Deficiencia de hormona de crecimiento (GH) en la edad pediátrica / Growth hormone (GH) deficiency in the pediatric age

La deficiencia de hormona de crecimiento (DGH) provoca manifestaciones clínicas distintas, según su etiología y la etapa del desarrollo, pero siempre existe un denominador común: Las otras manifestaciones clínica dependerán d ela etiología (genética, adquirida o idiopática), de la intensidad de la deficienica y de si es la única hormona hipofisaria afectada o existe afectación de otras hormonas hipofisarias. Los avances de los últimos años han ampliado el conocimiento de sus bases moleculares y han caracterizado mejor las formas adquiridas. Sin embargo, la mayor parte de DGH no tienen una causa conocida y son catalogadas como idiopáticas. Mientras que los criterios clínicos y moleculares del diagnóstico de DGH están bien establecidos, los criterios hormonales continúan siendo un rompecabezas a esar de los esfuerzos realizados para armonizar las técnicas bioquímicas de análisis de GH y de IGF-1. Los diagnósticos basados en los estímulos secretores de GH han demostrado ser la escasa utilidad clínica para predecir la respueta terapéutica a la GH (AU)

Growth hormone (GH) deficiency manifests differently according to the individual´s developmental stage. During the paediatric period, one of the msot prominent clincial features is chronic skeletal growth retardation. Clinical signs also depend on the cause (genetic, acquired or idiopathic), deficiency intensity and whether GH is the only pituitary-affected hormone or is combined with that of other pituitary hormones. Growing knowledge of the genetic basis of GH deficiency continues to provide us with useful information to further characterise to provide us with useful information to further characterise mutation types and mechanisms for prevously-described and new candidate genes. Despite these advances, a high proportion of GH deficiencies with no recognisable acquired basis continue to be labelled as idiopathic. The hormonal diagnoses continue to be a conundrum despite efforts to harmonise biochemical assays for GH and IGF-1 analysis, and the diagnosis based on the so-called GH secretion stimulation tests with prove to be of limited usefulness for predicting response to GH therapy (AU)

Novel (60%) and recurrent (40%) androgen receptor gene mutations in a series of 59 patients with a 46,XY disorder of sex development.

BACKGROUND: Androgen receptor (AR) gene mutations are the most frequent cause of 46,XY disorders of sex development (DSD) and are associated with a variety of phenotypes, ranging from phenotypic women [complete androgen insensitivity syndrome (CAIS)] to milder degrees of undervirilization (partial form or PAIS) or men with only infertility (mild form or MAIS). OBJECTIVE: The aim of the study was to characterize the contribution of the AR gene to the molecular cause of 46,XY DSD in a series of Spanish patients. SETTING: We studied a series of 133 index patients with 46,XY DSD in whom gonads were differentiated as testes, with phenotypes including varying degrees of undervirilization, and in whom the AR gene was the first candidate for a molecular analysis. METHODS: The AR gene was sequenced (exons 1 to 8 with intronic flanking regions) in all patients and in family members of 61% of AR-mutated gene patients. RESULTS: AR gene mutations were found in 59 individuals (44.4% of index patients), of whom 46 (78%) were CAIS and 13 (22%) PAIS. Fifty-seven different mutations were found: 21.0% located in exon 1, 15.8% in exons 2 and 3, 57.9% in exons 4-8, and 5.3% intronic. Twenty-three mutations (40.4%) had been previously described and 34 (59.6%) were novel. CONCLUSIONS: AR gene mutation is the most frequent cause of 46,XY DSD, with a clearly higher frequency in the complete phenotype. Mutations spread along the whole coding sequence, including exon 1. This series shows that 60% of mutations detected during the period 2002-2009 were novel.

