Die Reifung der Zona reticularis der Nebennieren-Rinden (NNR) und ihrer Androgen-Sekretion vor der Pubertät unterscheidet sich bei Menschen und höheren Primaten von der NNR-Reifung anderer Species, z.B. der Nager. Die Sekretion der NNR-Androgene leitet die Pubertätsentwicklung ein. Die NNR-Androgene erlangen medizinische Bedeutung dadurch, dass sie bei Frauen zu Hirsutismus und Fertilitätsstörungen führen können. Neben diesen Symptomen stellen sie einen Risikofaktor für die Entwicklung eines Polycystischen-Ovar-Syndroms (PCOS) dar, das ungefähr 7 % der prämenopausalen Frauen betrifft. Lange Zeit war nicht bekannt, wie die Differenzierung der Zona reticularis beim Menschen reguliert wird. Sicher ist ACTH bei weitem das bedeutsamste übergeordnete Hormon für die globale adrenocorticale Differenzierung und Funktion. Weitere Faktoren sind speziell für die Androgensekretion verantwortlich, aber nicht genau definiert. Nun wurde zunächst in zellbiologischen Experimenten belegt, dass die ACTH-Wirkung durch ein Spezies-spezifisches Muster von Wachstumsfaktoren autokrin moduliert wird und so die postnatale Entwicklung der Nebenniere steuern kann. Die vorliegenden Untersuchungen an menschlichen NNR-Zellen von Kindern und Erwachsenen in Primärkultur zeigen erstmals, dass IGF-I und IGF-II differenzierte Funktionen dieser Zellen aufrecht erhalten. IGF-I und, mehr noch, IGF-II steigern die Steroid-Biosynthese und ACTH-Ansprechbarkeit, und sie fördern die Bildung von Androstendion, einem delta5-Androgen der Zona reticularis. Darüberhinaus bewirkt Insulin in physiologischen sowie in micromolaren Konzentrationen den IGFs ähnliche Änderungen der Steroidsynthese. In Querschnittsuntersuchungen an gesunden Kindern vor der Pubertät sowie Kindern mit einfacher Adipositas konnte gezeigt werden, dass die Körperzusammensetzung mit den NNR-Androgenen zusammenhängt. Über die Mediatoren IGF-I, Insulin und Leptin wird offensichtlich der NNR der Zustand von Gewicht und Wachstum des Kindes signalisiert, auch bei pathologischer Körperzusammensetzung, wie dem Prader-Willi-Syndrom. Während die Adipositas die Androgen-Bildung steigern kann, ist sie jedoch selbst nicht der kausale Faktor einer vorzeitigen Nebennierenrindenreifung. Der Prämaturen Pubarche können in 5 - 10 % der untersuchten weiblichen Population ein nicht-klassisches AGS oder NNR-Tumoren zugrunde liegen. Bei den verbleibenden Kindern besteht eine eigentlich harmlose Reifungsbeschleunigung mit normaler Wachstumsprognose. Betrachtet man diese Kinder mit idiopatischer Prämaturer Adrenarche jedoch genauer, so finden sich zwei Untergruppen mit langfristigen Risiken: erstens zeigen Kinder mit einer sogenannte manifesten Heterozygotie für einen 21-Hydroxylase-Defekt Auffälligkeiten des Wachstums, die eine Endgrössenreduktion bewirken könnten, und zweitens wird bei Jugendlichen mit einer Überstimulierbarkeit der NNR diese "Exaggerated Adrenarche" für ein nachfolgendes PCOS verantwortlich gemacht. Schliesslich scheint es vor dem Hintergrund der sich epidemieartig ausbreitenden Zunahme des Übergewichts im Kindesalter angezeigt, den Bezug dieser NNR-Störungen zur Adipositas und der Hyperinsulinämie weiter zu klären. / The prepubertal maturation of the zona reticularis of the adrenal cortex and its androgen secretion in man and higher primates differs from other species, e.g. rodents. The secretion of adrenal androgens induces the pubertal development. The importance of adrenal androgens is derived from them being the cause for hirsutism and fertility disorders in women. In addition they represent a risk factor for the development of the polycystic ovary syndrome (PCOS), that affects about 7% of all pre-menopausal women. The regulation of the differentiation of the zona reticularis was unknown for a long time. However, ACTH is by far the most important hormone to regulate the global adrenocortical differentiation and function. In addition, other yet undefined factors are specifically responsible for the secretion of adrenal androgens. The cell-biological experiments presented here demonstrate that the effects of ACTH can be modulated in an autocrine manner by a species-specific pattern of growth factors so as to allow for the control of the postnatal