Association Between Markers of Adiposity During Childhood and Puberty Onset in Latino Girls.

CONTEXT: Prepubertal adiposity is associated with earlier puberty. It is unclear when this association starts, if all adiposity markers are similarly associated, and whether all pubertal milestones are similarly affected. OBJECTIVE: To evaluate the association between different adiposity markers during childhood and the timing of different pubertal milestones in Latino girls. DESIGN, SETTING, AND PARTICIPANTS: Longitudinal follow-up of 539 female participants of the Chilean Growth and Obesity Cohort recruited from childcare centers (mean age 3.5 years) from the southeast area of Santiago, Chile. Participants were singletons born between 2002 and 2003 within the normal birthweight range. Since 2006, a trained dietitian measured weight, height, waist circumference (WC) and skinfolds to estimate body mass index (BMI) Centers for Disease Control and Prevention percentiles, central obesity, percentage of fat mass (%FM), and fat mass index (FMI, fat mass/height2). MAIN OUTCOME: Since 2009, sexual maturation was assessed every 6 months to assess age at (1) thelarche, (2) pubarche, (3) menarche, and (4) peak height velocity (PHV). RESULTS: At thelarche, 12.5% were obese and 2% had central obesity. The median age of pubarche, menarche, and PHV were all associated with markers of adiposity at different time points during childhood whereas thelarche only with %FM and FMI. Adiposity clusters models showed that children with trajectories of high WC, %FM, and FMI during childhood were related with earlier thelarche, pubarche, menarche, and PHV but BMI trajectories only with menarche and PHV. CONCLUSIONS: Higher WC, %FM, and FMI were associated with earlier age at thelarche, pubarche, menarche, and PHV. The effect of BMI was less consistent.

Differences in hormonal levels between heterozygous CYP21A2 pathogenic variant carriers, non-carriers, and females with non-classic congenital hyperplasia

ABSTRACT Objective: CYP21A2 mutation heterozygote carriers seem to have an increased risk of hyperandrogenism. However, the clinical relevance of the heterozygote carrier status and the reliability of hormonal testing in discriminating a carrier from a non-carrier are puzzling questions. We aimed to characterize a population of Portuguese females suspected of having non-classic congenital adrenal hyperplasia (NC-CAH) due to clinical and biochemical criteria and who have undergone CYP21A2 molecular analysis. Subjects and methods: Retrospectively, we have analyzed the clinical records of 131 females (32 girls aged 3-9 and 99 adolescents and premenopausal women aged 13-49) who underwent complete CYP21A2 molecular analysis due to suspicion of NC-CAH. We divided included participants into three groups according to the CYP21A2 molecular analysis: NC-CAH females (46), heterozygous carriers (49), and wild type (36). We then compared clinical signs and symptoms as well as biochemical and molecular data between carriers and NC-CAH individuals and between carriers and wild type females. We measured 17OHP by electrochemiluminescence immunoassay. Results: Clinical features were similar between groups. Heterozygous carriers presented higher basal and post-cosyntropin 17-hydroxyprogesterone (17OHP) than wild type individuals (p < 0.05) and lower basal and stimulated 17OHP levels than NC-CAH patients (p < 0.05). We discovered a considerable overlap between 17OHP levels among groups. The most common pathogenic variant we identified was p.Val282Leu. Conclusion: In this population of hyperandrogenic women and children, heterozygous carriers showed higher basal and stimulated 17OHP than non-carriers although normal basal and stimulated 17OHP responses do not exclude heterozygosity for CYP21A2 pathogenic variants. In this study, only the molecular analysis presented good sensitivity in identifying heterozygotes.

Differences in hormonal levels between heterozygous CYP21A2 pathogenic variant carriers, non-carriers, and females with non-classic congenital hyperplasia.