Fisiopatología del hipotiroidismo congénito primario / Physiopathology of primary congenital hypothyroidism

El pronóstico del hipotiroidismo congénito ha cambiado radicalmente desde la instauración en la mayoría de países de las unidades de cribado precoz y seguimiento de esta endocrinopatía. Sin embargo, sus factores etiológicos aún son poco conocidos. En el hipotiroidismo congénito transitorio, las causas principales son, durante el parto, la sobrecarga yodada que puede experimentar el feto por pincelaciones antisépticas con povidona yodada y la vía materna, y en el período de recién nacido (fenómeno de Wolf-Chaikoff), la inmadurez del sistema hipotálamo-hipofisario que condiciona una deficiencia de funcionalismo del tiroides del prematuro, más aun si se trata de un prematuro patológico, y una relativa deficiencia de yodo en las fórmulas de la leche. En el hipotiroidismo congénito definitivo las principales etiologías son las mutaciones que ocurren en los factores de transcripción y en el complejo enzimático preciso para la formación de hormonas tiroideas (dishormonogénesis). Hoy se conocen una serie de factores de transcripción: FOXE I (TITF 2), NK X2.1 (TITF 1), PAX 8 y Shh (en ratones) cuyas mutaciones son causa de las disgenesias tiroideas, aunque expliquen sólo un pequeño porcentaje de ellas. Dentro de las dishormonogénesis están bien estudiadas las mutaciones de la mayoría de los trastornos enzimáticos que ocurren tanto en el borde basocelular como en el apical del tirocito, y que ocasionan un hipotiroidismo congénito con glándula normosituada. El hipotiroidismo congénito definitivo ha pasado de ser considerado como una simple embriopatía o malformación a una entidad de gran interés en los estudios de biología molecular para conocer el entramado de genes que son precisos para el normal funcionamiento de la glándula (AU)

In most countries the prognosis of congenital hypothyroidism (CH) has changed dramatically since the introduction of units for the early screening and follow-up of this endocrine disorder. However, the etiological factors involved have not yet been well characterized. In transitory CH the main causes are iodine overload in the fetus due to antiseptic brushing with povidone-iodine, maternal transfer during delivery and in the neonatal period (the Wolf-Chaikoff effect), immaturity of the hypothalamus-pituitary system leading to thyroid function deficiency in premature infants, especially if abnormalities are present, and a relative deficiency of iodine in formula milk. In definitive CH the main etiological factors are mutations in transcription factors and in the enzyme complex required for the formation of thyroid hormones (dyshormonogenesis). Currently, a series of transcription factors are known ­ FOXE I (TITF 2), NK X2.1 (TITF 1), PAX 8 and Shh (in mice) ­ whose mutations give rise to thyroid dysgenesis, although these mutations explain only a small percentage of them. Within dyshormonogenesis, mutations of most of the enzyme disorders that occur both in the basal and apical borders of thyroid cells and that cause CH in normally located glands are well known. Definitive CH is no longer considered a simple embryo disorder or malformation and is currently of great interest in molecular biology to determine the network of genes required for normal thyroid function (AU)

Mesa redonda: estado en la edad adulta y propuesta de optimización terapéutica de algunas endocrinopatías infantiles: Introducción / No disponible

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Long-Term GH therapy: epidemiology and auxologic outcome.

OBJECTIVES: Epidemiologic and auxologic characteristics of patients treated with GH during childhood and adolescence and entered in a national registry in Catalonia were studied between 1988 and 1997. At the end of 1997, prevalence was 53.2 treatments/100,000 inhabitants aged 0-14 years. Maximum annual incidence rates were observed in 1990 and 1991 (34.0-35.6 cases/100,000 inhabitants aged 0-14 years). STUDY DESIGN: Analysis of treatments terminated in 1993 (n = 548) revealed, for the three principal reasons for cessation of treatment ('near-final height', 'adequate height but further growth potential', and 'poor growth response'), that males began and ended treatment at older ages with a better auxologic situation in SDS than girls at the beginning and end of therapy in the first two subgroups, with a similar duration of therapy. Severe GH deficiency (GHD) [both multiple pituitary hormone deficiency (MPHD) and the most severe isolated GHD (IGHD-A)] was more frequent in the group ending treatment at 'near-final height', whereas cessation of therapy because of 'poor growth response' was more frequent in the group with 'other causes of short stature' and no demonstrable GHD by routine tests. In the near-final height group, after excluding Turner's syndrome, MPHD and GHD cases secondary to brain tumors and GH deficiencies associated with malformative syndromes, positive linear correlations were observed between HSDS at the end of treatment and HSDS at the beginning, predicted adult height SDS (PAHSDS) and target height SDS (THSDS). Multiple regression analysis showed that in this group of patients, 41.4% of the variability in HSDS increment can be explained by the equation: HSDS increment = -0.33 + 0.29 THSDS - 0.68 HSDS at the beginning of treatment. RESULTS: The outcome showed a reasonable use of GH, since good-response cases generally continued treatment until final height whereas therapy was suspended in doubtful cases.