development of the adrenal gland. The present investigations in human adrenocortical cells of children and adults in primary culture show for the first time that IGF-I and IGF-II maintain the differentiated function of these cells. IGF-I and to an even greater extent IGF-II enhance the biosynthesis of steroids and ACTH-responsiveness, and they promote the production of androstenedione, a delta5-androgen of the zona reticularis. Moreover, insulin, in physiological as well as in micromolar concentrations, induces changes in steroid production similar to the IGFs. In cross-sectional studies of healthy pre-pubertal children and children with simple obesity, it was shown that body composition is associated with adrenal androgens. Mediated by IGF-I, insulin and leptin, body composition apparently signals the child's state of weight and growth to the adrenals, even in patients with abnormal body composition, e.g. the Prader-Willi syndrome. While obesity may enhance androgen production, it is not the direct causal factor to induce premature adrenal maturation. In 5-10% of the female population investigated, premature pubarche is caused by non-classical adrenal hyperplasia or an adrenocortical tumour. In the remaining children, there is merely a harmless acceleration of maturation with normal growth prediction. A closer look at the children with idiopathic premature adrenarche, however, reveals two subgroups with long-term risks: First, children with a so called manifest heterozygosity of a 21-hydroxylase-defect show growth abnormalities, possibly reducing final height. Second, in adolescents with enhanced stimulation of the adrenal cortex, this 'exaggerated adrenarche' is held responsible for the subsequent development of PCOS. Finally, with regard to the rapidly spreading epidemic of overweight in children, it seems essential to study into greater depth the relationship between these adrenal dysfunctions and obesity or hyperinsulinism.

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No. of bitstreams: 1 DissVOF.pdf: 3835001 bytes, checksum: 76a7690d0dcbe93db09803bc9ca4b037 (MD5) Previous issue date: 2016-03-21 / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) / Introduction: Premature adrenarche (PA) is characterized by the appearance of pubic hair and/or axillary, acne and body odor before age 8 in girls and before 9 in boys and these individuals are at increased risk of developing metabolic syndrome (MetS). Vitamin D and irisin seem to have an active role in the metabolism of carbohydrates and lipids, however, little is known of the role of these hormones in the PA. Objective: To analyze the vitamin D and irisin levels in children diagnosed with PA and the relationship of these substances with body composition of these children. Methodology: a quantitative exploratory cross-sectional study that evaluated 15 children diagnosed with PA and 15 controls (C) matched recruited in the public health of the city of São Carlos, Brazil. Anthropometric data were analyzed: height, weight, waist circumference (WC), triceps skinfold thickness (TSF), systolic blood pressure (SBP) and diastolic blood pressure (DBP). The participants did tests of FSH, LH, testosterone, estradiol, blood glucose, insulin, 17OHP, total cholesterol (TC), LDL, HDL, triglycerides (TG), S-DHEA, 25(OH)D and irisin. Data analysis was performed using the GraphPad Prism 5 program. The paired Wilcoxon test was used to assess the difference between means and the correlation through the Spearman test, with 5% significance level. Results: There was no significant difference between the C and PA groups in anthropometric data. The TG levels (99 ± 14.8 mg/dl in the children C versus 68 ± 9.1 mg/dl in children with PA) (p= 0.0233) and 25(OH)D (26 ± 0.9 ng/ml in the children C versus 30.2 ± 1.6 ng/ml in children with PA) (p= 0.0307) significantly were different between groups. In group C the variable that correlated significantly with irisin was 25(OH)D (r= -0.9358); in the PA group: LDL (r= 0.5620), 17OHP (r= 0.6014), TG (r= 0.6434), insulin (r= 0.5998) and relationship glucose/insulin (r= -0.7033). In group C the variable that was significantly correlated with vitamin D was irisin (r = -0.9358); there was no significant