Prepubertal girls with premature adrenarche have greater bone mineral content and density than controls.

Body composition in premature adrenarche (PA) has not been described. We hypothesized that the increased adrenal androgens in PA would have a trophic effect on lean body components. We studied 14 PA subjects and 16 controls, all prepubertal Hispanic girls. The body composition parameters tested included height, weight, bone mineral density (BMD), bone mineral content (BMC), nonbone fat-free mass, total body potassium, total body water, and extracellular water. Bone age was determined in all PA subjects. Compared with controls, PA subjects had significantly higher BMC (P = 0.02) and BMD (P = 0.03) when adjusted for age, weight, height, and fat mass, but were not different in the following lean body components: fat-free mass, total body potassium, total body water, and extracellular water. There was no difference in BMD or BMC between the PA subjects with and without advanced bone age. These data suggest a specific effect of PA on bone mineral, but not on other lean body components. The absence of a correlation between bone age and bone mineral in this small group leads us to propose there are separate promoters of bone age advancement and bone mineral accrual. Candidate hormones for these processes include adrenal androgens, E, and IGF-I. The findings of this study suggest that hormonal alterations associated with PA affect bone mineral accrual and may elucidate the mechanisms involved in this process.

Comparison of simple measures of insulin sensitivity in young girls with premature adrenarche: the fasting glucose to insulin ratio may be a simple and useful measure.

Insulin resistance is a strong predictor of the development of type 2 diabetes mellitus and cardiovascular disease. Girls with premature adrenarche (PA) or obesity may be at an increased risk for the development of insulin resistance. Recently, in prepubertal girls with PA, a fasting glucose to insulin ratio (FGIR) of less than 7 was found to be predictive of insulin resistance as determined by the frequently sampled iv glucose tolerance test. We sought to compare the FGIR with 2 insulin sensitivity measures, SiM (an adjusted mean measure of insulin sensitivity based on fasting and 2 h post glucose load insulin sensitivity measures) and the composite whole body insulin sensitivity index, ISI(comp), both derived from the 2-h oral glucose tolerance test in 2 groups of children at risk: girls with PA and obese girls. We studied 25 prepubertal girls with PA and/or obesity and further classified them as insulin resistant (IR) or insulin sensitive (IS) based on the FGIR. Four simple measures of insulin sensitivity [FGIR, quantitative insulin sensitivity check index (QUICKI), fasting insulin resistance index, and fasting insulin] were compared with SiM and ISI(comp). Additionally, we characterized the subjects in terms of risk factors associated with insulin resistance according to their insulin resistance status based on the FGIR. In our subjects the strongest correlations overall appeared to be between FGIR and SiM, FGIR and ISI(comp), QUICKI and SiM, and QUICKI and ISI(comp) [correlations (r) ranged from 0.81--0.84]. Furthermore, the IR group had higher body mass index and body mass index z-scores and triglyceride levels than the IS group and were over 3 times more likely to have triglycerides greater than the 95th percentile compared with national norms. We conclude that the FGIR and QUICKI are highly correlated with oral glucose tolerance test measures of insulin sensitivity. An FGIR less than 7 in young girls with PA or obesity may be helpful in the early identification of children at risk for complications of insulin resistance.

Primary central nervous system lymphoma in childhood presenting as progressive panhypopituitarism.

We report a 15-year-old boy who had isolated central diabetes insipidus initially diagnosed at age 11 years. A brain magnetic resonance imaging (MRI) was normal at the time. At age 12 years, growth hormone (GH) testing was performed because of a decline in linear growth rate and demonstrated GH deficiency. After a repeat normal brain MRI, GH therapy was begun. Three years later, hormonal testing revealed prepubertal gonadotropins and low testosterone levels, free thyroxine index, and morning cortisol levels. Repeat brain MRI demonstrated a 9-mm enhancing lesion in the region of the pituitary stalk. The pathologic diagnosis was that of a high-grade malignant B-cell lymphoma, suggestive of Burkitt Lymphoma. Growth hormone therapy has not been associated with an increased incidence of lymphoma. This report underscores the need for vigilance in follow-up brain imaging and hormonal evaluation in children with diabetes insipidus, especially those with evolving anterior hormone deficiencies.