Longitudinal study of the pubertal growth spurt in children born small for gestational age without postnatal catch-up growth.

Most children born small for gestational age (SGA) experience extensive catch-up growth during the first months of life (87%) and by the age of 2 years only 13% are below -2 SDS for height. The long-term outcome, including pubertal growth spurt, of the subset of children born SGA without postnatal catch-up (SGAWPC) has been evaluated in very few surveys, and in none of them was the landmarks of puberty well described. Thus, a longitudinal study was conducted in these children throughout puberty since this is the only reliable way to accurately evaluate the pubertal growth spurt. In an observational, retrospective and multicenter collaborative study, from an initial group of 553 SGA children, a subset of 15 boys (BW = 2,070 +/- 379.6 g) and 16 girls (BW = 2,244 +/- 331.1 g) SGAWPC whose data were recorded regularly during puberty were selected. Growth standards for growth and maturity during puberty were Tanner and Whitehouse and Spanish Hernandez and Sobradillo charts. In pubertal growth spurt, 'take-off' occurred later than in the reference populations with a height SDS deficiency of -2.3 and -2.2 for boys and -2.0 and -1.9 for girls, compared with Spanish and Tanner references, respectively. Peak height velocity was normal in chronology and intensity, but the total pubertal gain was smaller. However, considering their growth from the same chronological age at which the reference populations took off until adulthood, the total gain was not significantly different in the three cohorts (32.5 +/- 5.4 cm vs 30.9 +/- 4.4 in boys, and 23.3 +/- 4.1 vs 25.7 +/- 5.4 cm in girls - Spanish reference - and 27.2 +/- 6.3 vs 27.6 +/- 3.5 cm in boys - Tanner charts), except in the case of girls (21.1 +/- 3.9 vs 25.3 +/- 4.1 cm, p <0.005 - Tanner charts). Adult height was significantly reduced (161.9 +/- 3.9 cm in males and 147.0 +/- 2.6 cm in females). Therefore, although the pubertal growth was smaller in these children, puberty probably did not modify their short final height.

Cribado, diagnóstico definitivo y seguimiento del hipotiroidismo congénito / Screening, definitive diagnosis and follow-up of congenital hypotyroidism

En los pacientes con hipotiroidismo congénito (HC), el inicio temprano del tratamiento previene del desarrollo de alteraciones mentales. Antes de la introducción del cribado neonatal, los niños con HC eran diagnosticados de forma tardía, cuando la sintomatología era ya muy evidente. Dado que los signos y síntomas son poco específicos y aparecen de forma gradual, en los niños el diagnóstico se realizaba cuando ya no se podían prevenirlas graves alteraciones. En este artículo se comenta la historia natural del diagnóstico del hipotiroidismo congénito en España y los resultados obtenidos. Entre los principales factores que intervienen en el éxito del programa se encuentran: a) función tiroidea materna normal con trasferencia de hormonas tiroideas al feto a través de la placenta; b) confirmación temprana del diagnóstico después del cribado positivo; c) inicio del tratamiento con una dosis adecuada de tiroxina (10 pg/kg/día), y d) control regular del tratamiento mediante la determinación de T4 y TSH en plasma. El seguimiento a largo plazo precisa un control endocrino estricto durante los primeros años, con evaluación psicológica y neurológica ocasional por otros especialistas. Estos pacientes deben recibir tratamiento en centros hospitalarios que cuenten con las especialidades mencionadas. La mayoría de los niños diagnosticados de HC, tratados de forma temprana, tienen la función cognitiva y un desarrollo psicomotor normales (AU)

Hyperinsulinemia in pre- and post-pubertal children born small for gestational age.