correlation of variables with 25(OH)D in the AP group. Discussion and Conclusion: This study showed higher percentage of individuals with hyperinsulinemia, insulin resistance and CA high in the PA group, important markers of MetS and future cardiovascular disease. An innovative result of this study was the strong negative correlation between irisin and 25(OH)D found in C children, suggesting an interaction of these two hormones in these individuals, which may be related to compensatory modulation of irisin in response to changing metabolism lipid found in this group. In children with PA, the highest correlation of metabolic parameters with irisin may represent a physiological modulation of this hormone by elements related to carbohydrate metabolism (as in control children C) and a specific modulation in PA, due to the same pathophysiological mechanisms that result in unfavorable metabolic profile. Since the PA can lead to an increased risk of cardiovascular disease, these children must have a suitable and long-term clinical follow-up. / Introdução: A adrenarca precoce (AP) é caracterizada pelo surgimento de pelos pubianos e/ou axilares, acne e odor corporal antes dos 8 anos de idade em meninas e antes dos 9 em meninos e estes indivíduos têm risco aumentado de desenvolver síndrome metabólica (SM). A vitamina D e a irisina parecem ter um papel ativo no metabolismo de carboidratos e lipídeos, no entanto, pouco se sabe do papel desses hormônios na AP. Objetivo: Analisar os valores de vitamina D e irisina em crianças com diagnóstico de AP e a relação dessas substâncias com a composição corporal dessas crianças. Metodologia: Estudo quantitativo transversal exploratório, no qual foram avaliadas 15 crianças com diagnóstico de AP e 15 controles (C) pareados, recrutados na rede pública de saúde da cidade de São Carlos, SP. Foram determinados dados antropométricos: altura, peso, circunferência abdominal (CA), prega cutânea tricipital (PCT), pressão arterial sistólica (PAS) e pressão arterial diastólica (PAD). Os participantes realizaram exames de glicemia, insulina, colesterol total (CT), LDL, HDL, triglicerídeos (TG), DHEA-S, 17OHP, 25(OH)D e irisina. A análise dos dados foi realizada através do programa GraphPad Prism 5. O teste de Wilcoxon pareado foi utilizado para avaliar a diferença entre as médias e sua correlação através do teste de Spearman, com nível de significância de 5%. Resultados: Não houve diferença significativa entre os grupos C e AP quanto aos dados antropométricos. Os valores de TG (99 ± 14,8 mg/dl nos indivíduos C versus 68 ± 9,1 mg/dl nos indivíduos com AP) (p= 0,0233) e de 25(OH)D (26 ± 0,9 ng/ml nos indivíduos C versus 30,2 ± 1,6 ng/ml nos indivíduos com AP) (p= 0,0307) foram significativamente diferentes entre os grupos. No grupo C a variável que se correlacionou significativamente com a irisina foi a 25(OH)D (r= -0,9358); no grupo AP: LDL (r= 0,5620), 17OHP (r= 0,6014), TG (r= 0,6434), insulina (r= 0,5998) e relação glicemia/insulina (r= -0,7033). No grupo C a variável que se correlacionou significativamente com a 25(OH)D foi a irisina (r= - 0,9358), não houve correlação significativa das variáveis com a 25(OH)D no grupo AP. Discussão e conclusão: Este estudo evidenciou maior porcentagem de indivíduos com hiperinsulinemia, resistência insulínica e CA elevada no grupo AP, importantes marcadores de SM e doenças cardiovasculares futuras. Um resultado inovador deste estudo foi a forte correlação negativa entre a irisina e a 25(OH)D encontrada em crianças controle, sugerindo uma interação destes dois hormônios nesses indivíduos, que pode estar relacionada a uma modulação compensatória da irisina em resposta à alteração do metabolismo lipídico encontrada nesse grupo. Em crianças com AP, a maior correlação dos parâmetros metabólicos com a irisina pode representar uma modulação fisiológica desse hormônio por fatores relacionados ao metabolismo de carboidratos (assim como nas crianças controles) e uma modulação específica na AP, decorrente dos mesmos mecanismos fisiopatológicos que resultam num perfil metabólico desfavorável. Como a AP pode levar a um risco aumentado de doença cardiovascular, essas crianças devem ter um acompanhamento clínico adequado e de longo prazo.

