045). Children with PA had an earlier AR compared with controls; mean age at AR in girls with PA was 3.73 (1.03) years vs 4.93 (1.36) years for control girls (P = .001) and in boys with PA was 3.45 (0.73) vs 5.10 (1.50) years in control boys (P = .048). Both obese and nonobese girls with PA were taller and had earlier age at AR compared with nonobese controls. CONCLUSIONS: Early AR and constitutional advancement of growth may be triggering factors for adrenal androgen production and PA.

Early BMI Gain and Later Height Growth Predicts Higher DHEAS Concentrations in 7-Year-Old Chilean Children.

BACKGROUND: Accelerated weight and height gain in infancy have been associated with premature adrenarche. However, the exact tempo of these events remains undefined. Thus, our goal was to assess the relationship between early BMI and height growth in different periods before 7 years of age and plasma DHEAS levels at 7 years of age. METHODS: This is a longitudinal follow-up of participants of the Growth and Obesity Chilean Cohort Study (GOCS) that represents Chilean children from low- to middle-income families. The subjects were 972 children (48% girls) with birth weights of 2,500-4,500 g for whom serial weight and height measurements from birth until 7 years were available. At 7 years of age, we also measured DHEAS, IGF-I, leptin, insulin, and other metabolic markers in serum. The main outcome of interest was plasma DHEAS concentrations at 7 years of age. RESULTS: At 7 years of age, children with DHEAS >75th percentile of the sample were taller and fatter and presented higher HOMA-IR and IGF-I than their counterparts (p < 0.05). Children with higher DHEAS were heavier at 4 years of age and beyond compared to their counterparts (higher BMI [BMI SDS at 4 years: 1.16, 95% CI 1.02-1.29 vs. 0.83, 95% CI 0.76-0.91, p < 0.001]) and taller at 7 years of age (height SDS at 7 years: 0.19, 95% CI -0.08 to 0.31 vs. -0.001, 95% CI -0.06 to 0.06, p < 0.005). CONCLUSIONS: We observed weight and BMI from 2 to 4 years, and height gains from 4 to 7 years were associated with higher DHEAS levels at 7 years.

Crecimiento compensador, adrenarca y función hipotálamo-hipofiso-gonadal en función del polimorfismo del gen del receptor de Hormona de Crecimiento en nacidos pequeños para edad gestacional / Compensatory growth, adrenarche, and hypothalamic-pituitary-gonadal function as a function of growth hormone receptor gene polymorphism in small-for-gestational-age infants

INTRODUCCIÓN El receptor de la hormona de crecimiento (GHR) presenta un polimorfismo causado por la deleción del exon 3 que simula un splicing alternativo. Este polimorfismo ha sido asociado con aumento de la respuesta al tratamiento con rhGH en pacientes pequeños para edad gestacional (PEG). Sin embargo, existen pocos datos acerca del crecimiento compensador espontáneo y la adrenarca en relación con las variantes alélicas de GHR en esta población y se ahn reportado datos controversiales acerca de su influencia en la edad de inicio puberal. OBJETIVO El objetivo del estudio es evaluar la relación entre las variantes polimórficas de GHR y la adrenarca, edad de inicio puberal y el crecimiento compensador en pacientes PEG. DISEÑO Estudio descriptivo de corte transversal. Se incluyeron sesenta (60) pacientes púberes y prepúberes (38 varones) que asistieron al servicio de endocrinología de un hospital pediátrico de alta complejidad. Se tipificaron las variantes de GHR mediante PCR-duplex. Se documentaron los datos antropométricos y la edad de inicio puberal establecida utilizando parámetros clínicos y hormonales mediante la determinación de los niveles séricos de gonadotrofinas, testosterona y estradiol. Los niveles séricos de DHEAS fueron utilizados para evaluar la adrenarca. RESULTADOS La proporción de pacientes que presentaron crecimiento compensador fue significativamente mayor en los portadores de al menos un alelo d3 (GHRd3/-)(n=11/22; 50%) cuando se los compraró con el grupo de pacientes GHRfl/fl (n=7/38; 18%) p= 0,02. En concordancia, los valores de IGF1 séricos ajustados por edad fueron más elevados en los pacientes GHR d3/- (-0.25 ±0.96) cuando se los comparó con los portadores del genotipo GHRfl/fl (-0.46 ±1.09 ), p=0.03. No se encontraron diferencias en la edad de inicio puberal ni en los valores séricos de DHEAS entre los diferentes genotipos. DISCUSIÓN En pacientes PEG, la deleción del exón 3 de GHR se asocia un mayor crecimiento compensador y a niveles sericos mas elevados de IGF1 en función del sexo y la edad. Los resultados del estudio permiten proponer que la delecion del exón 3 en el genotipo del GHR podría ser una variable involucrada en el crecimiento compensador de los PEG. Sin embargo este polimorfismo no estaría asociado al inicio de la adrenarca humana