Bone mineral in prepubertal children: gender and ethnicity.

Previous reports of gender and ethnic differences in bone mineral in prepubertal children have been inconsistent due to different methodologies, the problematic nature of bone density by dual-energy X-ray absorptiometry (DXA) calculated as the ratio of bone mineral mass to projected bone area (BA), and the generally small study populations. The aim of this study was to test the hypothesis that gender and ethnic differences in bone mineral by DXA are present in prepubertal children. The subjects were 336 healthy Asian, black, and white prepubertal children (172 females and 164 males). Total body bone mineral content (TBBMC) was adjusted for total body BA (TBBA), age, height, and weight. Adjusted mean TBBMC was greater in males than in females (p = 0.01). The gender difference was independent of ethnicity. Adjusted mean TBBMC was different for black compared with nonblack children (p = 0.001). The ethnic difference was a function of TBBA and weight. This study in a multiethnic population of prepubertal children shows (1) a gender difference in TBBMC and (2) an ethnic difference in TBBMC.

Effect of puberty on the relationship between circulating leptin and body composition.

Circulating concentrations of leptin are better correlated with absolute amounts of adipose tissue [fat mass (FM)] than with relative body fatness (body mass index or percent body fat). There is a clear sexual dimorphism in circulating concentrations of leptin (females > males) at birth and in adulthood. However, whether such dimorphism is present in the interval between these periods of development remains controversial. We examined body composition and clinical (Tanner stage) and endocrine (pituitary-gonadal axis hormones) aspects of sexual maturation in relationship to circulating concentrations of leptin in 102 children (53 males and 49 females, 6-19 yr of age) to evaluate the relationship between circulating leptin concentrations and body composition before and during puberty. Pubertal stage was assigned by physical examination (Tanner staging) and also assessed by measurement of plasma estradiol, testosterone, and pituitary gonadotropins. Body composition was determined by dual-energy x-ray absorptiometry and by anthropometry. Circulating concentrations of leptin in the postabsorptive state were determined by a solid-phase sandwich enzyme immunoassay. The effect of gender on the relationship between circulating leptin concentrations and FM was determined by ANOVA at each Tanner stage. Stepwise multiple linear regression analyses, including circulating concentrations of pituitary-gonadal axis hormones, and FM were performed, by gender, to determine whether the relationship between circulating concentrations of leptin and FM changes during puberty. Plasma leptin concentrations were significantly correlated with FM at all Tanner stages in males and females. Plasma leptin concentrations, normalized to FM, were significantly higher in females than males at Tanner stages IV and V but not at earlier stages of pubertal development. Plasma leptin concentrations, normalized to FM, were significantly greater in females at Tanner stage V compared with females at Tanner stage I and significantly lower in males at Tanner stage IV and V compared with males at Tanner stage I. These significant gender and maturational differences were confirmed by demonstrating that the regression equation relating circulating leptin concentrations to FM in females and males at Tanner stages IV and V were significantly different (predicted lower leptin concentrations in males than females with identical body composition) and that the regression equations relating circulating concentrations of leptin to FM in each gender before puberty (Tanner stage I) were significantly different (predicted higher plasma concentrations of leptin in prepubertal males and lower leptin concentrations in prepubertal females) than the same regression equations in later puberty. Circulating concentrations of testosterone were significant negative correlates of circulating concentrations of leptin normalized to FM in males when considered as a group over all pubertal stages. The inclusion in multivariate regression analyses of circulating concentrations of testosterone and estradiol, FM, fat-free mass, and gender did not eliminate a significant gender-effect (P < 0.05) on circulating concentrations of leptin at Tanner stages IV and V. The circulating concentration of leptin, normalized to FM, declines significantly in males and rises significantly in females late in puberty to produce a late-pubertal/adult sexual dimorphism. These studies confirm a potent role for gonadal steroids as mediators of this sexual dimorphism in circulating concentrations of leptin. (ABSTRACT TRUNCATED)

Body composition changes during Tanner stage 5.