Objective: CYP21A2 mutation heterozygote carriers seem to have an increased risk of hyperandrogenism. However, the clinical relevance of the heterozygote carrier status and the reliability of hormonal testing in discriminating a carrier from a non-carrier are puzzling questions. We aimed to characterize a population of Portuguese females suspected of having non-classic congenital adrenal hyperplasia (NC-CAH) due to clinical and biochemical criteria and who have undergone CYP21A2 molecular analysis. Methods: Retrospectively, we have analyzed the clinical records of 131 females (32 girls aged 3-9 and 99 adolescents and premenopausal women aged 13-49) who underwent complete CYP21A2 molecular analysis due to suspicion of NC-CAH. We divided included participants into three groups according to the CYP21A2 molecular analysis: NC-CAH females (46), heterozygous carriers (49), and wild type (36). We then compared clinical signs and symptoms as well as biochemical and molecular data between carriers and NC-CAH individuals and between carriers and wild type females. We measured 17OHP by electrochemiluminescence immunoassay. Results: Clinical features were similar between groups. Heterozygous carriers presented higher basal and post-cosyntropin 17-hydroxyprogesterone (17OHP) than wild type individuals (p < 0.05) and lower basal and stimulated 17OHP levels than NC-CAH patients (p < 0.05). We discovered a considerable overlap between 17OHP levels among groups. The most common pathogenic variant we identified was p.Val282Leu. Conclusion: In this population of hyperandrogenic women and children, heterozygous carriers showed higher basal and stimulated 17OHP than non-carriers although normal basal and stimulated 17OHP responses do not exclude heterozygosity for CYP21A2 pathogenic variants. In this study, only the molecular analysis presented good sensitivity in identifying heterozygotes.

Genome-Wide Association Study and Polygenic Risk Scores of Serum DHEAS Levels in a Chilean Children Cohort.

CONTEXT: Adrenarche reflects the developmental growth of the adrenal zona reticularis, which produces increasing adrenal androgen secretion (eg, dehydroepiandrosterone [DHEA]/dehydroepiandrosterone sulfate [DHEAS]) from approximately age 5 to 15 years. OBJECTIVE: We hypothesized that the study of the genetic determinants associated with variations in serum DHEAS during adrenarche might detect genetic variants influencing the rate or timing of this process. METHODS: Genome-wide genotyping was performed in participants of the Chilean pediatric Growth and Obesity Chilean Cohort Study (GOCS) cohort (n = 788). We evaluated the genetic determinants of DHEAS levels at the genome-wide level and in targeted genes associated with steroidogenesis. To corroborate our findings, we evaluated a polygenic risk score (PRS) for age at pubarche, based on the discovered variants, in children from the same cohort. RESULTS: We identified one significant variant at the genome-wide level in the full cohort, close to the GALR1 gene (P = 3.81 × 10-8). In addition, variants suggestive of association (P < 1 × 10-5) were observed in PRLR, PITX1, PTPRD, NR1H4, and BCL11B. Stratifying by sex, we found variants suggestive of association in SERBP1 and CAMTA1/VAMP3 for boys and near ZNF98, TRPC6, and SULT2A1 for girls. We also found significant reductions in age at pubarche in those children with higher PRS for greater DHEAS based on these newly identified variants. CONCLUSION: Our results disclose one variant associated with DHEAS concentrations at the level of genome-wide association study significance, and several variants with a suggestive association that may be involved in the genetic regulation of adrenarche.

A Polygenic Risk Score Suggests Shared Genetic Architecture of Voice Break With Early Markers of Pubertal Onset in Boys.

