Leptina en relación con el sexo, el índice de masa corporal, el estadio puberal y la insulina en niños con déficit de hormonas de crecimiento con y sin tratamiento sustitutivo / Leptin levels and their correlation with sex, body mass index, pubertal status and insulin concentrations in growth-hormone treated and untreated adolescents with growth hormone deficiency

Introducción: En este estudio nos proponemos investigar las concentraciones de leptina y su relación con el sexo, el índice de masa corporal, el estadio puberal y las concentraciones de insulina en un grupo de adolescentes con deficiencia de hormona de crecimiento que recibía tratamiento con la hormona, en un grupo con deficiencia que no recibía tratamiento y en un grupo de control sano. Métodos: Se estudió a 22 sujetos con déficit de hormona de crecimiento; 15 recibían hormona de crecimiento (grupo A) y 7 no la recibían (grupo B). La edad del grupo A era de 12 ± 2,9 años, 7 mujeres y 8 varones, 7 prepúberes y el resto puberales; recibieron 0,1 U/kg/día de hormona de crecimiento por un período de 3,8 ± 1,2 años. La edad del grupo B era de 13,6 ± 1,8, 3 mujeres y 4 varones, 3 prepuberales y el resto puberales que nunca habían recibido hormona de crecimiento. Diecinueve sujetos sanos sin deficiencia de hormona de crecimiento, ajustados por edad ósea e índice de masa corporal más que por edad cronológica participaron como controles (grupo C); 9 mujeres y 10 varones, 11 prepúberes y 8 puberales. Se les tomó el peso y la talla, se calculó el índice de masa corporal y se determinaron las concentraciones basales de leptina e insulina. Resultados: No hubo diferencias en las variables antropométricas y en las concentraciones de insulina y leptina entre los grupos. Se detectó un valor significativamente elevado de leptina en las mujeres y en los pacientes puberales, en los grupos A y C. No se encontraron diferencias significativas en el índice de masa corporal según el sexo, pero sí entre sujetos prepuberales y puberales. La elevación de la leptina en las mujeres fue evidente tanto en el grupo prepuberal como en el puberal, mientras que no se observaron diferencias en relación con el índice de masa corporal. Las variables independientes que predijeron significativamente la concentración de leptina fueron el sexo y el índice de masa corporal. Conclusiones: a) La concentración de leptina e insulina no fue diferente en niños con deficiencia de hormona de crecimiento comparados con niños sanos, ajustados para el índice de masa corporal; b) se confirma el dimorfismo sexual, caracterizado por concentraciones más elevadas de leptina en las mujeres, evidente desde la edad prepuberal y que persiste en los estados de deficiencia de hormona de crecimiento, y c) el índice de masa corporal y el sexo fueron las variables independientes predictoras de las concentraciones de leptina (AU)

Introduction: The aim of this study was to investigate leptin levels and their correlation with gender, body mass index (BMI), pubertal status and insulin concentrations in a group of growth hormone deficient (GHD) adolescents treated with growth hormone (GH), a group of untreated GHD subjects and a group of healthy controls. Methods: We studied 22 GHD subjects; 15 were receiving GH (group A) and seven were not receiving GH (Group B). The mean chronological age in group A was 12.0 ± 2.9 years. There were seven girls and eight boys; seven were prepubertal and the rest were pubertal. All subjects in group A received 0.1 IU/Kg/day of GH for a period of 3.8 ± 1.2 years. The mean age of group B was 13.6 ± 1.8 years. There were three girls and four boys; three were prepubertal, while the rest were pubertal. None had received GH treatment. Nineteen healthy subjects without GHD, matched for bone age and BMI participated in the study as controls (group C). There were 9 girls and 10 boys; 11 were prepubertal, while 8 were pubertal. Weight and height were measured, BMI was calculated and basal leptin and insulin levels were measured. Results: No differences among groups were found in anthropometric variables or insulin and leptin levels. Leptin levels were significantly elevated in girls and in pubertal patients in groups A and C. BMI did not significantly differ between sexes but was significantly different between prepubertal and pubertal subjects. The increase of leptin concentrations in girls was evident in both prepubertal and pubertal subjects, while no differences were noted in relation to BMI. The independent variables that predicted leptin levels were sex and BMI. Conclusions: a) No differences in leptin and insulin levels were found between subjects with GHD and controls, matched for BMI values. b) A sexual dimorphism characterized by increased leptin levels in girls was evident from prepubertal age and persisted in GHD.c) The independent variables that predicted leptin concentrations were BMI and sex (AU)