Clinicians use the combination of Tanner stage 5 (T5) of puberty, final height, and epiphyseal fusion to define maturity. We tested the hypothesis that changes in body composition related to age are identifiable during T5. Asian, Black, Hispanic, and White T5 adolescents (n = 148, 72 females) had measurements taken of their height, weight, total body potassium by 40K counting, total body water by D2O dilution; and total body bone mineral, fat-free mass, and fat mass by dual-energy X-ray absorptiometry. The relative increases with age in lean body components were greater than those in height and weight, and were greater in males. Age was a significant determinant of all body components in males, but of only bone mineral in females. The effect of age was independent of ethnicity. These findings suggest an independent effect of age on body composition during T5, especially in males. We propose that peak levels of lean body components should be included in the definition of maturity in certain clinical and metabolic situations.

Osteoporosis: an unusual presentation of childhood Crohn's disease.

Osteoporosis is known to be associated with Crohn's disease. We report a 12-yr-old boy without a history of steroid use, in whom severe osteoporosis and multiple collapsed vertebrae were the presenting manifestations of Crohn's disease. After treatment of the Crohn's disease, he resumed normal growth and progressed through puberty. Concomitantly, he demonstrated a substantial recovery of vertebral bone mineral density and structure. Possible pathophysiological mechanisms underlying the osteoporosis and the subsequent improvement in bone density are discussed.

Correlations between skeletal muscle mass and bone mass in children 6-18 years: influences of sex, ethnicity, and pubertal status.

A constant sex-specific relationship between skeletal muscle mass and bone mass was observed in healthy adults based on TBK/TBCa, using TBK (total body potassium) by 40K counting and TBCa (total body calcium) by in-vivo neutron activation analysis (Ellis and Cohn, 1975). We revisited this topic in children by studying correlations between TBK and TBCa, and by comparing TBK/TBCa between sexes, pubertal groups (prepubertal and pubertal) and ethnic groups in 141 white, 101 black, and 62 Asian healthy children, aged 6 - 18 years, living in New York City. TBK was measured by 40K counting, and TBCa by dual energy x-ray absorptiometry. TBK and TBCa were significantly correlated from 6 to 18 years (r > 0.93), but the correlation equations varied by gender and ethnicity. Boys had significantly more TBK and greater TBK/TBCa than girls at a given age and weight, reflecting greater skeletal muscle mass in boys from 6 years, the age at which the study started. TBK/TBCa in blacks was significantly smaller than whites and Asians in both sexes in prepuberty and puberty, and pubertal black girls had the smallest mean TBK/TBCa. No significant differences were found between whites and Asians. TBK/TBCa decreased as body weight increased in prepubertal girls, and decreased as body weight and age increased in pubertal girls, but did not change with body weight or age in boys of any subgroup. The inverse relationship between TBK/TBCa and age in pubertal girls suggests greater increase in TBCa compared to TBK than in other groups, while the constant TBK/TBCa in boys reflects proportional increases in TBK and TBCa. Thus TBK/TBCa can be used as an index of relative growth in skeletal muscle mass and bone mass in white, black, and Asian children according to sex, age and pubertal status.

Age at onset of puberty following high-dose central nervous system radiation therapy.

OBJECTIVE: To determine if a relationship exists between age at irradiation, sex of the patient, and age at onset of puberty and pubarche in children treated with high-dose radiation to the central nervous system. DESIGN: Case series. SETTING: Tertiary care institutional practices and clinics. PATIENTS: Thirty-six children treated with high-dose irradiation (hypothalamic pituitary dose, 30-72 Gy) by conventional (n = 29) or hyperfractionated (n = 7) schedules. Girls were treated before age 8 years and boys before age 9 years. Twenty-six of the 36 children also received chemotherapy. All tumors were distant from the hypothalamic-pituitary region. MAIN OUTCOME MEASURE: Age at onset of puberty and pubarche. RESULTS: In girls, the median age at onset of puberty was 9.3 years vs 10.9 years for controls (P < .01); pubarche occurred at 9.4 years vs 11.2 years for controls (P < .01). In boys, the median age at onset of puberty--genital II--was 11.0 years vs 11.5 years for controls (P = .30); pubarche occurred at a median age of 10.5 years vs 12 years for controls (P = .25). A censored-data normal linear regression model was used to account for children (n = 6) who had not reached puberty. Age at diagnosis (P < .01) and sex (P = .01) were significant predictors of age at onset of puberty. Body mass index SD score (z score) was inversely related to age at onset of puberty (r = -0.77) and was greater at onset of puberty in girls than in boys. CONCLUSION: In children who have received high-dose cranial radiation therapy, a significant positive correlation exists between age at diagnosis and age at onset of puberty in boys and girls.