CONTEXT: Voice break, as a landmark of advanced male puberty in genome-wide association studies (GWAS), has revealed that pubertal timing is a highly polygenic trait. Although voice break is easily recorded in large cohorts, it holds quite low precision as a marker of puberty. In contrast, gonadarche and pubarche are early and clinically well-defined measures of puberty onset. OBJECTIVE: To determine whether a polygenic risk score (PRS) of alleles that confer risk for voice break associates with age at gonadarche (AAG) and age at pubarche (AAP) in Chilean boys. EXPERIMENTAL DESIGN: Longitudinal study. SUBJECTS AND METHODS: 401 boys from the Growth and Obesity Chilean Cohort Study (n = 1194; 49.2% boys). MAIN OUTCOME MEASURES: Biannual clinical pubertal staging including orchidometry. AAG and AAP were estimated by censoring methods. Genotyping was performed using the Multi-Ethnic Global Array (Illumina). Using GWAS summary statistics from the UK-Biobank, 29 significant and independent single nucleotide polymorphisms associated with age at voice break were extracted. Individual PRS were computed as the sum of risk alleles weighted by the effect size. RESULTS: The PRS was associated with AAG (ß=0.01, P = 0.04) and AAP (ß=0.185, P = 0.0004). In addition, boys within the 20% highest PRS experienced gonadarche and pubarche 0.55 and 0.67 years later than those in the lowest 20%, respectively (P = 0.013 and P = 0.007). CONCLUSIONS: Genetic variants identified in large GWAS on age at VB significantly associate with age at testicular growth and pubic hair development, suggesting that these events share a genetic architecture across ethnically distinct populations.

Role of the Androgen Receptor Gene CAG Repeat Polymorphism on the Sequence of Pubertal Events and Adiposity in Girls with High Dehydroepiandrosterone Sulfate Level.

STUDY OBJECTIVE: The androgen receptor (AR) harbors a variable repeat number of glutamine residues codified by (CAG)n, which seems to inversely affect AR transcriptional activity. We assessed whether (CAG)n affects the sequence of the androgen-sensitive pubertal events and body composition in prepubertal girls. DESIGN, SETTING, PARTICIPANTS, AND INTERVENTIONS: Nested case-control study within the Growth and Obesity Cohort Study of 1196 low-middle income children (approximately 50% girls) from a university clinic in Santiago, Chile. Cases were girls with high dehydroepiandrosterone sulfate (DHEAS; >42 µg/dL; HD) at age 7.0 (±0.4) years (n = 58). On follow-up, 32 of them had thelarche (TB2) before the age of pubarche (PH2) and 26 had PH2 before the age of TB2. As controls, 107 age-matched girls with normal DHEAS (≤42 µg/dL; ND) were selected. MAIN OUTCOME MEASURES: Methylation-weighted mean (CAG)n (mw[CAG]n) was calculated through X-chromosome methylation-sensitive enzyme restriction and polymerase chain reaction followed by automated capillary electrophoresis in peripheral blood DNA. RESULTS: Girls with HD and PH2 before the age of TB2 showed a trend to higher frequency (7/26, 26.9%) of mw(CAG)n <20 compared with ND girls (12/107; 11.2%; P = .087). Accordingly, a direct correlation between age of PH2 and mw(CAG)n was observed in HD (r = 0.352; P = .007) and in ND girls (r = 0.207; P = .033). Moreover, HD girls with mw(CAG)n less than 20 had lower waist circumference and waist/height ratio than HD girls with mw(CAG)n from 20 to less than 25 (P = .027 and P = .012, respectively) at age of DHEAS determination. CONCLUSION: Our results suggest that a greater transcriptional activity of the AR, given by short number of CAG repeats, might favor the onset of pubarche and reduce central adiposity in prepubertal girls with HD.

Hipertricosis cubital en una paciente con pubarquia precoz: Caso clmico / Hypertrichosis cubiti in a girl with precocious puberty: Case report

La hipertricosis cubital es un aumento localizado de la densidad, longitud y espesor del vello. Es una entidad benigna con muy escasos pacientes descritos en la literatura médica (alrededor de medio centenar). La mitad de los casos descritos asocian otros defectos o malformaciones, y la otra mitad son problemas puramente estéticos. La pubarquia precoz en niñas se define como el inicio del vello púbico antes de los 8 años de edad. Se presenta a una paciente de 6 años con la asociación no descrita previamente de hipertricosis cubital y pubarquia precoz.

Hypertrichosis cubiti is a localized increase in hair density, length and thickness. It is an uncommon and benign entity with very few patients described in the medical literature (more or less than half a hundred). Half of the described patients associate other defects or malformations and the other half are purely aesthetic cases. Early pubarche in girls is defined as the onset of pubic hair before 8 years of age. We present a six-year-old patient with the association not previously described of hypertrichosis cubiti and precocious pubarche.