Decreased bone mineral density and bone formation markers shortly after diagnosis of clinical type 1 diabetes mellitus.

We recently demonstrated that children with type 1 diabetes mellitus (DM) have decreased lumbar spine bone mineral density (BMD) as early as four years after clinical diagnosis of the disease. In order to determine whether osteopenia is already present in patients very early on after diagnosis of clinical DM, we evaluated the bone mineral status of a group of newly diagnosed children (5.8 +/- 1.5 mo after diagnosis). We studied 23 prepubertal children (7 M, 16 F) with a mean chronological age of 9.5 +/- 2.2 yr and a mean glycosylated hemoglobin of 8.9 +/- 2.4%. Lumbar spine and femoral neck BMD were measured by dual X-ray absorptiometry, while bone turnover was assessed by the determination of the serum concentration of the carboxy-terminal propeptide of type I collagen (PICP) and the carboxy-terminal cross-linked telopeptide of type I collagen (N-telopeptide). Results were compared to those of age, height, and pubertal status matched controls. Lumbar spine BMD Z-scores were decreased in patients compared to controls (Z-scores of -0.89 +/- 1.2, with 10 of 22 patients showing values >1 SD below the mean). When lumbar spine Z-scores were analyzed in those patients with <3 months or > or =3 months since diagnosis of DM a significant difference was noticed between groups (-0.648 +/- 1.12 vs -1.267 +/- 1.17; p <0.02). No significant differences were noted in femoral neck BMD and total BMD between groups. Serum PICP levels were decreased when compared to controls (233.6 +/- 39.3 vs 375.9 +/- 50.7 microg/l; p <0.002), while serum N-telopeptide concentrations, although increased, were not significantly different (9.3 +/- 1.3 vs 5.7 +/- 1.5 microg/l). In summary, early on after the diagnosis of type 1 DM, children present with decreased lumbar spine BMD and decreased bone formation markers.

Cardiac mass and function, carotid artery intima-media thickness, and lipoprotein levels in growth hormone-deficient adolescents.