Altered sensitivity to low dose dexamethasone in a subset of patients with premature adrenarche.

During adrenarche, levels of adrenal androgens increase. Although the regulatory mechanisms of adrenarche and premature adrenarche (PA) are not fully understood, it has been suggested that, unlike the cortisol (F) response to glucocorticoid suppression, which is not age dependent, before adrenarche the major adrenal androgen, dehydroepiandrosterone sulfate, is not suppressible by glucocorticoid. As these studies were performed using long term, high dose glucocorticoids, we sought to evaluate the F and adrenal androgen or androgen precursor suppression in response to low dose glucocorticoids [a single evening dose of dexamethasone (DEX), 0.3 mg/m2]. Twenty-four children (aged 1.3-8.75 yr; 4 males and 20 females) known to have PA, as determined by their response to ACTH-(1-24) (Cortrosyn; 0.25 mg, given by iv bolus), were studied. The children with PA could be divided into two groups, as defined by their morning F level after DEX administration: group I (n = 12), F levels below 5 micrograms/dL; and group II (n = 12), F levels of 5 micrograms/dL or more. Although the mean baseline values of F, testosterone, dehydroepiandrosterone, delta 4-androstenedione, 17-hydroxyprogesterone, and delta 5-17-hydroxypregnenolone did not differ between groups I and II, the mean levels in group I vs. group II of dehydroepiandrosterone, delta 4-androstenedione, and delta 5-17-hydroxypregnenolone were significantly greater in response to ACTH and lower in response to DEX (P < 0.05). Although no clinical difference was noted between the 2 groups, the mean SD for bone age adjusted for chronological age was greater and approached significance in group I, suggesting a greater degree of biological maturity in this group. These results suggest an increased sensitivity of the hypothalamic-pituitary-adrenal axis to changes in ACTH secretion in this subgroup of patients with PA.

Prenatal diagnosis and treatment of congenital adrenal hyperplasia.

Advances in technology have made possible the prenatal diagnosis and treatment of female fetuses with classical congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Hormonal measurement of 17-hydroxyprogesterone, androstenedione, testosterone and 21-deoxycortisol and HLA typing and DNA analysis for 21-OH/C4/HLA class I and II genes in chorionic villus cells and amniocytes are utilized for prenatal diagnosis. Maternal dexamethasone administration begun in the first trimester has prevented or ameliorated virilization in approximately three-fourths of infants. Maternal estriol levels appear to be the most accurate measure of fetal adrenal suppression. Maternal side effects are not infrequent and include excess weight gain, edema, glucose intolerance, hypertension and gastrointestinal problems. Severe permanent striae have been reported. Although no complications of prenatal treatment in the treated fetus or child have been reported long-term follow-up with careful neuropsychologic evaluation is not yet available and is necessary to fully evaluate possible long-term side-effects of prenatal dexamethasone treatment.

Altered cortisol response and hippocampal atrophy in pediatric HIV disease.

The hippocampus is a major center for the regulation of the hypothalamic-pituitary-adrenal axis. There is experimental evidence that chronic exposure to high levels of glucocorticoids may be toxic to the hippocampus. We observed elevated mean basal and 60-min cortisol (F) levels in response to adrenocorticotropin stimulation (0.25 mg cortrosyn, i.v. bolus infusion) in 15 children with HIV infection. Furthermore, in eight of the children for whom data was available, in addition to high peripheral cortisol levels, neurologic dysfunction and hippocampal atrophy were noted on CT scan. These preliminary data suggest that in HIV-infected children an altered cortisol secretion may be associated with specific central nervous system damage.