BACKGROUND: Reduced fetal growth is a potential risk factor for development of metabolic abnormalities in later life. The relationship between low birthweight and impaired glucose tolerance, type 2 diabetes and insulin resistance in adulthood has been well documented. PURPOSE: Assuming that fetal undernutrition is associated with insulin resistance in middle age, we elected to study whether this process may already be present in young adults and adolescents born small for gestational age (SGA). SUBJECTS AND METHODS: Children born in Vall d'Hebron Hospital Infantil, Barcelona, between 1986 and 1989 and between 1978 and 1983 with birthweights below the third centile for the local standard values, were invited to participate in the present study. Of those, 51 (22 girls and 29 boys) were pre-pubertal with 9.4 +/- 0.2 years of age and 49 (29 girls and 20 boys ) were post-pubertal, with 17.3 +/- 0.3 years of age. All patients underwent a standard, 2-hour oral glucose tolerance test. Insulin and glucose responses were compared with our previously published data in control children with normal birthweight. RESULTS: The insulin response at 30 min after glucose load was significantly higher (p < 0.001) in pre- and post-pubertal girls and boys formerly SGA than in controls. In addition, the girls also had a higher insulin response at 60 and 120 min. Mean serum insulin (MSI), the area under the insulin curve during the glucose challenge, was statistically increased in pre- and post-pubertal boys and girls born SGA when compared to controls. CONCLUSION: The presence of high insulin levels after an oral glucose challenge in children and adolescents born SGA might be considered as an early marker of subsequent insulin resistance in adulthood. Furthermore, our population offers the opportunity to study the natural course of hyperinsulinemia and its outcome. Follow-up of this cohort may be helpful in distinguishing a subset of young children and adolescents in whom therapeutic intervention could be done.

Spontaneous, but not induced, puberty permits adequate bone mass acquisition in adolescent Turner syndrome patients.

Lumbar L2-L4 bone mineral density (BMD) values were measured in 37 adolescent and young adult Turner syndrome patients. Nine had developed spontaneous puberty and had had regular menses since menarche (12.55 years +/- 1.17 years) to the time of BMD evaluation (14.96 years +/- 1.26 years). In the other 28, puberty was induced with increasing doses of oral ethinyl estradiol (2.5-10.0 microg/day, for 2 years) and later administration of estrogen/gestagen therapy up to the time of BMD evaluation. In 18, the adolescent group, menarche appeared at 14.68 years +/- 0.63 years and BMD was evaluated at 17.77 years +/- 0.70 years, and in the other 10, the young adult group, menarche appeared at 14.47 years +/- 0.53 years and BMD was evaluated at 20.90 years +/- 0.68 year. BMD values were in the normal range in those who had developed spontaneous puberty (Z score values, -0.24 +/- 0.22) and in the osteopenia range in those in whom puberty was induced (Z score values, -2.09 +/- 0.79 and -2.18 +/- 0.32 for the adolescent and young adult groups, respectively) p < 0.0001. Height Z score values were similar in all three groups (-3.45 +/- 0.77, -3.15 +/- 0.83, and -3.08 +/- 0.33, respectively). No significant differences in calcium intake or physical activity were found among groups. Neither the karyotype distribution nor growth hormone (GH) therapy (five in the spontaneous puberty and six in the induced puberty groups had been treated for a 3.5- to 4.4-year period) explained the differences in BMD values. Because the main difference between groups was the availability of estrogens to bone tissue from infancy to menarche and of estrogens/gestagens from then on up to the time of BMD evaluation, our results suggest that normal gonadal function from infancy to adulthood may be required for adequate bone mass peaking. Early detection of osteopenia and improvement in general measures for adequate bone mass peaking (calcium intake and physical activity) should be considered mandatory in the health care of these patients.

Low areal bone mineral density values in adolescents and young adult turner syndrome patients increase after long-term transdermal estradiol therapy.

OBJECTIVE: To study the effects of long-term estradiol therapy on areal bone mineral density (aBMD) values in young adult Turner syndrome patients. METHODS: The effects of 2-year transdermal estradiol administration on lumbar, L2-L4, aBMD values were evaluated in 12 Turner syndrome patients, 15.41-21.85 years old, who had reached adult height and had low aBMD values. Puberty was induced in all at a chronological age above 12 years and menarche appeared between 13.82 and 15.40 years. The patients were on oral estrogen/gestagen therapy from then until the start of the study. Adhesive patches of 17-beta-estradiol designed to be worn for 72 h and deliver 100 microg of estradiol per day, which results in a steady mean serum estradiol level of 75 pg/ml, were used for 21 days. From day 11 to day 21, 10 mg of oral didrogesterone were also added. Nutritional and physical activity habits were evaluated at the beginning, after 1 year and at the end of the study. RESULTS: aBMD values significantly increased from 0.910 +/- 0.065 to 1.005 +/- 0.086 g/cm2 (10.06 +/- 3.37%) and the z-score from -2.38 +/- 0.63 to -1.54 +/- 0.71 (0.81 +/- 0.30 z-score). No significant differences were observed in body mass index, calcium intake and physical activity habits at the start, during and at the end of the study. CONCLUSION: In summary, our results underline the importance of estrogens for bone mass peaking and suggest that this therapeutic protocol may be useful in the therapy of Turner syndrome patients with low bone mass.

