Role of 11-oxygenated androgens in the diseases of pediatric hyperandrogenism / 国际儿科学杂志

Previously the diseases of pediatric hyperandrogenism were mainly diagnosed and evaluated by testing traditional androgens such as testosterone and androstenedione.However, clinical application has revealed a poor correlation between traditional androgens and the clinical manifestations of hyperandrogenism in some patients.It has been proposed that adrenal-derived 11-oxygenated androgen may also be involved in the course of this type of disease.The concentrations of 11-oxygenated androgen are elevated in androgen excess diseases, and they fulfill a variety of roles in human physiology and disease.This article discusses three aspects of the synthesis process, activity and content of 11-oxygenated androgen and their application in three androgen excess diseases: congenital adrenocortical hyperplasia, premature adrenarche and polycystic ovary syndrome, in order to help clinicians expand their clinical understanding and investigative thoughts on 11-oxygenated androgen.

Clinical characteristics and etiological analysis of premature pubarche:A report of 55 cases / 中国实用儿科杂志

OBJECTIVE: To analyse the clinical characteristics,aetiology distribution,and metabolic risk parameters of patients with with premature pubarche(PP). METHODS: A retrospective study was performed in 55 patients affected by PP,who received ACTH stimulation test,and the data were evaluated. Among them 17 cases were detected CYP21 A2 gene,and indicators of lipid metabolism of idiopathic premature adrenarche(IPA,15 cases)and idiopathic premature pubarche(IPP,14 cases)were analyzed. RESULTS: The sample included 55 patients with PP(53 female and 2 male),with a mean pubarche age of(7.2±0.9)years for girls and(7±0.8)years for boys. There was an accelerated bone age(BA/CA ratio>1)(1.20 ± 1.5)in girls. A total of 9 patients were classified as non-classic congenital adrenal hyperplasia(NCCAH,16.4%),15 as IPA(27.3%),14 as IPP(25.4%),16 as HPGA function launch(29.1%)and 1 with exaggerated adrenarche(EA,1.8%). There was no significant difference in the diagnostic rate of NCCAH between ACTH stimulation test and CYP21 A2 gene detection(P=0.596). The sex hormone binding protein(SHBP)of IPA was reduced(P=0.007). CONCLUSION: The etiology of premature pubarche-non-classic congenital adrenal hyperplasia(16.4%)is not uncommon. The ACTH stimulation test is useful for the diagnosis of NCCAH,but the sensitivity is not 100%.

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.

El adelanto en la telarquia y edad de la menarquia se relacióna con la malnutrición por exceso en niñas chilenas pero no en varones: estudio de base poblacional / The advance in thelarche and age of menarche is related to malnutrition by excess in Chilean girls but not in boys: population-based study

Introduction: Puberty normally begins after 8 years in girls and 9 years in boys. Objective: To determine the prevalence of signs of precocious puberty (PP), breast development in girls, premature gonadal development (PGD), premature adrenarche (PA), menarche age (MA) and its association with nutritional status (NS). Material and Methods: From a sample of 3.010 children from 5 to 14 years randomly selected in Santiago of Chile were chosen a subsample of 873 kids according to the cutoff to define PP. Survey was applied to obtain MA. Logistic regression were used to evaluate the relationship between PP and NS. Results: In boys the prevalence of PGD and PP was 8.55% and 3.16% respectively, no relationship was found with nutritional status In girls the prevalence of breast development and PA was 8.13% and 0.9% respectively. Only there be association between PP and NS in women: with a prevalence of 1,2%, 13,9% and 21,1% in well-nourished, Overweight and obesity are at greater risk of showing PP compared with eutrophic girls with an OR of 25,5 (IC 95% 3,2-203,0) and 46.93 (IC 95% 6,1-361,5). MA was 12,01 ± 0,94 years in eutrophic girls and 11,40 ± 0,96years in obese girls (p< 0,05). Conclusion: There was a positive correlation in females between overweight and obesity an PP and MA. There is a secular trend in MA, to compare these findings with other national studies. Obesity could have an important role in explaining the advancement observed in pubertal development.