Desenvolvimento sexual e maturação puberal / Sexual and puberal development

Os fenômenos do desenvolvimento sexual e puberal são eventos progressivos e coordenados. Dependem de fatores cromossômicos - gênicos, gonadais e hormonais. Tais eventos nos indivíduos do sexo masculino e feminino, sendo sincrônicos, permitirão um conveniente desenvolvimento sexual e puberal. Analisar tais fenômenos é o propósito deste estudo.(AU)

The sexual and puberal modifications are coordinate and progressive during differents life phases. Many factors are involved like genic-chromosomic, gonadal and hormonal. Those events that occurred in males and females are synchronous and to create a perfect development. Our proposal is review those situations.(AU)

Obesity is positively associated with dehydroepiandrosterone sulfate concentrations at 7 y in Chilean children of normal birth weight.

BACKGROUND: In low-birth-weight girls, obesity increases the risk of premature adrenarche and metabolic complications. However, the consistency of this association in normal-birth-weight children and its potential mediators remain unknown. OBJECTIVES: The objectives were to assess the associations between obesity indicators and dehydroepiandrosterone sulfate (DHEAS) at 7 y of age and to evaluate the role of hormonal markers on these associations. DESIGN: We assessed in 969 participants (6.9 y; 48% girls; all Tanner I) in the Growth and Obesity Chilean Cohort Study the associations between DHEAS and weight, BMI, waist circumference (WC), waist-to-height ratio, skinfold thickness, and percentage total fat (bioimpedance) and determined whether these associations were related to insulin, insulin-like growth factor I (IGF-I), and leptin. We also compared BMI and height growth from 0 to 7 y of age in nonobese and obese children with normal and high DHEAS (≥75th percentile) at 7 y. RESULTS: DHEAS concentrations were similar between girls (30.3 ±1.86 µg/dL) and boys (29.4 ±1.73 µg/dL) (P > 0.05); 17.3% of children were obese (BMI-for-age z score ≥2 SD). Adiposity indicators were positively and similarly associated with DHEAS [ie, BMI, ß standardized regression coefficient: 0.23 (95% CI: 0.17, 0.29); WC, ß standardized regression coefficient: 0.23 (95% CI: 0.16, 0.30)]; these associations were only partially related to IGF-I and leptin. Obese children had twice the risk of high DHEAS (OR: 2.16; 95% CI: 1.51, 3.09); at 7 y, obese children with high DHEAS were fatter and more centrally obese than their counterparts (P < 0.05), although their previous growth was similar (P > 0.05). None of the results differed by sex (P > 0.05). CONCLUSION: In children of normal birth weight, obesity is positively associated with DHEAS at 7 y of age.

Interrelationship of extent of precocious adrenarche in appropriate for gestational age girls with clinical outcome.

OBJECTIVE: To assess the interrelationship between extent of adrenarche at presentation in girls with precocious adrenarche (PA) born appropriate for gestational age and their growth pattern, pubertal course and adult height. STUDY DESIGN: We reviewed clinical and laboratory data from medical charts of 85 girls with PA aged 5.0 to 8.8 years at referral, stratified in 3 subgroups according to bone age (BA) minus chronological age (CA) ≤0 years; 0 1 year. RESULTS: Extent of pubarche and dehydroepiandrosterone-sulfate levels were greatest in the BA-CA >1 subgroup (P=.02, P=.008, respectively), who also were taller at diagnosis (P=.002) and during childhood (P=.01). In all subgroups, pubertal onset was within normal range; menarche occurred earlier than in control subjects (P<.02); all attained adult height within their mid-parental height range. Predicted adult height was overestimated in girls with BA ≤CA (P=.04) and underestimated with BA-CA >1 (P<.001). CONCLUSIONS: Although a more pronounced adrenarche and BA advancement at diagnosis in girls with PA born appropriate for gestational age had an impact on their pre-pubertal growth pattern, it was not associated with early and rapid progression of puberty or reduced adult height. This reassuring clinical course indicates that PA is a benign condition, irrespective of the extent of adrenarche at presentation. Adult height prediction is unreliable in PA.

Utility of early insulin response and proinsulin to assess insulin resistance.