The objective of our study was to evaluate whether cardiac mass and function, carotid artery intima-media thickness, and serum lipid and lipoprotein(a) levels are abnormal in adolescents with GH deficiency. Young adults with childhood-onset and adulthood-onset GH deficiency have been found to have a higher cardiovascular risk, as manifested among other factors by reduced left ventricular mass, impaired systolic function, significant increase in arterial intima-media thickness, and dyslipidemia. Twelve adolescents (seven males and five females) with GH deficiency (10 idiopathic and 2 organic), with an age of 14.2 +/- 2.8 yr and a height of 140.6 +/- 17.9 cm (height SD score, -2.6 +/- 0.3), were studied. Six children had received GH in the past but were off therapy for several years, whereas six patients had never been treated with GH. Fasting blood samples were obtained for serum lipids and lipoprotein(a) analysis. Patients underwent transthoracic M-mode and two-dimensional echocardiographic evaluation for measurement of interventricular septal thickness, left ventricular posterior wall thickness, and left ventricular mass, as well as left ventricular ejection fraction at rest and pulmonary venous flow velocities; carotid artery intima-media thickness was measured using high-resolution mode B ultrasound. Seven GH-deficient (GHD) adolescents on GH at the time of the study and 19 healthy adolescents, all comparable for age, pubertal status, height, weight, blood pressure, and pulse, participated in this study as controls. Interventricular septal thickness (6.5 +/- 1.3 vs. 7.0 +/- 1.5 mm), left ventricular posterior wall thickness (7.0 +/- 1.8 vs. 7.5 +/- 2.0 mm), and left ventricular mass after correction for body surface area (71.2 +/- 21.8 vs. 70.7 +/- 18.0 g/m(2)) were similar in untreated GHD patients and healthy controls. Similarly, the left ventricular ejection fraction at rest was similar in untreated GHD subjects and controls (70.0 +/- 0.7 vs. 70.0 +/- 0.6%), as were the pulmonary venous flow velocities (0.54 +/- 0.16 vs. 0.55 +/- 0.10 m/s for diastolic peak velocity; 0.51 +/- 0.16 vs. 0.50 +/- 0.09 m/s for systolic peak velocity; and 0.19 +/- 0.06 vs. 0.19 +/- 0.05 m/s for atrial reversal filling). Carotid artery intima-media thickness (0.60 +/- 0.02 mm and 0.59 +/- 0.02 mm for the right and left carotid arteries, respectively) was also normal in our untreated GHD patients when compared with healthy controls. In addition, all echocardiographic measurements were similar in GHD subjects on or off GH at the time of the study. Low-density lipoprotein cholesterol levels were increased in untreated GHD patients when compared with healthy controls (3.17 +/- 0.70 vs. 2.33 +/- 0.36 mmol/L; P < 0.01), whereas total cholesterol, high-density lipoprotein cholesterol, and triglyceride concentrations were similar to that of controls. Total cholesterol levels were increased in our untreated GHD adolescents when compared with GHD subjects receiving GH therapy at the time of the study, while low-density lipoprotein cholesterol and triglyceride levels were also elevated, although not significantly. Lipoprotein(a) levels were elevated in untreated GHD adolescents when compared with healthy controls, and untreated GHD subjects had higher lipoprotein(a) concentrations than GH-treated patients. GHD adolescents, regardless of whether or not they received GH therapy, do not seem to show alterations in cardiac mass and function or early atherosclerotic changes. They must, however, be followed carefully because they already present cardiovascular risk factors such as dyslipidemia, which may increase their cardiovascular morbidity over time.

Acipimox, a nicotinic acid analog, stimulates growth hormone secretion in short healthy prepubertal children.

Recent studies in adult volunteers have demonstrated that the free fatty acid reduction induced by acipimox, a nicotinic acid analog, stimulated GH secretion per se and enhanced in an additive manner the GH secretion elicited by such different stimuli as pyridostigmine, GHRH and GHRP-6. In order to evaluate whether acipimox administration stimulates GH secretion in prepubertal children, we administered a single oral dose of acipimox (100 mg for children weighing <30 kg and 200 mg for those >30 kg) to 14 healthy prepubertal children with a mean age of 8.2 +/- 1.9 years, a mean bone age of 6.2 +/- 3.0 years, growing along the 5-10th percentiles, and with normal thyroid function and IGF-I levels. Acipimox administration elicited a sustained increase in GH from a mean baseline level of 0.6 +/- 0.4 to 6.7 +/- 2.4 microg/l at the end of the test (p<0.05), with a mean GH peak of 10.5 +/- 3.5 microg/l. GH release was delayed so that peak GH levels were achieved 180 minutes after acipimox administration. In order to determine whether acipimox was capable of enhancing the GH secretion elicited by levodopa (L-Dopa), we administered either oral L-Dopa (250 mg for children weighing <30 kg and 500 mg for those >30 kg) or oral acipimox plus L-Dopa to the same children on different days. GH concentrations increased in a similar fashion following either of these tests (from a baseline level of 1.2 +/- 0.4 and 0.7 +/- 0.4 microg/l to 8.4 +/- 2.7 and 9.3 +/- 2.9 microg/l at the end of the test (p<0.001), with peak GH concentrations of 13.1 +/- 4.1 and 11.8 +/- 3.3 microg/l after L-Dopa or acipimox plus L-Dopa, respectively). Although the peak GH concentrations obtained after the combined administration of acipimox plus L-Dopa were similar to those obtained after either acipimox or L-Dopa administration, a larger number of our patients reached a GH cut-off point of >7 microg/l following combined therapy than with either stimulus alone (13/14 patients with combined therapy and 10/14 with acipimox alone). No side effects other than mild facial flushing were noted after acipimox administration. These results indicate that: 1) following the administration of a single oral dose of acipimox, significant GH secretion was elicited in healthy short prepubertal children; 2) the combined administration of acipimox plus L-Dopa did not, however, enhance the GH secretion of this group of children; 3) acipimox was well tolerated with minimal side effects; and 4) further studies in both GH sufficient and GH deficient children are necessary to evaluate acipimox's usefulness in assessing GH reserve.