Introducción: El desarrollo puberal se inicia normalmente después de los 8 años en niñas y de los 9 años en varones. Objetivo: Estimar la prevalencia de signos de pubertad precoz (sPP): crecimiento genital (CG) en varones, telarquia en niñas y vello púbico (VP) en ambos sexos; y determinar edad de la menarquia (EM) en una muestra de escolares de Santiago de Chile), y evaluar la asociación de estas variables con el estado nutricional (EN). Material y Métodos: Se examinaron 3.010 escolares de clase media baja de 6 a 14 años, pertenecientes a 10 colegios de Santiago de Chile y seleccionados aleatoriamente. En todos ellos se consignó peso, talla, IMC y desarrollo puberal según Tanner. Se aplicó una encuesta a los padres para obtener la EM a la población total de mujeres (n= 1.433). Para determinar sPP se analizaron por separado los 867 niños (62% mujeres) menores a la edad establecida como puntos de corte para definir PP. Se utilizó regresión logística para determinar la asociación existente entre sPP y el EN. Resultados: En varones la prevalencia de CG y VP fue de 8,55% y 3,16% y no se asocio al EN. La prevalencia de telarquia y VP en niñas fue de 8,13% y 0,9% respectivamente. Se observó una fuerte asociación entre telarquia y EN con prevalencias de 1.2%, 13.9% y 21.1% en eutróficas, sobrepeso y obesas, respectivamente (p< 0,0001) (Gráfico 1). La presencia de sobrepeso y/o obesidad otorgan un mayor riesgo de presentar telarquia, vs comparación con las niñas eutróficas con un OR de 25,5 (IC 95% 3,2-203,0) y 46.93 (IC 95% 6,1-361,5), respectivamente. La EM fue 12,01 ± 0,94 años en niñas eutróficas siendo de 11,40 ± 0,96 años en niñas obesas (p< 0,05). Conclusión: Se observó una correlación positiva solo en el sexo femenino entre malnutrición por exceso, telarquia precoz y EM. Se observa una tendencia secular en la EM al comparar los hallazgos con otros estudios nacionales.

Interpretation of androgen and anti-Mullerian hormone profiles in a Hispanic cohort of 5- to 8-year-old girls with premature adrenarche

PURPOSE: Premature adrenarche (PA) often leads to polycystic ovary syndrome (PCOS). Higher anti-mullerian hormone (AMH) levels are reported in PCOS. We studied the androgen profile and AMH profiles in Hispanic girls with PA (aged 5–8 years) and age and body mass index (BMI) matched controls. METHODS: Retrospective review of electronic medical records of girls who met the inclusion criteria for premature adrenarche were done. RESULTS: PA girls (n=76) were matched to control girls (n=12) for age (mean±standard deviation) (6.7±1 years vs. 6.2±1.3 years) and BMI (20±10 kg/m2 vs. 17.8±2.7 kg/m2). Dehydroepiandrostenedione sulfate (63.3±51.3 μg/dL vs. 29.8±17.3 μg/dL, P < 0.001) and testosterone levels (11.4±4.8 ng/dL vs. 8.2±2.9 ng/dL, P=0.001) were significantly higher in the PA group than controls. AMH values ( < 14 years: reference range, 0.49–3.15 ng/mL) were 3.2±2.2 ng/mL vs. 4.6± 3.2 ng/mL respectively in the PA and control groups and were not different (P=0.4). AMH did not show a correlation with bone age (P=0.1), and testosterone (P=0.9) in the PA group. 17-hydroxyprogesterone levels (17-OHP ng/dL) were 39.5±30.5 ng/dL vs. 36.8±19.8 ng/dL in PA versus control girls. The concentration of 17-OHP was not statistically different between the control and PA groups. CONCLUSIONS: Higher AMH was not observed in PA girls and no correlation with BA and androgen levels was observed.

Risco cardiovascular em meninas com pubarca precoce isolada / Cardiovascular risk in girls with isolated premature pubarche

Introdução: Pubarca precoce é o aparecimento de pelos pubianos antes dos 8 anos em meninas e dos 9 anos em meninos, sendo mais frequente em meninas. Entre suas etiologias, a adrenarca precoce é a mais comum. A literatura traz associações entre pubarca precoce e fatores de risco para doenças cardiovasculares Objetivos: O presente estudo pretende avaliar os fatores de risco para doenças cardiovasculares em meninas com pubarca precoce isolada. Métodos: Trata-se de um estudo observacional utilizando dados secundários extraídos de prontuários médicos de 41 meninas com diagnóstico de pubarca precoce isolada entre 1999 e 2013, acompanhadas em policlínica universitária na área de endocrinologia pediátrica. As variáveis de estudo foram: peso, estatura, índice de massa corporal, pressão arterial, peso ao nascimento, idade óssea, dislipidemia, glicemia e insulina de jejum e androgênios basais. Resultados: A média de idade foi de 7,8±1,4 anos. A frequência de excesso de peso foi de 42,1%, baixo peso ao nascimento de 13,1%, pressão arterial elevada de 17,3% e elevação de colesterol total em 45,8%. A idade óssea foi superior à cronológica em 81,8%. Não foram verificadas hiperinsulinemia nem resistência insulínica. O hiperandrogenismo acometeu aproximadamente um terço das pacientes. Conclusões: A maioria das pacientes apresentou ao menos um fator de risco para doença cardiovascular, sendo os mais prevalentes o excesso de peso e a dislipidemia. Aproximadamente 1/3 das pacientes apresentavam hiperandrogenismo (AU)