付記する学位プログラム名: 霊長類学・ワイルドライフサイエンス・リーディング大学院 / 京都大学 / 0048 / 新制・課程博士 / 博士(理学) / 甲第20964号 / 理博第4416号 / 新制||理||1634(附属図書館) / 京都大学大学院理学研究科生物科学専攻 / (主査)准教授 Michael Alan Huffman, 准教授 足立 幾磨, 教授 友永 雅己 / 学位規則第4条第1項該当 / Doctor of Science / Kyoto University / DGAM

Les hyperplasies micronodulaires pigmentées de la surrénale (PPNAD) sont les tumeurs endocrines les plus fréquentes d’un syndrome multinéoplasique d’origine génétique, le Complexe de Carney. Ces hyperplasies bilatérales sont associées à des mutations inactivatrices de PRKAR1A, le gène codant la sous-unité régulatrice R1 de la protéine kinase dépendante de l’AMPc (PKA). Ces tumeurs bénignes conduisent à une activation constitutive de la PKA responsable d’un hypercortisolisme indépendant de l’ACTH (syndrome de Cushing), associant diverses comorbidités telles que l’obésité centrale, le diabète, l’ostéoporose, des troubles de l’humeur ou encore des complications cardiovasculaires. Cependant, les mécanismes de cette tumorigenèse restent mal compris. Afin d’évaluer les conséquences de l’activation de la signalisation PKA sur l’induction tumorale et l’activité endocrine, l’équipe a précédemment généré un modèle de souris transgéniques reproduisant l’inactivation de Prkar1a dans la corticosurrénale. Ces souris développent une hyperplasie bilatérale composée de cellules présentant des caractéristiques fœtales naturellement absente d’une surrénale adulte. L’objectif général de ce travail de thèse était d’identifier l’origine des cellules constituant cette hyperplasie retrouvée dans le cortex interne des souris mutantes. Nous avons utilisé pour cela une approche génétique de lignage cellulaire afin de tracer chez la souris, l’origine de ces tumeurs après invalidation de Prkar1a dans les précurseurs du cortex définitif ou dans ceux du cortex fœtal. Les résultats montrent que l’activation de la signalisation PKA dans le cortex surrénalien adulte est suffisante pour promouvoir le développement d’hyperplasies surrénaliennes associées à la mise en place d’un syndrome de Cushing. L’invalidation de Prkar1a dans les précurseurs du cortex fœtal ne conduit à aucune anomalie endocrine ni tumorale. En revanche, l’activation de la signalisation PKA dans le cortex adulte favorise le renouvellement cellulaire centripète, l’identité fasciculée et sa conversion en identité réticulée dans la partie interne. L’activation de la signalisation PKA, conjointement à la croissance corticale, apparait donc comme un moteur possible de l’adrénarche, normalement restreinte aux grands primates.L’analyse transcriptomique des surrénales et les expériences de lignages cellulaires montrent que la prédisposition des femelles au syndrome de Cushing et au développement d’hyperplasies « pseudo-réticulée » pourraient reposer sur un dimorphisme sexuel des capacités de recrutement des cellules progénitrices et sur le métabolisme du cholestérol.En parallèle de ces travaux, l’exploration des mécanismes conduisant à la présence inappropriée de cellules « pseudo-réticulée » nous a amené à tester l’implication de la SUMOylation dans les défauts de zonation observés. Nos résultats montrent que l’activation de la signalisation PKA in vitro et in vivo exerce une hypoSUMOylation globale, d’origine transcriptionnelle. En accord avec cet effet, les nodules présents chez les patients atteints de PPNAD sont hypoSUMOylés. Enfin nous montrons chez les deux espèces, un gradient de SUMOylation régionalisé dans le cortex qui suggère l’implication de cette modification dans la zonation de la glande surrénale. / Primary Pigmented Nodular Adrenal Disease (PPNAD) is the most frequent endocrine manifestation of a rare, dominantly inherited multiple endocrine neoplasia syndrome, the Carney Complex. These bilateral hyperplasia are associated with inactivating mutations of PRKAR1A, the gene encoding the R1 regulatory subunit of cAMP-dependent protein kinase (PKA). These benign tumors lead to constitutive activation of PKA, responsible for an ACTH-independent hypertcortisolism (Cushing's syndrome), associating various comorbidities such as central obesity, diabetes, osteoporosis, mood disorders or cardiovascular complications. However, the mechanisms of tumorigenesis remain poorly understood. In order to evaluate the consequences of activation of PKA signaling on tumor induction and endocrine activity, the team previously generated a model of transgenic mice reproducing the inactivation of Prkar1a in the adrenal cortex. These mice develop bilateral hyperplasia composed of cells with fetal characteristics naturally absent from an adult adrenal gland.The general objective of this thesis was to identify the origin of the cells constituting this hyperplasia found in the internal cortex of the mutant mice. We used a genetic approach of cell lineage to trace the origin of these tumors after deletion of Prkar1a in the precursors of the adult or fetal cortex.The results show that activation of PKA signaling in the adult cortex is sufficient to promote the development of adrenal hyperplasia associated with Cushing's syndrome. The ablation of Prkar1a in the precursors of the fetal cortex does not lead to any endocrine or tumor abnormalities. On the contrary, activation of PKA signaling in the adult cortex promotes centripetal cell renewal, fasciculata identity and its conversion into reticularis identity in the internal part of the gland. The activation of PKA signaling, together with cortical growth, therefore appears to be a possible motor of adrenarche, normally restricted to human and some primates.Transcriptomic analysis of the adrenals and cell lineage experiments show that female predisposition to Cushing's syndrome and development of "pseudo-reticularis" hyperplasia may be based on sexual dimorphism of progenitor cell recruitment capacities and on metabolism of cholesterol.In parallel, the exploration of the mechanisms leading to the inappropriate presence of "pseudo-reticularis" cells led us to test the involvement of SUMOylation in the observed zonation defects. Our results show that the activation of PKA signaling in vitro and in vivo exerts a global hypoSUMOylation, of transcriptional origin. In agreement with this effect, the nodules present in patients with PPNAD are hypoSUMOylated. Finally, we show in both species a regionalized SUMOylation gradient in the cortex that suggests the implication of this modification in the zonation of the adrenal gland.