Multiple endocrine abnormalities in a child with Blackfan-Diamond anemia and hemochromatosis. Significant improvement of growth velocity and predicted adult height following growth hormone treatment despite liver damage.

We evaluated a short, prepubertal 13.9 year-old boy with Blackfan-Diamond anemia and significant liver iron stores due to multiple blood transfusions and found him to have several endocrine abnormalities, including hypothyroidism, hypoparathyroidism, primary and secondary hypogonadism and IGF-I insufficiency. Growth velocity was poor despite treatment with levothyroxine, calcitriol, calcium and aggressive therapy with chelating agents. After 25 months of treatment with rhGH his growth velocity, height for age and PAH increased significantly, suggesting a degree of sensitivity to GH despite his liver damage.

Growth velocity, final height and bone mineral metabolism of short children treated long term with growth hormone.

Since human recombinant growth hormone (GH) became available a large number of short GH deficient and GH-sufficient children have been treated with growth hormone. Growth hormone deficient patients have been followed to final height and several studies have shown that even when treated with GH from very early on in life they tend to end up shorter than their target height. There is, however, a clear increase in their growth velocities particularly during the first 4-5 years of GH therapy so that patients end up with a height-SD score of aproximately -0.8. Recent studies have demonstrated decreased bone mineral densities (BMD) in children with growth hormone deficiency, both by areal and volumetric analysis. Therapy with growth hormone clearly increases their BMD with an increase in bone formation markers, as will be reviewed in detail. Growth hormone therapy of non-growth hormone deficient short children has increased their growth velocity short term, particularly in girls with Turner's syndrome and in children with chronic renal insuficiency. Recent final height data by Rosenfeld et al. and by Swedish and Dutch groups have demonstrated a gain of 8-12 cm in girls with Turner's syndrome treated with GH or with a combination of GH and oxandrolone. Neely et al. and we have demonstrated that growth hormone treated prepubertal age girls and adolescents with Turner's syndrome have normal BMD and Shaw et al. has suggested that they have normal BMD despite GH or estrogen therapy. However, we found the BMD of a group of previously GH treated young women with Turner's syndrome on estrogen replacement to be decreased compared to both age and gender matched controls and to controls of the same weight and pubertal status. Growth hormone therapy increases the growth velocity and the final height of children with chronic renal insuficiency, particularly in prepubertal children treated with GH before dialysis. We have demonstrated how the BMD of these patients, which at baseline is low when compared to healthy age matched controls, but normal when compared to height and bone age matched controls, increases with growth hormone treatment significantly, moreso than in untreated uremic controls or in untreated healthy controls paired for height and bone age. Short, slowly growing, non growth hormone deficient patients (idiopathic short stature) have been treated for prolonged periods of time with GH. We and others have demonstrated a clear increase in their growth velocity short term, but improvement of their final height remains unclear and controversial. After 4-8 years of GH treatment, Hintz et al. have found a 5-6 cm increase in final height compared to the predicted adult height before beginning therapy, but most patients did not reach their target heights. Other studies, however, have found no improvement in final height and Kawai et al. even suggests that GH therapy diminishes the final height of treated children due to an earlier puberty and a shorter pubertal growth spurt. We, have found decreased BMD in children with idiopathic short stature when compared to controls of their same height and bone age with a significant increase in BMD following 12 months of GH and with an increase in bone turnover as measured by bone formation and resorption markers. Recent short term studies in patients with hypophosphatemic rickets and osteogenesis imperfecta treated with rhGH have also yielded similar results which will be specified in the review. Some 10-20% of children born with intrauterine growth retardation (IUGR) end up short and we had already demonstrated 20 years ago how 2 years of GH therapy were capable of increasing their growth velocities significantly with an improvement of their height-SD scores. Recent studies mainly from Europe have corroborated this data long term, so that IUGR children have been shown by de Zegher et al. to increase their growth velocities and their height for age after 6 years of treatment, entering into the low normal centiles of their growth curves for age. Long term studies of these children to final height will be necessary to determine the usefulness and safety of this form of therapy.