Introduction: Premature pubarche is the appearance of pubic hair before 8 years in girls and 9 years in boys, being more frequent in girls. Among its etiologies, precocious adrenarche is the most common. The literature shows associations between precocious pubarche and risk factors for cardiovascular diseases. Aim: This study intends to evaluate the risk factors for cardiovascular diseases in girls with isolated premature pubarche. Methods: This is an observational study using secondary data extracted from medical records of 41 girls diagnosed with early pubarche between 1999 and 2013, followed by a university polyclinic in the area of pediatric endocrinology. The study variables were weight, height, body mass index, blood pressure, birth weight, bone age, dyslipidemia, glycemia, and fasting insulin and basal androgens. Results: Mean age was 7.8 ± 1.4 years. The frequency of overweight was 42.1%, low birth weight 13.1%, high blood pressure 17.3%, and total cholesterol elevation 45.8%. Bone age was higher than chronological age in 81.8%. No hyperinsulinemia and insulin resistance were observed. Hyperandrogenism affected approximately one-third of the patients. Conclusions: Most patients presented at least one risk factor for cardiovascular disease, the most prevalent being overweight and dyslipidemia. Approximately 1/3 of the patients had hyperandrogenism (AU)

Prepubal hyperandrogen exposure induces reproductive changes in adult female rats / 医学研究生学报

Objective Androgen is an important precursor for the synthesis of estrogen in vivo and is involved in the regulation of female reproductive function.In this study, we explored the influence of different lengths of prepubertal exposure to hyperandrogen on the reproductive function of adult female rats. Methods Twenty-five 23-day-old female rats were equally randomized into five groups:oil control, 2-wk dehydroepiandrosterone (DHEA), 4-wk DHEA, 6-wk DHEA, and 8-wk DHEA, injected with oil or DHEA daily for 2, 4, 6, and 8 weeks respectively, and mated at 80 days old.We detected serum concentrations of total testosterone (tT), estradiol (E2), follicle-stimulating hormone ( FSH) and luteinizing hormone ( LH) by ELISA, observed the time of vaginal opening and changes of the estrous cycle, and recorded the rates of mating and pregnancy, the number of the offspring and their survival rate. Results The tT lev-el was elevated after 2 weeks of DHEA injection, fell to normal after drug withdrawal in the 2-wk and 4-wk DHEA groups, and remained at a high level in the 6-wk group.The E2 level was markedly increased in at 2 and 4 weeks but showed a falling trend at 6 and 8 weeks. DHEA injection did not change the level of FSH significantly but re-markably lifted that of LH with the increased concentration of tT.The vaginal opening time was significantly advanced in the 2-wk DHEA group as compared with the controls ([26.60 ±0.89] d vs [35.20 ± 2.49] d, P0.05). Conclusion Prepubertal expo-sure to hyperandrogen may advance adrenarche and gonadarche and affect the initiation of the sexual gland function in female rats.Impro-ving the hyperandrogen status in the early pubertal stage can reverse the disorder of the estrous cycle, while long-term exposure to DHEA may significantly reduce the fecundity at the childbearing age.

Effects of gonadotropin-releasing hormone analogue treatment on adrenarche in girls with idiopathic central precocious puberty / 中华内分泌代谢杂志