[Hypertrichosis cubiti in a girl with precocious puberty: Case report]. / Hipertricosis cubital en una paciente con pubarquia precoz: Caso clmico.

Hypertrichosis cubiti is a localized increase in hair density, length and thickness. It is an uncommon and benign entity with very few patients described in the medical literature (more or less than half a hundred). Half of the described patients associate other defects or malformations and the other half are purely aesthetic cases. Early pubarche in girls is defined as the onset of pubic hair before 8 years of age. We present a six-year-old patient with the association not previously described of hypertrichosis cubiti and precocious pubarche.

La hipertricosis cubital es un aumento localizado de la densidad, longitud y espesor del vello. Es una entidad benigna con muy escasos pacientes descritos en la literatura médica (alrededor de medio centenar). La mitad de los casos descritos asocian otros defectos o malformaciones, y la otra mitad son problemas puramente estéticos. La pubarquia precoz en niñas se define como el inicio del vello púbico antes de los 8 años de edad. Se presenta a una paciente de 6 años con la asociación no descrita previamente de hipertricosis cubital y pubarquia precoz.

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

Pubertad en adolescentes de áreas rurales y urbanas / Puberty in adolescent of rural and urban areas

Introducción: los factores genéticos determinan un crecimiento potencial, pero el medio ambiente, inhibe o acelera su expresión. Objetivo: determinar el comportamiento según procedencia urbana o rural, de variables relacionadas con el desarrollo puberal: telarquia, pubarquia, menarquia...

Introduction: the genetic factors determine a potential growth, but the environment inhibits and to speed up its expression. Objective: to determine the behavior according the urban or rural origin of the variables related to the pubertal development: telarche, pubarche and menarche. Methods: a correlation and descriptive study was conducted in urban and rural adolescents from the Holguín province...

Pubertad en adolescentes de áreas rurales y urbanas / Puberty in adolescent of rural and urban areas

Introducción: los factores genéticos determinan un crecimiento potencial, pero el medio ambiente, inhibe o acelera su expresión. Objetivo: determinar el comportamiento según procedencia urbana o rural, de variables relacionadas con el desarrollo puberal: telarquia, pubarquia, menarquia...

Introduction: the genetic factors determine a potential growth, but the environment inhibits and to speed up its expression. Objective: to determine the behavior according the urban or rural origin of the variables related to the pubertal development: telarche, pubarche and menarche. Methods: a correlation and descriptive study was conducted in urban and rural adolescents from the Holguín province...

Vitamin D receptor gene polymorphisms and sex steroid secretion in girls with precocious pubarche in Southern Brazil: A pilot study.

BACKGROUND: Evidence suggests that precocious pubarche (PP) girls may have higher risk of developing polycystic ovary syndrome (PCOS) at later ages. Vitamin D receptor (VDR) gene polymorphisms have been implicated in the risk of diabetes and PCOS, but little is known about the role of VDR in PP. AIM: To assess the frequencies of VDR gene ApaI, TaqI, BsmI, and FokI polymorphisms and to determine whether these variants are associated with sex hormone concentrations in patients with PP and controls from southern Brazil. SUBJECTS AND METHODS: Blood was collected from 36 girls with PP and 197 controls for genotyping of BsmI and FokI polymorphisms using real-time PCR and of ApaI e TaqI polymorphisms using restriction fragment length polymorphism. Hormone levels were also determined. RESULTS: Genotype GG of the ApaI single nucleotide polymorphism (SNP) was more frequent in PP (30.6%) than in controls (16.2%) [odds ratio (OR): 2.269; confidence interval 95% (95%CI): 1.015-5.076; p=0.042]. This genotype was also associated with lower estradiol [35.30 (14.80-50.48) pg/ml vs 12.22 (6.49-23.69) pg/ml; p=0.025] and total testosterone levels (0.52 (0.39-0.84) ng/ml vs 0.20 (0.11-0.47) ng/ml; p=0.005) as compared with the TT + TG genotypes in girls with PP. The distribution of TaqI, BsmI, and Fokl SNP was similar in PP and controls, and no association was found between these polymorphisms and sex steroid levels. CONCLUSIONS: The ApaI SNP of the VDR gene was associated with PP in the studied population and may modulate ovarian steroid secretion in these girls.