Decreased bone mass despite long-term estrogen replacement therapy in young women with Turner's syndrome and previously normal bone density.

OBJECTIVE: To determine whether young women with Turner's syndrome who had normal bone mineral density (BMD) before the induction of puberty maintain normal BMD in young adulthood. DESIGN: Controlled clinical study. SETTING: A private hospital clinical research setting. PATIENTS: Young women with Turner's syndrome in Tanner stage V of puberty with previously normal BMD. INTERVENTIONS: Oral conjugated estrogens and progesterone acetate were administered continuously for a mean (+/-SD) of 4.1+/-1.0 years. Bone mineral densities and blood samples were evaluated. MAIN OUTCOME MEASURE(S): The BMD of the lumbar spine and the femoral neck was determined during young adulthood. The change in BMD over the previous 6 years also was evaluated. Serum concentrations of the carboxy-terminal propeptide of type 1 collagen and of the carboxy-terminal cross-linked telopeptide of type 1 collagen were measured. RESULT(S): The BMD of the lumbar spine was reduced significantly in our patients. There was no change in the BMD of the femoral neck or lumbar spine over a period of 6.1 years. Concentrations of the carboxy-terminal propeptide of type 1 collagen were decreased, whereas concentrations of the carboxy-terminal cross-linked telopeptide of type 1 collagen were increased. CONCLUSION(S): Young women with Turner's syndrome do not attain normal peak bone mass even when estrogen replacement therapy is begun in adolescence. Their low BMD seems to be due to decreased bone formation and increased bone resorption.

Decreased trabecular bone mineral density in children with idiopathic short stature: normalization of bone density and increased bone turnover after 1 year of growth hormone treatment.

Patients with growth hormone (GH) deficiency have impaired bone mineral metabolism; treatment with GH leads to an improvement in their bone mineral density (BMD). The effect of GH on the BMD of children with idiopathic short stature is unknown. We studied 14 short, slowly growing, otherwise healthy, prepubertal children without GH deficiency (7 girls and 7 boys) with a chronological age of 10.9 +/- 1.4 years, bone age of 8.8 +/- 1.5 years, and height of 127.8 +/- 8.5 cm (height SD score of -2.2 +/- 0.5). Growth velocity increased from 3.9 +/- 1.1 cm/y to 8.0 +/- 1.9 cm/y, and height SD score improved from -2.2 +/- 0.5 to -1.8 +/- 0.5 after 12 months of GH treatment (P <.007 and P <.001, respectively). Baseline lumbar spine BMD was decreased when compared with that of a control group of children matched for bone age and height (0.645 +/- 0.09 g/cm(2) vs 0.730 +/- 0.08 g/cm(2); P <.003). Lumbar spine BMD increased in subjects with ISS after 1 year of GH treatment from 0.645 +/- 0.09 g/cm(2) to 0.808 +/- 0.04 g/cm(2) (P <.05), reaching levels similar to those of control subjects, followed up without therapy (0.808 +/- 0.04 g/cm(2) vs 0.760 +/- 0.08 g/cm(2)); lumbar spine BMD increased 25.3% in the subjects with ISS and 4.1% in the control subjects. Femoral neck BMD did not change during treatment. Serum concentrations of the carboxy-terminal propeptide of type 1 collagen increased from 231.6 +/- 65.5 microg/L to 351.6 +/- 87.2 microg/L, and levels of the carboxy-terminal cross-linked telopeptide of type 1 collagen increased from 9.9 +/- 5.9 microg/L to 13.9 +/- 2.4 microg/L. Children with ISS have decreased lumbar spine BMD, which increases with GH therapy, reaching levels similar to those of control subjects. Bone turnover increased as indicated by a rise in bone formation and bone resorption markers.