Paternal sex chromosome aneuploidy as a possible origin of Turner syndrome in monozygotic twins: case report.

The meiotic or mitotic origin of most cases of Turner syndrome remains unknown, due to the difficulty in detecting hidden mosaicisms and to the lack of meiotic segregation studies. We have had the opportunity to study one pair of monozygotic twins concordant for Turner syndrome of paternal origin. The paternal origin of the single X chromosome was determined by polymerase chain reaction (PCR) amplification. No mosaicism was detected for the X or Y chromosome. In this case, a meiotic error during gametogenesis would be a likely origin of X monosomy. To determine if meiotic errors are more frequent in the father of these monozygotic twins concordant for Turner syndrome of paternal origin, molecular studies in spermatozoa were conducted to analyse sex chromosome numerical abnormalities. A total of 12520 sperm nuclei from the twins' father and 85338 sperm nuclei from eight normal donors were analysed using three-colour fluorescent in-situ hybridization. There were significant differences between the twins' father and control donors for XY disomy (0.22 versus 0.11%, P < 0.001) and total sex chromosome disomy (0.38 versus 0.21%, P < 0.001). These results could indicate an increased tendency to meiotic sex chromosome non-disjunction in the father of the Turner twins.

PCR protocol to detect parental origin and hidden mosaicism inSex chromosome aneuploidies.

In this study, we report an accurate method to determine the parental origin of sex chromosome aneuploidies or polyploidies and to detect low percentage mosaicisms. We have amplified by polymerase chain reaction (PCR) five polymorphic markers along the X chromosome (DXS1283E, DYS II, DMD49, AR and DXS52) and three markers along the Y chromosome (SRY, DYZ3 and DYZ1). False-negative results were discarded by the simultaneous amplification of Y markers and of internal controls. We have applied this protocol to a series of 14 Turner syndrome patients with a 45,X karyotype. We have detected sex chromosome mosaicisms in two patients. The parental origin of the syndrome has been determined in the other 12 patients.

[The effectiveness of recombinant growth hormone in height deficiency due to intrauterine growth retardation]. / Efectividad de la hormona de crecimiento recombinante en el déficit de talla debido a retraso de crecimiento intrauterino.

BACKGROUND: Intrauterine growth retardation (IUGR) is considered to be responsible for approximately 20% of short stature in adulthood. Although GH secretion is normal in the majority of cases, excellent results have been published by some authors using GH to treat children with height deficiency due to IUGR. PATIENTS AND METHODS: Thirty children with a history of IUGR with chronological ages between 2 and 7 years and height less than 2 SD were randomized in two groups for one year: a) control group, no treatment, 14 cases, and b) treatment group, 1 U/kg/week of recombinant GH, 16 cases. Growth and maturation were analysed periodically in both groups. In addition, serum levels of GH, IGF-I, IGFBP3 and GHBP were measured before and under treatment and adverse events were assessed in treatment group. RESULTS: In the treated group significant increments in growth rate, cm/year (median = 6.91 vs 9.94), improvement in height SDS (median = -2.19 vs -1.63) and positivation of growth rate (median = -0.13 vs 3.17) were observed compared with the control group. Bone age evolved parallelly to chronological age and the height age/bone age ratio increased throughout the study under GH therapy. Hormonal findings in the treated group showed a significant increase in IGF-I and IGFBP3 values. Glycaemia levels increased without exceeding upper normal levels in the treated group. CONCLUSION: GH was effective in promoting growth in this short-term study in children with height deficiency due to IUGR. Close follow-up is required to detect any adverse event, particularly those related to carbohydrate metabolism.