Forma no clásica de hiperplasia adrenal congénita en la niñez y adolescencia / Non-classic way of congenital adrenal hyperplasia in childhood and adolescence

INTRODUCCIÓN: la hiperplasia adrenal congénita es un trastorno hereditario de la esteroidogénesis suprarrenal, trasmitido por mutaciones genéticas con carácter autosómico recesivo, las cuales afectan las enzimas que intervienen en la biosíntesis del cortisol. La causa la constituye en 90 a 95 por ciento de los casos la deficiencia de la enzima 21 hidroxilasa. OBJETIVO: exponer la experiencia de los autores de este trabajo en la forma no clásica de esta enfermedad. MÉTODOS: se realizó la caracterización de 7 pacientes diagnosticados en la sala de endocrinología pediátrica del Instituto Nacional de Endocrinología, ubicada en el Hospital Pediátrico del Cerro, durante el período 1998-2008. Todos los pacientes pertenecían al sexo femenino. RESULTADOS: los síntomas se iniciaron a una edad promedio de 8,8 años y más de la mitad de los casos presentaron pubarquia precoz. La menarquia se produjo a una edad media de 10,7 años. Se logró el diagnóstico bioquímico al obtenerse valores elevados de 17 hidroxiprogesterona (en condiciones basales). Se emplearon distintas modalidades de tratamiento según la edad de cada paciente y los síntomas predominantes en cada caso. CONCLUSIONES: se corroboró la mayor frecuencia de diagnóstico de esta enfermedad en el sexo femenino, así como la importancia del estudio y el seguimiento ante un paciente con pubarquia precoz(AU)

INTRODUCTION: the congenital adrenal hyperplasia is an inherited disorder of suprarenal esteroidogenesis, transmitted by genetic mutations with a autosomal recessive character affecting the enzymes intervening in cortisol biosynthesis. In the 90 to 95 percent of cases, the cause is a deficiency of Hydroxylase enzyme 21. OBJECTIVE: to show the current paper authors' experience in the non-classic way of this entity. METHODS: we made a characterization of 7 female patients diagnosed in the Children Endocrinology Ward of the National Institute of Endocrinology located in the Children Hospital, Cerro municipality during 1998-2008. RESULTS: symptoms started at a mean age of 8,8 years and more the a half of cases had an early pubarche. Menarche appeared at a mean age of 19,7 years. We made a biochemical diagnosis achieving higher values of 17 hydroxyprogesterone (in basal conditions). Different treatment modalities were used according to each patient and predominant symptoms in each case. CONCLUSIONS: we verified the great frequency of this entity in female sex, as well as the study and follow-up significance in face of a patient presenting early pubarche(AU)

Forma no clàsica de hiperplasia adrenal congénita en la niñez y adolescencia / Non-classic way of congenital adrenal hyperplasia in childhood and adolescence

INTRODUCCIÓN: la hiperplasia adrenal congénita es un trastorno hereditario de la esteroidogénesis suprarrenal, trasmitido por mutaciones genéticas con carácter autosómico recesivo, las cuales afectan las enzimas que intervienen en la biosíntesis del cortisol. La causa la constituye en 90 a 95 por ciento de los casos la deficiencia de la enzima 21 hidroxilasa. OBJETIVO: exponer la experiencia de los autores de este trabajo en la forma no clásica de esta enfermedad. MÉTODOS: se realizó la caracterización de 7 pacientes diagnosticados en la sala de endocrinología pediátrica del Instituto Nacional de Endocrinología, ubicada en el Hospital Pediátrico del Cerro, durante el período 1998-2008. Todos los pacientes pertenecían al sexo femenino. RESULTADOS: los síntomas se iniciaron a una edad promedio de 8,8 años y más de la mitad de los casos presentaron pubarquia precoz. La menarquia se produjo a una edad media de 10,7 años. Se logró el diagnóstico bioquímico al obtenerse valores elevados de 17 hidroxiprogesterona (en condiciones basales). Se emplearon distintas modalidades de tratamiento según la edad de cada paciente y los síntomas predominantes en cada caso. CONCLUSIONES: se corroboró la mayor frecuencia de diagnóstico de esta enfermedad en el sexo femenino, así como la importancia del estudio y el seguimiento ante un paciente con pubarquia precoz(AU)