OBJECTIVE: To determine whether obesity and premature adrenarche are additive events increasing the risk of insulin resistance and beta-cell failure, using early insulin response (EIR) or the insulinogenic index and proinsulin (PI) as markers. STUDY DESIGN: This was a prospective case-control study conducted at a tertiary care academic medical center involving 81 prepubertal, predominantly Hispanic children (34 males, 47 females), classified as lean controls (4 males, 6 females; mean age, 6.5 +/- 1.2 years; mean body mass index [BMI] z-score, 0.08 +/- 0.6), obese controls (20 males, 10 females; mean age, 7.2 +/- 1.5 years; mean BMI z-score, 2.5 +/- 0.5), lean premature adrenarche (3 males, 11 females; mean age, 7.1 +/- 1.2 years; mean BMI z-score, 0.09 +/- 0.6), and obese premature adrenarche (7 males, 20 females; mean age, 7.3 +/- 1.0; mean BMI z-score, 2.2 +/- 0.4). Fasting glucose (G(0)), insulin (I(0)), PI(0), androgen levels, insulin-like growth factor 1, insulin-like growth factor binding protein 1, and lipid levels were obtained. An oral glucose tolerance test was performed. EIR was calculated as (I(30) - I(0))/(G(30) - G(0)). Between-group differences were assessed by 2-way analysis of variance, with interactions and associations explored with correlation/regression. RESULTS: EIR was greater in the obese subjects with and without premature adrenarche. Combined analysis of the independent variables obesity and premature adrenarche showed that the obese premature adrenarche group had the highest EIR. The obese subjects with premature adrenarche had greater fasting PI levels than their lean counterparts. The differences in fasting PI/I ratio among the groups were not statistically significant. CONCLUSIONS: Using EIR and PI as markers to assess the risk of insulin resistance and impaired insulin secretion indicates that obese children with premature adrenarche may be at greater risk for the development of prediabetes and type 2 diabetes mellitus compared with their lean counterparts.

Girls with premature adrenarche have accelerated early childhood growth.

OBJECTIVE: To evaluate the effect of premature adrenarche (PA) on prepubertal growth. STUDY DESIGN: The prepubertal growth of 54 girls with PA and 52 control girls was analyzed retrospectively. Birth measures were noted, and childhood length/height and weight were measured annually until age 5 years and at the current visit (at a median age of 7.6 years). The growth variables were correlated with serum insulin-like growth factor (IGF)-1, dehydroepiandrosterone sulfate, and insulin concentrations. RESULTS: There were no significant differences in birth length or weight standard deviation scores (SDSs) between the 2 study groups. The girls with PA demonstrated a significant length SDS increment during the first 2 years of life (median +1.0 SDS; P < .001). Compared with controls, they were taller (median current height 1.2 vs 0 SDS; P < .001) and gained more weight throughout childhood. The difference in weight-for-height became significant at a later age compared with the difference in height. Median serum IGF-1 concentration adjusted for both age and body mass index SDS was higher in the PA group (24 vs 19 nmol/L; P < .031). CONCLUSIONS: PA was not associated with small birth size in our population. Girls with PA had enhanced growth already in early childhood, which was not explained by weight gain. Enhanced IGF-1 production may contribute to the prepubertal growth acceleration in PA.

Expression of the IGF and the aromatase/estrogen receptor systems in human adrenal tissues from early infancy to late puberty: implications for the development of adrenarche.

Adrenarche is a process of postnatal sexual maturation occurring in higher primates, in which there is an increase in the secretion of adrenal androgens. It is the consequence of a process of postnatal organogenesis characterized by the development of a new zone in the adrenal cortex, the zona reticularis (ZR). The mechanism of this phenomenon remains poorly understood, suggesting that it might be a multifactorial event. A relationship between circulating IGF-I, insulin sensitivity, and adrenal androgens has been postulated. Boys and girls have different patterns of changes in insulin sensitivity at puberty, perhaps secondary to differences in the estrogen milieu. Estrogen effects may also play a role in premature adrenarche. Peripheral or local IGF-1 actions could regulate adrenal progenitor cell proliferation and migration. Since adrenal progenitor cells as well as IGF-I and the IGF-R1 are located in the outer zone of the adrenal cortex during childhood and adolescence, this peripheral cell layer, below the capsule, may contain undifferentiated progenitor cells. Therefore, the IGF-R1 signaling pathway might positively modulate the proliferation and migration of adrenal progenitor cell to stimulate the development of adrenal zones, including ZR. However, no evidence of a direct action of IGF-I on ZR was found. In addition, a role for estrogens in the ontogenesis of ZR is suggested by the presence of aromatase (CYP19) in the subcapsular zona glomerulosa and in the adrenal medulla. Estrogens produced locally could act on ZR by interacting with estrogen receptor beta (ERbeta), but not alpha, and membrane estrogen receptor GPR-30. An estradiol-induced increase in DHEA/cortisol ratio was indeed seen in cultures of adrenocortical cells from post-adrenarche adrenals. In summary, several lines of evidence point to the action of multiple factors, such as local adrenal maturational changes and peripheral metabolic signals, on postnatal human adrenal gland ZR formation.