Diagnosis and treatment in utero of goiter with hypothyroidism caused by iodide overload.

A fetal goiter was detected by ultrasonography in a woman receiving potassium iodide. After this medication was discontinued at 29 weeks, a fetal hypothyroidism was confirmed by cordocentesis, and two doses of levothyroxine were administered by amniocentesis. At 34 weeks repeated cordocentesis showed fetal euthyroidism and ultrasonography shrinkage of the goiter. Growth and development normal at 1 year.

Bone mineral density in prepubertal and in adolescent and young adult patients with the salt-wasting form of congenital adrenal hyperplasia.

OBJECTIVE: To evaluate bone mineral density (BMD) in prepubertal and in adolescent and young adult patients with the salt-wasting form of congenital adrenal hyperplasia (CAH). DESIGN: A relationship between bone mineral content and risk for osteoporotic fractures has been observed in adulthood. Infancy, childhood, and adolescence are critical periods for skeletal mineralization; thus, chronic diseases may impair bone mass peaking, particularly if children and adolescents are overexposed to glucocorticoids, as may occur in patients with CAH. Lumbar L2-L4 BMD values were measured by dual x-ray absorptiometry and compared with those of 471 age- and sex-matched controls. PATIENTS: Thirty-three patients with the salt-wasting form of CAH were studied. Sixteen (10 girls and 6 boys; age range, 1.5 to 8.3 years) were prepubertal and 17 (13 women and 4 men; age range, 17.1 to 28.2 years) were adolescent and young adults who had reached final height and had presented normal pubertal development and normal gonadal function thereafter. The average doses of hydrocortisone (mg/m body surface/day) received from diagnosis in the neonatal period to BMD evaluation were 21.2 +/- 2.2 and 22.3 +/- 2.6, respectively. RESULTS: Mean BMD Z score values were 0.16 +/- 1.01 in prepubertal patients and 0.06 +/- 1.02 in adolescent and young adult patients with no statistically significant differences with age- and sex-matched controls. Mean height Z score values were -0.03 +/- 1.13 in prepubertal patients and -1.13 +/- 0.62 in adolescent and young adult patients with significant differences between the latter and their respective age- and sex-matched controls. CONCLUSION: Long-term glucocorticoid therapy does not impair bone mass peaking in CAH patients with normal gonadal function, even though their adult height values are low.

Cross-sectional growth study of the child and adolescent population of Catalonia (Spain).

A cross-sectional growth study was undertaken on a sample of 5472 school-children aged between 4 and 17. The sample was representative of the Catalan population. Results on height, weight and age at menarche are presented. Cross-sectional centile curves on height and weight were constructed using non-parametric methods. The height of Catalan children was compared with that of children from the United Kingdom (1965 and 1990), France, Greece and the Basque country (Spain). Until puberty Catalan children were similar in height to English (1990) and Greek children, and taller than children in the other studies mentioned. Only differences in final height compared with the English (1990) population were detected. Parents' place of birth and father's profession are associated with height. 'Probit analysis' revealed that the average age of menarche (12.31 years) was similar to that of other Mediterranean countries and lower than in other parts of Spain and northern European countries. There were differences in age at menarche according to the father's occupation. The secular trend of height of the Catalan child population has increased during the twentieth century, rising more than 2 cm per decade.

[Adult height, pattern of growth and pubertal development in patients with congenital adrenal hyperplasia, salt losing form]. / Talla adulta, patrón de crecimiento y desarrollo puberal en pacientes con hiperplasia suprarrenal congénita, forma perdedora de sal.

BACKGROUND: The height growth pattern in 24 patients with the salt-wasting from of congenital adrenal hyperplasia was retrospectively evaluated from the neonatal period to attainment of adult height. PATIENTS AND METHODS: All patients were on mineralcorticoid therapy and received hydrocortisone (mg/m2 body surface and day. Mean +/- SD): 34.53 +/- 8.2 during the first year of life, 22.83 +/- 4.1 from then to the puberty onset and 21.83 +/- 3.6 during puberty. Height was measured every 3-4 months and compared with that of the normal age- and sex-matched controls. RESULTS: Height differences with respect to reference population (M +/- SD) were: +0.38 +/- 0.82 in the neonatal period; -2.21 +/- 1.1 at one year of age; -0.76 +/- 1.25 at three years of age; -0.45 +/- 0.99 at the onset of puberty and -1.34 +/- 0.79 at attainment of adult height. Adult height differed significantly (p < 0.01) from control values and in girls from those of their mothers (p < 0.05). Hyperandrogenism, evaluated through urinary 17-ketosteroids, testosterone, delta 4 androstenedione and DA-S, was not documented during prepuberty and puberty. CONCLUSIONS: Our patients showed a lower growth rate than those of the control population during the two periods of higher growth potentiality: the first year of life and puberty, and this results in adult height impairment.