INTRODUCTION: the congenital adrenal hyperplasia is an inherited disorder of suprarenal esteroidogenesis, transmitted by genetic mutations with a autosomal recessive character affecting the enzymes intervening in cortisol biosynthesis. In the 90 to 95 percent of cases, the cause is a deficiency of Hydroxylase enzyme 21. OBJECTIVE: to show the current paper authors' experience in the non-classic way of this entity. METHODS: we made a characterization of 7 female patients diagnosed in the Children Endocrinology Ward of the National Institute of Endocrinology located in the Children Hospital, Cerro municipality during 1998-2008. RESULTS: symptoms started at a mean age of 8,8 years and more the a half of cases had an early pubarche. Menarche appeared at a mean age of 19,7 years. We made a biochemical diagnosis achieving higher values of 17 hydroxyprogesterone (in basal conditions). Different treatment modalities were used according to each patient and predominant symptoms in each case. CONCLUSIONS: we verified the great frequency of this entity in female sex, as well as the study and follow-up significance in face of a patient presenting early pubarche(AU)

Pubarquia precoz: Experiencia en 173 casos / Precocious pubarche: Experience in 173 cases

Background: Precocious pubarche (PP), defined as the development of sexual pubic hair before 8 years of age in females and before 9 years in males, is usually a benign condition but it can also be the first sign of an underlying disease. Aim: To analyze the etiology andperform a short term follow up in a cohort of patients with PP. Material and methods: A group of 173 patients (158 females) consulted for PP with a mean age of 7.4±0.1 years. These patients were followed between 15 to 60 months. Anthropometric measurements, bone age, serum levels of total testosterone, 17 OH progesterone (17 OHP) and dehydroepiandrosterone sulphate (DHEAS) were evaluated. Results: Mean birth weight and length was 3024.1±50.5 g and 48.5±0.3 cm,respectively. Ten percent of children were small for gestational age at birth. Bone age was accelerated by 1.1±0.01 years. One hundred and twelve patients were classified as having idiopathicPP (64.7%; 105 females), 29 as central precocious puberty (16.8%; only females), 16 as exaggerated adrenarche (EA 9.2%; 13 females) and 16 as non classical adrenal hyperplasia (9.2%; 11 females). Conclusions: PP represents a common and usually benign sign. However, 26% of cases had apathologic underlying condition. Therefore, all children with PP should be evaluated by a pediatric endocrinologist. Low birth weight was not frequent in this cohort and these patients did not show EA

Update on the etiology, diagnosis and therapeutic management of sexual precocity: [review]

Precocious puberty is defined as the development of secondary sexual characteristics before the age of 8 years in girls and 9 years in boys. Gonadotropin-dependent precocious puberty (GDPP) results from the premature activation of the hypothalamic-pituitary-gonadal axis and mimics the physiological pubertal development, although at an inadequate chronological age. Hormonal evaluation, mainly through basal and GnRH-stimulated LH levels shows activation of the gonadotropic axis. Gonadotropin-independent precocious puberty (GIPP) is the result of the secretion of sex steroids, independently from the activation of the gonadotropic axis. Several genetic causes, including constitutive activating mutations in the human LH-receptor gene and activating mutations in the Gs protein a-subunit gene are described as the etiology of testotoxicosis and McCune-Albright syndrome, respectively. The differential diagnosis between GDPP and GIPP has direct implications on the therapeutic option. Long-acting gonadotropin-releasing hormone (GnRH) analogs are the treatment of choice in GDPP. The treatment monitoring is carried out by clinical examination, hormonal evaluation measurements and image studies. For treatment of GIPP, drugs that act by blocking the action of sex steroids on their specific receptors (cyproterone, tamoxifen) or through their synthesis (ketoconazole, medroxyprogesterone, aromatase inhibitors) are used. In addition, variants of the normal pubertal development include isolated forms of precocious thelarche, precocious pubarche and precocious menarche. Here, we provide an update on the etiology, diagnosis and management of sexual precocity.