Pubarca precoce (PP), definida como o surgimento de pelos pubianos antes dos oito anos de idade em meninas após exclusão de causas secundárias, tem sido associada a maior prevalência de componentes da síndrome metabólica e desenvolvimento da síndrome dos ovários policísticos (PCOS) na adolescência. Em mulheres com PCOS, foi relatado aumento da massa ventricular esquerda (MVE) e disfunção diastólica, associados à resistência insulínica (RI). Os objetivos dos estudos foram: 1) avaliar a MVE e a função cardíaca sistólica e diastólica através de ecocardiografia em meninas com PP e controles, além de analisar a associação entre os parâmetros cardíacos com androgênios e marcadores de RI; 2) determinar a frequência da PCOS em uma coorte de meninas com PP na pós-menarca e avaliar se existem preditores para o desenvolvimento da PCOS. Variáveis clínicas, hormonais e metabólicas, ecocardiografia e composição corporal foram obtidas em 35 meninas com PP e 35 controles saudáveis pareadas pela idade (artigo 1). Trinta e quatro meninas com mais de dois anos pós-menarca da coorte de PP da Unidade de Endocrinolgia Ginecológica do Hospital de Clínicas de Porto Alegre (UEG/HCPA) foram classificadas em PCOS e não-PCOS e seus dados pré-puberais foram analisados para detectar preditores do desenvolvimento de PCOS e comparados com os de 17 meninas controles saudáveis da mesma idade (artigo 2). Após ajuste para gordura corporal total, a MVE foi maior no grupo PP (97,31 ± 33,37 vs. 81,25 ± 19,06 g, p = 0,017), bem como a onda A’ (5,66 ± 1,34 vs. 5,09 ± 0,98 cm / s, p = 0,025), uma medida da função diastólica. O índice de androgêncios livres (FAI) e gordura corporal total foram preditores independentes de maior MVE e, juntamente com HOMA-IR contribuíram com 72% da variabilidade da MVE no grupo PP (artigo 1). No segundo artigo, 44,1% das meninas com PP foram diagnosticadas com PCOS na pósmenarca. Na pré-puberdade, esse grupo apresentou maior índice de massa corporal (IMC) e HOMA-IR em relação às controles, bem como níveis mais elevados de testosterona, escore de hirsutismo e insulina em jejum quando comparadas às não-PCOS e às controles. O risco para o desenvolvimento de PCOS entre as PPs esteve associado ao IMC z-escore ≥ 2 (odds ratio [OR] = 4; intervalo de confiança 95% [IC] 1.33 – 18.66); escore de Ferriman-Galwey ≥ 4 (OR = 2,7; IC 95% 1,15-5,14); HOMA-IR ≥ 2,42 (OR = 7; IC 95% 1,39-12,0) e volume ovariano ≥ 1,17 mL (OR = 8; IC 95% 1,60-39,9) no período pré-puberal. Em conclusão, meninas com PP apresentaram maior MVE associada aos níveis de androgênios, RI e gordura corporal total. Além disso, foi encontrada alta freqüência de PCOS na coorte de PP da UEG/HCPA. Obesidade, maior escore de hirsutismo, RI e volume ovariano na pré-puberdade foram preditores de desenvolvimento da PCOS na adolescência. / Precocious pubarche (PP) in girls, defined as idiopathic appearance of pubic hair before the age of eight years, has been associated with higher prevalence of components of metabolic syndrome and post pubertal development of polycystic ovary syndrome (PCOS). Increased left ventricular mass (LVM) and diastolic dysfunction have been reported in women with PCOS associated with insulin resistance (IR). The aims of the studies were: 1) to assess LVM and cardiac systolic and diastolic function using echocardiography in girls with PP and controls, and to analyze the relationship between cardiac parameters with androgens and IR; 2) to determine the frequency of PCOS in a cohort of postmenarcheal PP girls and to assess whether possible predictors exist for development of PCOS Clinical, hormonal