Final height after combined growth hormone and gonadotrophin-releasing hormone analogue therapy in short healthy children entering into normally timed puberty.

OBJECTIVE: Combined gonadotrophin-releasing hormone analogue and recombinant human growth hormone therapy has been used in an attempt to improve the final height of short non-GH deficient adolescents with normally timed puberty; its use, however, is still controversial as only short-term studies in a very limited number of patients have been undertaken, with either improvement in height prognosis or no beneficial effect on predicted growth. We have treated a group of extremely short healthy children with very low predicted adult heights entering into normally timed puberty with combined therapy, in order to determine whether we could improve their final height above their pretreatment predicted adult height. PATIENTS: We treated 10 healthy adolescent short children (7 girls and 3 boys) simultaneously for 30.0 +/- 5.2 months with the GnRH analogue leuprolide acetate (0.3 mg/kg im every 28 days) and with rhGH (0.1 U/kg/day, sc, 6 days a week). The mean chronological age of our patients was 11.8 +/- 1.3 years, with a mean bone age of 11.2 +/- 0.9 years, height of 128.9 +/- 7.5 cm (-2.4 +/- 0.4 SD below the mean) and a predicted adult height of 150.7 +/- 9.8 cm; they were all in Tanner stage II-III of puberty. Ten healthy short children (7 girls and 3 boys) in the early stages of puberty with a mean chronological age of 11.4 +/- 1.0 years, a mean bone age of 11.0 +/- 0.8 years, height of 128.9 +/- 7.8 cm (-2.3 +/- 0.4 SD below the mean) and a mean adult predicted height of 151.8 +/- 10.1 cm served as controls and were simultaneously followed without therapy for the same study period. MEASUREMENTS: Height and pubertal status were followed every 3 months during combined therapy and until final height of our patients was reached; bone ages were obtained every 6 months. Growth hormone deficiency was ruled out in all our subjects prior to beginning of the study by a normal response to oral clonidine and normal IGF-1 levels. Basal serum testosterone and/or oestradiol levels, as well as LH and FSH following administration of LH-releasing hormone were obtained before treatment and after 6 weeks and 4 months of combined therapy and every 6 months thereafter. Routine biochemistry as well as thyroid function tests were obtained at each visit. RESULTS: Combined treatment resulted in an interruption of pubertal development with a suppression of gonadal steroids and of the LH response to LH-releasing hormone. Growth velocity decreased from 6.5 +/- 1.6 cm/year before treatment to 5.5 +/- 1.5 cm/year and 3.9 +/- 1.3 cm/year during the first and second year of treatment (P < 0.02 and P < 0.05, respectively) resulting in a height Z score reduction, declining from -2.4 +/- 04 to -2.6 +/- 0.7 SD. Bone age maturation declined averaging 0.75 bone age year/year of treatment but height SDS for bone age declined from -1.7 +/- 0.7 to -2.2 +/- 0.5 at the end of the second year of therapy with no improvement in predicted adult height (150.7 +/- 9.8 cm before and 150.0 +/- 8.0 after 2 years of therapy). After discontinuing treatment growth velocity did not improve and bone maturation advanced more rapidly (averaging 2.0 +/- 0.4 year/year of follow up) and the mean final height of our patients was 151 +/- 2.4 cm (-2.6 +/- 0.6 SD below the mean) which was not greater than the mean pretreatment predicted adult height and well below their target height; these results were also similar to those of the control population in whom the predicted adult height at the beginning of the study and after 2 years of follow up, was not different from their final height and well below their target height. CONCLUSIONS: We conclude that combined rhGH and GnRH analogue therapy in short adolescents with normally timed puberty does not contribute to increase their final height above their pretreatment predicted adult height; we can therefore not recommend this form of therapy for this group of patients given the poor results obtained, as well as the cost of these medications and the

Decreased lumbar spine bone mass and low bone turnover in children and adolescents with insulin dependent diabetes mellitus followed longitudinally.