A puberdade precoce é definida como o desenvolvimento dos caracteres sexuais secundários antes dos 8 anos nas meninas e dos 9 anos nos meninos. A puberdade precoce dependente de gonadotrofinas (PPDG) resulta da ativação prematura do eixo hipotálamo-hipófise-gonadal e mimetiza o desenvolvimento puberal fisiológico, embora em idade cronológica inadequada. A avaliação hormonal, principalmente os valores de LH basal e após estímulo com GnRH exógeno confirmam a ativação do eixo gonadotrófico. A puberdade precoce independente de gonadotrofinas (PPIG) é o resultado da secreção de esteróides sexuais independentemente da ativação do eixo gonadotrófico. Diversas causas genéticas, incluindo mutações ativadoras constitutivas no gene do receptor do LH humano e mutações ativadoras no gene da subunidade a da proteína G representam as etiologias da testotoxicose e da síndrome de McCune Albright, respectivamente. O diagnóstico diferencial entre PPDG e PPIG tem implicação direta na opção terapêutica. Análogos de GnRH de ação prolongada é o tratamento de escolha da PPDG. A monitorização do tratamento da PPDG é realizada pelo exame clínico, avaliação hormonal e exames de imagem. Para o tratamento da PPIG, são usadas drogas que bloqueiam a ação dos esteróides sexuais nos seus receptores específicos (ciproterona, tamoxifeno) ou bloqueiam a sua síntese (cetoconazol, medroxiprogesterona e inibidores da aromatase). Variantes do desenvolvimento puberal normal incluem as formas isoladas de telarca, pubarca e menarca precoces. Nesta revisão, atualizamos a etiologia, o diagnóstico e tratamento da precocidade sexual.

Características clínicas, endocrinas y metabólicas de una población argentina de niñas con pubarca prematura / Clinical, hormonal and metabolic findings in argentinean girls with premature pubarche

La pubarca prematura se ha asociado con alteraciones hormonales y metabólicas. Se estudiaron 40 niñas con pubarca prematura de 7,23 ± 0,29 años (media ± ESM). Se evaluó grado de desarrollo, talla, edad ósea, IMC y peso al nacimiento (PN). Se dosaron andrógenos, gonadotrofinas, lípidos, glucemia e insulina, HOMA e índice glucemia/insulina (G/I) y se compararon con un grupo control normal de 25 niñas. Las pacientes se dividieron según el nivel de sulfato de dehidroepiandrosterona (SDHEA) en dos grupos, Pre A (Pre adrenarca), < 400 ng/ml, n= 17 y Post A (Post adrenarca) < 400 ng/ml , n= 23. El grupo Post A tuvo mayor edad cronológica, edad ósea y grado de vello pubiano que el Pre A, sin diferencias en IMC ni en peso de nacimiento (PN). Insulina y HOMA fueron mayores y G/I menor en Post A que en Pre A y grupo control. Dos niñas en Post A tuvieron franca resistencia a la insulina. 64 % de las niñas en Pre A y 59 % en Post A tuvieron valores elevados o limítrofes de colesterol total (CT). Conclusiones: el grupo Post A presentó menor sensibilidad insulínica y ambos grupos de pacientes tuvieron valores de CT elevados, alteraciones que podrían favorecer el riesgo de futuras complicaciones. Se recomienda el seguimiento a largo plazo de todas las niñas con pubarca prematura.