and metabolic profiles, echocardiography and body composition were examined in 35 PP girls and 35 healthy age-matched controls (article 1). Thirty-four postmenarcheal girls with PP of the Gynecological Endocrinology Unit, Division of Endocrinology of Hospital de Clínicas de Porto Alegre (GEU/HCPA) clinic cohort were classified as PCOS and non-PCOS and prepubertal data were analyzed to detect PCOS development predictors and compared with data of 17 age-matched controls (article 2). After adjusting for total body fat, LVM was higher in the PP group (97.31 ± 33.37 vs. 81.25 ± 19.06 g, p = 0.017) as well as A’ wave (5.66 ± 1.34 vs. 5.09 ± 0.98 cm/s, p=0.025), a measurement of diastolic function. Free androgen index (FAI) and total body fat were independent predictors of higher LVM, and together with HOMA-IR contributed with 72% of LVM variability in the PP group (article 1). In the second article, fifteen (44.1%) PP girls were classified as PCOS and had higher body mass index standard deviation score (BMI SDS) and HOMA-IR than controls, as well as higher testosterone, hirsutism score and fasting insulin than non-PCOS girls and controls in prepubertal period. The risk for PCOS development among PP girls increased with prepubertal BMI SDS ≥ 2 (odds ratio [OR] = 4; 95% confidence interval [CI] 1.33 – 18.66), Ferriman-Galwey hirsutism score ≥ 4 (OR = 2.7; 95% CI 1.15 - 5.14), HOMA-IR ≥ 2.42 (OR = 7; 95% CI 1.39 - 12.0) and ovarian volume ≥ 1.17 mL (OR= 8; 95 CI 1.60 – 39.9). In conclusion, PP girls had greater LVM associated with higher androgen levels, IR, and total body fat, occurred early in pubertal development. In addition, we found high frequency of PCOS in Southern Brazil PP cohort. Obesity, clinical androgenism, IR and ovarian volume were predictors of development of PCOS later.

Pubarca precoce (PP), definida como o surgimento de pelos pubianos antes dos oito anos de idade em meninas após exclusão de causas secundárias, tem sido associada a maior prevalência de componentes da síndrome metabólica e desenvolvimento da síndrome dos ovários policísticos (PCOS) na adolescência. Em mulheres com PCOS, foi relatado aumento da massa ventricular esquerda (MVE) e disfunção diastólica, associados à resistência insulínica (RI). Os objetivos dos estudos foram: 1) avaliar a MVE e a função cardíaca sistólica e diastólica através de ecocardiografia em meninas com PP e controles, além de analisar a associação entre os parâmetros cardíacos com androgênios e marcadores de RI; 2) determinar a frequência da PCOS em uma coorte de meninas com PP na pós-menarca e avaliar se existem preditores para o desenvolvimento da PCOS. Variáveis clínicas, hormonais e metabólicas, ecocardiografia e composição corporal foram obtidas em 35 meninas com PP e 35 controles saudáveis pareadas pela idade (artigo 1). Trinta e quatro meninas com mais de dois anos pós-menarca da coorte de PP da Unidade de Endocrinolgia Ginecológica do Hospital de Clínicas de Porto Alegre (UEG/HCPA) foram classificadas em PCOS e não-PCOS e seus dados pré-puberais foram analisados para detectar preditores do desenvolvimento de PCOS e comparados com os de 17 meninas controles saudáveis da mesma idade (artigo 2). Após ajuste para gordura corporal total, a MVE foi maior no grupo PP (97,31 ± 33,37 vs. 81,25 ± 19,06 g, p = 0,017), bem como a onda A’ (5,66 ± 1,34 vs. 5,09 ± 0,98 cm / s, p = 0,025), uma medida da função diastólica. O índice de androgêncios livres (FAI) e gordura corporal total foram preditores independentes de maior MVE e, juntamente com HOMA-IR contribuíram com 72% da variabilidade da MVE no grupo PP (artigo 