Hyperinsulinemia in postpubertal girls with a history of premature pubarche and functional ovarian hyperandrogenism.

Previous studies have documented the association of insulin resistance and hyperandrogenism in adult women with functional ovarian hyperandrogenism (FOH) or polycystic ovary syndrome (a form of FOH). However, the possible impact of adrenal hyperandrogenism development during childhood in premature pubarche (PP) patients on postpubertal insulin secretion patterns remains unclear. The fasting insulin to glucose ratio, C peptide, early insulin response to glucose (IRG), mean blood glucose, mean serum insulin (MSI), glucose uptake rate in peripheral tissues (M), and insulin sensitivity indexes (SI) in response to a standard oral glucose tolerance test were evaluated in 13 PP girls with FOH (group A; age, 17.2 +/- 0.5 yr), 11 eumenorrheic nonhirsute PP girls (group B; age, 16.6 +/- 0.5 yr), and 21 age-matched controls (group C). Body mass indexes (BMI) were similar in the 3 groups (group A, 23.3 +/- 0.8; group B, 22.5 +/- 0.6; group C, 20.6 +/- 0.5 kg/m2). MSI values were significantly higher in FOH patients than in controls (74.7 +/- 17.6 vs. 45.7 +/- 4.1 mU/L; P < 0.01), but were not different from those in group B (63.3 +/- 11.1 mU/L). Thirty-eight percent of FOH patients (group A) and 27% of non-FOH patients (group B), all of whom had normal BMI, showed MSI levels well above the upper normal limit for controls (> 83.3 mU/L). MSI correlated with the degree of ovarian hyperandrogenism [defined by an abnormal 17-hydroxyprogesterone response to challenge with the GnRH analog leuprolide acetate; group A] and with the free androgen index [testosterone (nanomoles per L)/sex hormone-binding globulin (nanomoles per L) x 100; groups A and B)]. Although IRG, glucose uptake rate in peripheral tissues, mean blood glucose, and SI values were not significantly different in the 3 groups, 3 patients in group A and 1 patient in group B showed decreased insulin sensitivity and/or an enhanced early IRG. Among others, significant correlations between MSI and free androgen index values (r = 0.6; P < 0.002; groups A and B) and between BMI and SI (r = -0.53; P < 0.05; groups A and B) were found. Peak 17-hydroxyprogesterone responses to ACTH at PP diagnosis correlated positively with SI in both groups of patients (r = 0.53; P < 0.007). Hyperinsulinemia is a common feature in adolescent PP patients with FOH and appears to be directly related to the degree of androgen excess. Long term follow-up of PP patients into adulthood is warranted to ascertain whether hyperinsulinemia actually precedes FOH development and whether overt insulin resistance ensues.

Source localization of androgen excess in adolescent girls.