Precocious pubarche in girls is caused by premature adrenarche in most cases. Less frequently it occurs in absence of biochemical markers of adrenarche being ascribed to increased target tissue sensitivity. Premature pubarche with pronounced adrenarche has been associated with insulin resistance and dyslipemia, especially in girls with history of low birth weight. Most studies have been conducted in hispanic and affrican-american patients. We studied a total of 40 argentinean girls with isolated premature pubarche, aged 7.23 ± 0.29 years (mean ± SEM) at the moment of diagnosis. Grade of sexual development, height, weight, BMI and birth weight (BW) were recorded. Dehidroepiandrosterone sulphate (DHEAS), androstenedione (A), testosterone (T), 17OH progesterone (17 OHP), SHBG, LH, FSH, PRL and estradiol were measured. Total cholesterol (TC), LDL cholesterol (LDL- C), triglycerides (TGC), glucose, insulin, HOMA and fasting glucose/ insulin index (G/I) were evaluated and compared with those in a control group of 25 normal girls. Patients were divided into two groups: Pre A (Pre adrenarche), with DHEAS < 400 ng/ml, and Post A (Post adrenarche), with DHEAS > 400 ng/ml. Post A girls had higher chronological age, bone age advancement and grade of pubic hair development than Pre A girls. No difference was found regarding BMI or BW. Besides higher DHEAS levels, Post A girls showed elevated A and 17OHP levels than Pre A girls (86 ± 8 vs 35 ± 4 ng/dl, p<0. 0001 and 1.1 ± 0.09 vs 0.75 ± 0.07 ng/ml, p< 0.01, respectively). Insulin levels (µUI/ml) were 4.51 ± 0.75 in Pre A, 6.53 ± 1.11 in Post A and 4.05 ± 0.45 in control group. Fasting G/I was 24.07 ± 3.75 in Pre A , 18.4 ± 2.34 in Post A and 25.41 ± 2.31 in controls. HOMA was 0.90 ± 0.12 in Pre A, 1.35 ± 0.22 in Post A and 0.89 ± 0.11 in control group. Post A girls had higher insulin and HOMA and lower G/I than control group girls (p<0.05) while those parameters in Pre A girls were not different than in normal control subjects. Only two patients in Post A group had HOMA and G/I consistent with insulin resistance. TC was higher in Pre A than in control group (182.2 ± 4.9 vs156.7 ± 8.5 mg/dl, p<0.05). According to The National Cholesterol Education Program definition, 64 % of Pre A girls and 59 % of Post A girls had elevated or borderline TC levels. TGC values were not different among Pre A, Post A and control group (81.1 ±7.1, 77.6 ± 6.1 and 71.9 ± 4.7 mg/dl, respectively. Summary and Conclusions: In this cohort of argentinean girls with premature pubarche, we did not find a significant history of intrauterine growth retardation. Patients with biochemical pattern of adrenarche showed clinical signs of androgen exposure (accelerated bone age, more advanced degree of pubic hair development) and a serum profile suggestive of reduced insulin sensitivity compared with those without biochemical adrenarche. Both groups of patients had undesirable total cholesterol levels. These findings support the recommendation of long-term follow-up for all girls with premature pubarche.

Enfoque práctico de la pubarquia precoz

La pubarquia precoz, es considerada una variante normal del desarrollo, sin consecuencias a largo plazo. Recientemente se ha relacionado con alteraciones endocrino-metabólicas en la pre-pubertad y fundamentalmente en la post-pubertad. La pubarquia precoz, hoy por hoy, representa un factor predictivo de disfunción ovárica y/o adrenal y de síndrome metabólico. Este artículo es resultado de una revisión bibliográfica sobre esta entidad, realizado con el objetivo de disponer de las herramientas que nos permitan el diagnostico, la evaluación, el seguimiento y los tratamientos adecuados.

Precocious pubarche was believed to be a normal variant of pubertad developpement, without long-term consequences.Recently premature pubarche has been associated to endocrine-metabolic disturbances in the pre-puberal age and especially after puberty. At present, premature pubarche represent a predictive factor of ovarian and/or adrenal disfunction and Metabolic Syndrome. This article result from a bilbliographic review about this entity, the objective is to dispose of tools to make the adequate diagnosis, approach, treatment and follow-up.