Objective To explore the relationship between adrenarche and gonadarche.Methods Total 49 idiopathic central precocious puberty(ICPP)girls,whose serum dehydroepiandrosterone sulfate(DHEAS)Z scores for chronological age were higher than+2 s at diagnosis.were enrolled.Physical examinations during pubertal stage were repeated at 3-6 months intervals,and serum DHEAS levels were monitored yearly within an average period of 4.08 years.Of them,16 girls were followed up until more than one year after discontinuation of gonadotropin-releasing hormone analogue(GnRHa)treatment.Results Before GnRHa treatment,these49 girls presented a younger average age at attainment of pubic hair stage2(PH2)and pubic hair stage3(PH3)than normal(8.07 years vs 11.16 years,8.82 years vs 12.40 years respectively).During GnRHa treatment,the intervals between PH2 and PH3,PH3 and pubic hair stage4(PH4),breast stage 2(B2),and PH2 were longer than normal(1.69 years vs 0.83 years,1.64 years vs 0.60 years,and3.62 years vs 0.76 years respectively).The intervals between PH2 and PH3,as well as B2 and PH2 during GnRHa treatment were also longer than that before GnRHa treatment(1.69 years/35 0.88 years,3.62 years vs 1.13 years respectively).The serum DHEAS Z scores decreased during GnRHa treatment,and increased significantly after GnRHa cessation.Conclusion Gonadarche after age of 6-year-old may lead to earlier adrenarehe.GnRHa treatment might slow down the progression of adrenarche and suppress the hypothalamuspituitary-gonadal axis.

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

Growth and sex differentiation of children born small for gestational age / 소아과

The incidence of small for gestational age (SGA) births is frequent, accounting for 2.3% to 8% of all live births. Several childhood and adult diseases are related to early postnatal growth and birth size, and 10% of children born SGA may have a short stature throughout postnatal life. Additionally, they may have abnormal growth hormone (GH)-insulin like growth factor axis, HPA axis, and gonadal function. Permanent changes are detrimental in an environment of nutritional abundance, and predispose SGA children to an array of diseases in adolescence and adulthood. Such changes may also cause premature pubarche, adrenarche, and precocious puberty. The varying results from clinical studies necessitate more prospective case control studies. Reproductive tract abnormalities and reproductive dysfunction are related to SGA births. GH treatment is required for SGA infants who do not experience catch-up growth.

Adrenarquía precoz y marcadores del síndrome metabólico / Precocious adrenarche and components of metabolic syndrome

Introducción: la adrenarquia precoz (AP) puede asociarse con dislipidemia, hiperinsulinemia y hipertensión arterial en la vida adulta. Objetivo: evaluar características clínicas y de laboratorio, con énfasis en las alteraciones asociadas a síndrome metabólico, en niñas que presentaron AP. Pacientes y método: fueron evaluadas 51 niñas brasileñas: 30 con AP y 21 niñas normales. Resultados: Circunferencia cintura (65,2±11,2 cm versus 46,2±17,6 cm), presión arterial sistólica (111,3±12,3 mmHg versus 98,8±11,4 mmHg) y presión arterial diastólica (71,8±9,2 mmHg versus 65,0±8,1 mmHg) fueron más elevadas en las niñas con AP (p<0,05). Los valores de HDL fueron más bajos en el grupo con AP: 40,9±8,3 versus 43,7±5,7 (p=0,020). Las tasas de insulina (9,0±5,0 mUI/ml versus 5,2±3,0 mUI/ml), el índice HOMA-IR (3,2±1,4 versus 2,1±1,0), DHEA-S (594,2±288,2 ng/ml versus 285,8±213,9 ng/ml) y 17 OH progesterona (54,9±38,9 ng/dl versus 34,3±9,7 ng/dl, fueron más elevados en las niñas con AP (p<0,05). Conclusiones: niñas con AP presentan datos sugiriendo la presencia de resistencia insulínica y deberían ser estudiadas para prevenir aparición de síndrome metabólico.

Introduction: precocious adrenarche (PA) can be associated with dislipidemia, hyperinsulinemia and hypertension, in adult age. Objectives: to evaluate clinical and laboratory characteristics in the metabolic syndrome in the PA patients. Patients and method: we evaluated 51 brazilian girls: 30 with PA and 21 normal girls.Results: abdominal circumference (65,2±11,2 cm versus 46,2±17,6 cm), systolic blood pressure (111,3±12,3 mmHg versus 98,8±11,4 mmHg) and diastolic blood pressure (71,8±9,2 versus 65,0±8,1 mmHg), were higher in the PA group (p<0,05). HDL levels were lower in the PA group (40,9±8,3 versus 43,7±5,7 (p=0,020). Insulin (9,0±5,0 mUI/ml versus 5,2±3,0 mUI/mL), HOMA-IR index (3,2±1,4 versus 2,1±1,0), DHEA-S (594,2±288,2 ng/mL versus 285,8±213,9 ng/mL) and 17OH progesterone levels (54,9±38,9 godly versus 34,3±9,7 ng/dL) were higher in girls with PA (p<0,05). Conclusions: girls with PA usually show the presence of insulin resistance and its study is important in order to prevent metabolic syndrome in this group.