1). No segundo artigo, 44,1% das meninas com PP foram diagnosticadas com PCOS na pósmenarca. Na pré-puberdade, esse grupo apresentou maior índice de massa corporal (IMC) e HOMA-IR em relação às controles, bem como níveis mais elevados de testosterona, escore de hirsutismo e insulina em jejum quando comparadas às não-PCOS e às controles. O risco para o desenvolvimento de PCOS entre as PPs esteve associado ao IMC z-escore ≥ 2 (odds ratio [OR] = 4; intervalo de confiança 95% [IC] 1.33 – 18.66); escore de Ferriman-Galwey ≥ 4 (OR = 2,7; IC 95% 1,15-5,14); HOMA-IR ≥ 2,42 (OR = 7; IC 95% 1,39-12,0) e volume ovariano ≥ 1,17 mL (OR = 8; IC 95% 1,60-39,9) no período pré-puberal. Em conclusão, meninas com PP apresentaram maior MVE associada aos níveis de androgênios, RI e gordura corporal total. Além disso, foi encontrada alta freqüência de PCOS na coorte de PP da UEG/HCPA. Obesidade, maior escore de hirsutismo, RI e volume ovariano na pré-puberdade foram preditores de desenvolvimento da PCOS na adolescência. / Precocious pubarche (PP) in girls, defined as idiopathic appearance of pubic hair before the age of eight years, has been associated with higher prevalence of components of metabolic syndrome and post pubertal development of polycystic ovary syndrome (PCOS). Increased left ventricular mass (LVM) and diastolic dysfunction have been reported in women with PCOS associated with insulin resistance (IR). The aims of the studies were: 1) to assess LVM and cardiac systolic and diastolic function using echocardiography in girls with PP and controls, and to analyze the relationship between cardiac parameters with androgens and IR; 2) to determine the frequency of PCOS in a cohort of postmenarcheal PP girls and to assess whether possible predictors exist for development of PCOS Clinical, hormonal and metabolic profiles, echocardiography and body composition were examined in 35 PP girls and 35 healthy age-matched controls (article 1). Thirty-four postmenarcheal girls with PP of the Gynecological Endocrinology Unit, Division of Endocrinology of Hospital de Clínicas de Porto Alegre (GEU/HCPA) clinic cohort were classified as PCOS and non-PCOS and prepubertal data were analyzed to detect PCOS development predictors and compared with data of 17 age-matched controls (article 2). After adjusting for total body fat, LVM was higher in the PP group (97.31 ± 33.37 vs. 81.25 ± 19.06 g, p = 0.017) as well as A’ wave (5.66 ± 1.34 vs. 5.09 ± 0.98 cm/s, p=0.025), a measurement of diastolic function. Free androgen index (FAI) and total body fat were independent predictors of higher LVM, and together with HOMA-IR contributed with 72% of LVM variability in the PP group (article 1). In the second article, fifteen (44.1%) PP girls were classified as PCOS and had higher body mass index standard deviation score (BMI SDS) and HOMA-IR than controls, as well as higher testosterone, hirsutism score and fasting insulin than non-PCOS girls and controls in prepubertal period. The risk for PCOS development among PP girls increased with prepubertal BMI SDS ≥ 2 (odds ratio [OR] = 4; 95% confidence interval [CI] 1.33 – 18.66), Ferriman-Galwey hirsutism score ≥ 4 (OR = 2.7; 95% CI 1.15 - 5.14), HOMA-IR ≥ 2.42 (OR = 7; 95% CI 1.39 - 12.0) and ovarian volume ≥ 1.17 mL (OR= 8; 95 CI 1.60 – 39.9). In conclusion, PP girls had greater LVM associated with higher androgen levels, IR, and total body fat, occurred early in pubertal development. In addition, we found high frequency of PCOS in Southern Brazil PP cohort. Obesity, clinical androgenism, IR and ovarian volume were predictors of development of PCOS later.