The effects of insulin dependent diabetes mellitus (IDDM) on bone metabolism are still not well defined. We evaluated total bone mineral content (TBMC) and bone mineral density (BMD) at the lumbar spine and femoral neck using dual X-ray absorptiometry in 26 IDDM children (15 M, 11 F) with a mean chronological age of 12.1+/-3.1 yr (range 7.1-14.2 yr). Duration of diabetes was 4.3+/-2.9 yr, with a mean glycosylated hemoglobin of 9.2+/-0.4%. BMD and TBMC standard deviation scores (Z-scores) were determined by comparing our results to controls matched for age, sex and pubertal status. BMD and bone formation and resorption markers were determined at the beginning of the study and after one year of follow up. Mean lumbar spine Z-score was -1.06+/-0.2, with negative values in 24 of 26 children (92.6%); 14/26 patients (53.8%) had a lumbar spine Z-score >1.0 SD below the mean. Mean lumbar spine Z-score remained unchanged after one year of follow up (-1.02+/-0.3). No significant differences were obtained in femoral neck BMD or TBMC between groups. No correlation was observed between lumbar spine BMD Z-scores and duration of IDDM or degree of diabetes control, as assessed by the mean glycosylated hemoglobin. Daily urinary calcium excretion was elevated in our patients initially and after one year of follow up; however, no correlation was obtained between lumbar spine BMD and 24 h urinary calcium excretion. Carboxy-terminal propeptide of type 1 collagen values and levels of urinary cross-linked N-telopeptides of type 1 collagen in the diabetic children were significantly lower than those of the matched controls. Osteoblastic activity as assessed by serum osteocalcin and by the carboxy-terminal propeptide of type I collagen and bone resorption as measured by cross-linked N-telopeptides of type 1 collagen did not correlate with the lumbar spine Z-scores. When IDDM patients were subdivided into males and females and into children with more than or less than 2 yr duration of diabetes since diagnosis, no differences between groups were found. These results suggest that insulin dependent diabetes in children is associated with low bone turnover resulting in a deficit in bone mass which may be manifested as osteopenia in the growing bone. This defect is already present in trabecular bone early on in the disease and seems not to be related to glycemic control.

Serum lipids, lipoprotein lp(a), and plasminogen activator inhibitor-1 in patients with Turner's syndrome before and during growth hormone and estrogen therapy.

OBJECTIVE: To evaluate whether girls with Turner's syndrome have an increased risk for cardiovascular disease due to alterations in their lipoprotein metabolism. DESIGN: Controlled clinical study. SETTING: Private academic hospital. PATIENT(S): Fifteen untreated girls with Turner's syndrome were studied initially; 11 of these patients were evaluated further while on therapy. INTERVENTION(S): Serum lipids, lipoprotein lp(a), and plasminogen activator (PA) inhibitor-1 were measured before and during 6 months of either GH or estrogen (E) treatment. MAIN OUTCOME MEASURE(S): Serum lipids, lipoprotein lp(a), and PA inhibitor-1 (PAI-1). RESULT(S): Total and low-density lipoprotein (LDL) cholesterol, triglycerides, lipoprotein lp(a), and PA inhibitor-1 levels were normal in Turner's syndrome patients compared with age-matched controls; HDL cholesterol was increased. During GH treatment, a significant decrease in total and LDL cholesterol was noted, whereas lipids, lipoprotein(a), and PA inhibitor-1 levels did not change with E therapy. CONCLUSION(S): The normal lipoproteins of untreated adolescents with Turner's syndrome, as well as the further decrease of total and LDL cholesterol during GH treatment, would seem to indicate that lipoproteins do not increase the cardiovascular risk of these girls.