The adrenal incidentaloma. A pediatric perspective.

In our commentary, we have reviewed the literature on adrenal incidentalomas and specifically have tried to relate it to the pediatric population. The studies of others have shown that adrenal tumors are very common in patients with CAH (homozygote and heterozygote) and that these tumors are very rarely malignant and therefore should not routinely be surgically removed. In fact, we suggest that only under very rare circumstances is surgical removal justified. Perhaps, in the future, biochemical markers will allow us to distinguish between adrenal adenomas and carcinomas. We have tried to give broad guidelines for the care of patients with CAH with adrenal tumors, but these are guidelines only--they are not laws chiseled in stone. Finally, as radiological imaging is done more frequently and becomes even better at finding small adrenal tumors, this general topic will become increasingly relevant. We hope our thoughts will lead to lively discussion and useful studies in this "newly discovered" medical dilemma.

Combined bromocriptine and growth hormone (GH) treatment in GH-deficient children with macroprolactinoma in situ.

Experience with PRL-secreting macroadenomas in the pediatric and adolescent population is limited. Although use of synthetic GH after treatment of central nervous system tumors in children without active disease is accepted practice, reports of GH use in patients with central nervous system tumors in situ are rare. Furthermore, the effect of GH on tumor growth is not known. We report GH treatment (10 and 11.5 months), concomitant with bromocriptine (BC; dopamine agonist) therapy in two children, a 15.5-yr-old male and a 15.5-yr-old female, with PRL-secreting macroadenomas in situ. Surgical resection was deemed undesirable because of the risk of major morbidity due to the large size of the tumors and the close proximity to major vessels. Both patients were GH deficient and had heights below the fifth percentile coupled with arrested pubertal progress. During BC therapy, a decrease in tumor size and a reduction in serum PRL levels occurred in both patients, which continued after the addition of GH treatment. Neither patient experienced changes in visual acuity during combined treatment, and both experienced marked improvement in growth velocity. We conclude that in children with PRL-secreting tumors and GH deficiency in whom surgery is not advised, combined treatment with BC and GH appears to be safe and efficacious. To our knowledge, these patients represent the first report of the combined therapeutic use of BC and GH as the primary mode of treatment in children with prolactinoma in situ with documented GH deficiency.

Suppression of the pituitary-gonadal axis in children with central precocious puberty: effects on growth, growth hormone, insulin-like growth factor-I, and prolactin secretion.

To assess further the relationship between gonadal sex steroids and PRL, GH, and insulin-like growth factor-I (IGF-I) secretion and to help clarify the mechanism underlying the pubertal growth spurt, we studied 11 children (10 girls) with central precocious puberty before and during gonadal suppression with the GnRH agonist (GnRH-a) leuprolide acetate. Nocturnal sampling for plasma levels of GH and PRL, GH response to GH-releasing factor-(1-44), and plasma IGF-I levels were determined before and 3-6 months after pituitary-gonadal suppression. Treatment caused a significant decrease in the LH and FSH responses to GnRH (P less than 0.01) and the plasma concentration of estradiol (P less than 0.05). The patients' mean height velocity SD score for chronological age, initially 3.8 +/- 1.9, decreased significantly to 0.9 +/- 0.9 with treatment (P less than 0.005). Nocturnal GH secretion (mean GH concentration, sum of GH pulse areas, sum of GH pulse amplitudes, and GH pulse frequency) and mean IGF-I levels (1.38 +/- 0.6 vs. 1.72 +/- 0.34 U/mL) were not significantly altered by treatment. However, the mean peak GH response to GH-releasing factor-(1-44) was 29.2 +/- 6.8 micrograms/L before treatment and declined significantly to 17.7 +/- 3.4 micrograms/L after gonadal suppression (P less than 0.05). PRL secretion was similar before and after GnRH-a-induced suppression. These results indicate that the decrease in height velocity noted during GnRH-a treatment occurred independently of changes in nocturnal GH secretion and IGF-I levels. These data are consistent with the premise that sex steroids can modulate growth by a direct action on skeletal growth.