Pubarca precoce (PP), definida como o surgimento de pelos pubianos antes dos oito anos de idade em meninas após exclusão de causas secundárias, tem sido associada a maior prevalência de componentes da síndrome metabólica e desenvolvimento da síndrome dos ovários policísticos (PCOS) na adolescência. Em mulheres com PCOS, foi relatado aumento da massa ventricular esquerda (MVE) e disfunção diastólica, associados à resistência insulínica (RI). Os objetivos dos estudos foram: 1) avaliar a MVE e a função cardíaca sistólica e diastólica através de ecocardiografia em meninas com PP e controles, além de analisar a associação entre os parâmetros cardíacos com androgênios e marcadores de RI; 2) determinar a frequência da PCOS em uma coorte de meninas com PP na pós-menarca e avaliar se existem preditores para o desenvolvimento da PCOS. Variáveis clínicas, hormonais e metabólicas, ecocardiografia e composição corporal foram obtidas em 35 meninas com PP e 35 controles saudáveis pareadas pela idade (artigo 1). Trinta e quatro meninas com mais de dois anos pós-menarca da coorte de PP da Unidade de Endocrinolgia Ginecológica do Hospital de Clínicas de Porto Alegre (UEG/HCPA) foram classificadas em PCOS e não-PCOS e seus dados pré-puberais foram analisados para detectar preditores do desenvolvimento de PCOS e comparados com os de 17 meninas controles saudáveis da mesma idade (artigo 2). Após ajuste para gordura corporal total, a MVE foi maior no grupo PP (97,31 ± 33,37 vs. 81,25 ± 19,06 g, p = 0,017), bem como a onda A’ (5,66 ± 1,34 vs. 5,09 ± 0,98 cm / s, p = 0,025), uma medida da função diastólica. O índice de androgêncios livres (FAI) e gordura corporal total foram preditores independentes de maior MVE e, juntamente com HOMA-IR contribuíram com 72% da variabilidade da MVE no grupo PP (artigo 1). No segundo artigo, 44,1% das meninas com PP foram diagnosticadas com PCOS na pósmenarca. Na pré-puberdade, esse grupo apresentou maior índice de massa corporal (IMC) e HOMA-IR em relação às controles, bem como níveis mais elevados de testosterona, escore de hirsutismo e insulina em jejum quando comparadas às não-PCOS e às controles. O risco para o desenvolvimento de PCOS entre as PPs esteve associado ao IMC z-escore ≥ 2 (odds ratio [OR] = 4; intervalo de confiança 95% [IC] 1.33 – 18.66); escore de Ferriman-Galwey ≥ 4 (OR = 2,7; IC 95% 1,15-5,14); HOMA-IR ≥ 2,42 (OR = 7; IC 95% 1,39-12,0) e volume ovariano ≥ 1,17 mL (OR = 8; IC 95% 1,60-39,9) no período pré-puberal. Em conclusão, meninas com PP apresentaram maior MVE associada aos níveis de androgênios, RI e gordura corporal total. Além disso, foi encontrada alta freqüência de PCOS na coorte de PP da UEG/HCPA. Obesidade, maior escore de hirsutismo, RI e volume ovariano na pré-puberdade foram preditores de desenvolvimento da PCOS na adolescência. / Precocious pubarche (PP) in girls, defined as idiopathic appearance of pubic hair before the age of eight years, has been associated with higher prevalence of components of metabolic syndrome and post pubertal development of polycystic ovary syndrome (PCOS). Increased left ventricular mass (LVM) and diastolic dysfunction have been reported in women with PCOS associated with insulin resistance (IR). The aims of the studies were: 1) to assess LVM and cardiac systolic and diastolic function using echocardiography in girls with PP and controls, and to analyze the relationship between cardiac parameters with androgens and IR; 2) to determine the frequency of PCOS in a cohort of postmenarcheal PP girls and to assess whether possible predictors exist for development of PCOS Clinical, hormonal and metabolic profiles, echocardiography and body composition were examined in 35 PP girls and 35 healthy age-matched controls (article 1). Thirty-four postmenarcheal girls with PP of the Gynecological Endocrinology Unit, Division of Endocrinology of Hospital de Clínicas de Porto Alegre (GEU/HCPA) clinic cohort were classified as PCOS and non-PCOS and prepubertal data were analyzed to detect PCOS development predictors and compared with data of 17 age-matched controls (article 2). After adjusting for total body fat, LVM was higher in the PP group (97.31 ± 33.37 vs. 81.25 ± 19.06 g, p = 0.017) as well as A’ wave (5.66 ± 1.34 vs. 5.09 ± 0.98 cm/s, p=0.025), a measurement of diastolic function. Free androgen index (FAI) and total body fat were independent predictors of higher LVM, and together with HOMA-IR contributed with 72% of LVM variability in the PP group (article 1). In the second article, fifteen (44.1%) PP girls were classified as PCOS and had higher body mass index standard deviation score (BMI SDS) and HOMA-IR than controls, as well as higher testosterone, hirsutism score and fasting insulin than non-PCOS girls and controls in prepubertal period. The risk for PCOS development among PP girls increased with prepubertal BMI SDS ≥ 2 (odds ratio [OR] = 4; 95% confidence interval [CI] 1.33 – 18.66), Ferriman-Galwey hirsutism score ≥ 4 (OR = 2.7; 95% CI 1.15 - 5.14), HOMA-IR ≥ 2.42 (OR = 7; 95% CI 1.39 - 12.0) and ovarian volume ≥ 1.17 mL (OR= 8; 95 CI 1.60 – 39.9). In conclusion, PP girls had greater LVM associated with higher androgen levels, IR, and total body fat, occurred early in pubertal development. In addition, we found high frequency of PCOS in Southern Brazil PP cohort. Obesity, clinical androgenism, IR and ovarian volume were predictors of development of PCOS later.