Effectiveness and limitations of the use of the gonadotropin-releasing hormone agonist leuprolide acetate in the diagnosis of delayed puberty in males.

In order to evaluate the effectiveness of the gonadotropin-releasing hormone agonist leuprolide acetate in distinguishing gonadotropin deficiency from delayed puberty, a single subcutaneous dose of 20 micrograms/kg of leuprolide acetate was administered at 07.00 h to 14 patients with constitutionally delayed puberty and to 8 gonadotropin-deficient subjects, and serum gonadotropin and testosterone levels were determined at baseline and 1,2,3,6,12, and 24 h thereafter. The increase in gonadotropin and testosterone levels was significant in patients with delayed puberty, so that the mean peak luteinizing hormone and to a lesser degree the mean peak testosterone levels clearly differentiated normally delayed from gonadotropin-deficient puberty. However, when the peak gonadotropin and testosterone concentrations were analyzed individually, there was a considerable overlap between the two groups of males, limiting the usefulness of this test.

[High- and low-risk molecular sequences in autoimmune diseases. An analysis of type I diabetes in Latin America]. / Secuencias moleculares de alto y bajo riesgo en enfermedades autoinmunes. Un análisis de la diabetes tipo I en Latinoamérica.

Type I diabetes is an autoimmune and a polygenic disease, in which MHC-class II genes contribute to 48% of the disease. The aim of the present study, is to provide a guideline to understanding the molecular association of these genes, through the immunogenetic analysis of 3 Latin american mestizo populations. We included 606 individuals, 349 patients with DMDI and 257 healthy controls coming from 3 geographical areas: Mexico City, Mexico; Caracas, Venezuela and Medellin, Colombia. The results clearly indicate that in mestizo groups, the diabetogenic haplotypes are from mediterranean ancestry, while protection is due to Amerindian genes. It was demonstrated that the relevant sequences for IDDM expression are located to DRB1 and DQB1 loci with a minimal contribution of DQA1 residues. The sequences determining peptide recognition and the induction of TH1 cells mediating the cellular autoimmune response are in positions DRB1-57 and 74 (an aspartic acid and a glutamic acid respectively, confer protection), modulated by D-57 in the DQ, 8 chain. These data show that DRB1-DQB1 haplotypes are central for IDDM expression and open new pathways for the disease management.

Secuencias moleculares de alto y bajo riesgo en enfermedades autoinmunes. Un análisis de la diabetes tipo I en Latinoamérica / High and low risk molecular sequences in autoinmmune diseases. An analysis of type I diabetes in Latin America

La diabetes tipo I es una enfermedad autoinmune, poligénica con una contribución del 48 por ciento de los genes MHC Case II. El objeto de este trabajo es proveer una explicación para las asociaciones moleculares de dichos genes, mediante el análisis de la inmunogenética de 3 poblaciones mestizas de Latinoamérica. Se estudiaron un total de 606 individuos, 349 pacientes con DMDI y 257 sujetos sanos de tres localidades México DF, Caracas, Venezuela, Medellín, Colombia. Los resultados indican que en los grupos mestizos, los haplotipos diabetogénicos son de contribución mediterránea y que la mayoría de los hoplatipos de protección son de origen indígena. Se demostró que las secuencias relevantes en la expresión de la enfermedad están en los loci DRB1 y DQB1, con un aporte mínimo de DQA1 y que las secuencias relevantes en el reconocimiento del péptido y en la inducción de las células Th1 mediadoras de la activación de la respuesta celular, están localizadas en DRB1-57 y 74 (la presencia de ac. aspártico y ac. glutámico confieren resistencia), moduladas por la presencia de D-57 en DQp del antígeno DQ. Estos datos demuestran la participación de DRB1-DQB1 en la enfermedad y abren caminos para un nuevo manejo de la DMDI