Functional ovarian hyperandrogenism (FOH) is characterized by an abnormal ovarian response to challenge with the GnRH analogs nafarelin and leuprolide acetate, similar to that observed in women with well defined polycystic ovary syndrome, regardless of whether elevated LH levels or polycystic ovaries are present. We studied an unselected group of 42 hyperandrogenic adolescents (age range, 14-22 yr; mean, 18.1 +/- 2.5 yr) 1) to determine FOH incidence through the assessment of ovarian-steroidogenic response to a single dose of leuprolide acetate, 2) to assess the clinical characteristics of patients according to their responses to GnRH analog stimulation, and 3) to evaluate adrenal steroidogenic function and its relation to ovarian hyperandrogenism in patients with either normal or abnormal responses to leuprolide acetate challenge. All patients underwent leuprolide acetate and ACTH testing, dexamethasone and ovarian suppression tests, and pelvic ultrasonography. Twenty-four (58%) patients had supranormal plasma 17-hydroxyprogesterone (17-OHP) responses to leuprolide acetate characteristic of FOH, and in 18, the 17-OHP response was similar to that of controls (n = 24; age, 17.1 +/- 2.3 yr). Seven patients (5 with FOH and 2 with normal responses to leuprolide acetate) had an abnormal response to ACTH, but only 1 had conclusive evidence of 21-hydroxylase deficiency. In 16 patients, the response to both stimulation tests was normal. Only 13 (54%) of the 24 FOH patients had polycystic ovaries on ultrasonography, and in 11 (46%), basal plasma LH levels were elevated. In FOH patients, reduction in testosterone and androstenedione plasma levels was significantly greater after ovarian suppression than after dexamethasone challenge (P < 0.0005 and P < 0.02, respectively). Peak plasma 17-OHP levels postleoprolide acetate simulation correlated with dexamethasone-suppressed plasma testosterone concentrations, dexamethasone-suppressed plasma androstenedione levels, and the free androgen index postdexamethasone treatment (r = 0.4, P = 0.01; r+ 0.4, P < 0.05; and r = 0.41, P = 0.007, respectively), Plasma sex hormone-binding globulin levels after dexamethasone administration correlated negatively with the baseline free androgen index (r = -.0.67; P < 0.0001). Considering our diagnostic criteria, 26 (62%) of our collective of 42 patients had abnormal responses to one or both stimulation tests, whereas 16 (37%) had normal response. FOH is the most common cause in (58%) of androgen excess in adolescence. Short term leuprolide acetate stimulation is a reliable tool fro identification of the ovary as the source of their hyperandrogenism.

Use of leuprolide acetate response patterns in the early diagnosis of pubertal disorders: comparison with the gonadotropin-releasing hormone test.

The effects of a single injection (500 micrograms sc) of the GnRH agonist leuprolide acetate on gonadotropin secretion and those induced by a GnRH test were analyzed in 32 children (11 males and 21 females) referred for possible pubertal developmental disorders and in 9 prepubertal controls [group C; 4 males and 5 females; chronological age (CA), 7.4 +/- 1.2 yr]. The pituitary-gonadal secretory responses to the GnRH agonist were characterized in all subjects and in a control group in early puberty [10 females (Tanner breast stage II; CA, 11.3 +/- 1.1 yr) and 6 males (Tanner pubertal stage II; CA, 13.5 +/- 0.4 yr); group D]. Twelve girls (CA, 7.1 +/- 0.7 yr) presented with precocious breast development, 11 patients [6 boys (CA, 10.9 +/- 0.4 yr) and 5 girls (CA, 9.3 +/- 0.5 yr)] had advanced puberty and predicted adult heights below -2.0 SD score, and 9 patients [5 boys (CA, 14.6 +/- 0.3 yr) and 4 girls (CA, 14.4 +/- 1.1 yr)] had delayed puberty. Less than 6 months had elapsed since the appearance of pubertal signs in all patients with pubertal development. After a follow-up period of 12.9 +/- 2.0 months, 20 patients showed progression of pubertal signs (group A, progressive puberty), and in 12, puberty regressed or did not progress (group B, nonprogressive puberty). The results of hormonal tests in all patients were analyzed retrospectively according to their clinical outcome. Patients in group A had a mean plasma peak LH response significantly higher after leuprolide acetate stimulation than after GnRH challenge (13.1 +/- 0.2 vs. 7.3 +/- 0.9 IU/L; P < 0.003). Those in groups B and C had similar peak LH responses after both tests (3.3 +/- 0.2 vs. 3.1 +/- 0.4, and 1.5 +/- 0.1 vs. 1.8 +/- 0.4 IU/L, respectively). No differences in basal and poststimulated LH levels were found between boys and girls in the same group. In patients in groups A and D, LH consistently peaked 3 h postleuprolide acetate challenge; in those in groups B and C, the LH peak occurred 3-6 h postinjection. Maximal gonadal responses were elicited 24 h poststimulation. No overlap in poststimulated estradiol or testosterone values occurred between patients in groups A and D and those in groups B and C.(ABSTRACT TRUNCATED AT 400 WORDS)