Childhood and adolescent obesity. Prevalence and significance.

The prevalence of children and adolescents with body mass index (BMI) of greater than 95th percentile has doubled in the last 2 decades (present prevalence is 10.9%) and there is a 50% increase in the prevalence of those with a BMI greater than 85th percentile (present prevalence is 22.0%) in the US. There are substantial risks for morbidity in obese children even before they reach adulthood. Further, if obesity in childhood persists into the adult years, the morbidity and mortality is greater than if the obesity developed in the adult. Screening using appropriate historical and physical data will reveal those children most in need of modification of weight gain.

Role of hypothalamic-pituitary axis in EGF action on maturation of adrenal gland in fetal rhesus monkey in vivo.

We determined the route of action of epidermal growth factor (EGF) [intraperitoneal (IP) versus intraamniotic administration] on adrenal development and whether its effects are mediated via the fetal hypothalamic-pituitary axis in the fetal rhesus monkey in vivo. EGF (40 microg) was administered IP (n = 9) or intraamniotic (n = 6) at 121, 123, 125, and 127 d gestation (term, approximately 165 +/- 10 d gestation). In addition, a competitive corticotropin-releasing factor antagonist ([D-phenylalanine(12), Norleucine(21,38)] corticotropin-releasing factor(12-41) to block fetal pituitary ACTH secretion; 400 microg IP) and metyrapone (11beta-hydroxylase inhibitor to block adrenal cortisol synthesis; 15 mg IP and 15 mg intraamniotic) were administered, in combination with EGF (EGF+BLOCK; 40 microg IP; n = 4 fetuses). Control fetuses (n = 6) received saline injections in an equivalent volume. On gestational d 128, a hysterotomy was performed, and fetal adrenals were collected for morphometric analyses and immunocytochemical localization of 3beta -hydroxysteroid dehydrogenase (3betaHSD) and cytochrome P-450 11beta -hydroxylase/aldosynthase. Definitive zone (DZ) width and cortical width of 3betaHSD staining were significantly greater (p < 0.05) in the EGF IP-treated fetuses compared with controls and EGF+BLOCK. With EGF IP, 3betaHSD was increased in the DZ and induced extensively in the transitional zone of the fetal adrenal cortex, and cytochrome P-450 11beta-hydroxylase/aldosynthase immunoreactivity was induced to detectable levels in the DZ. The administration of EGF+BLOCK inhibited the expression of 3betaHSD in the transitional zone, but 3betaHSD expression was still increased in the DZ and cytochrome P-450 11beta-hydroxylase/aldosynthase immunoreactivity was induced in the DZ. EGF intraamniotic administration had no significant effect on the width of the DZ or cortical width of 3betaHSD staining compared with controls. These data suggest that EGF acts via the hypothalamic-pituitary axis to modulate adrenal cortical growth and functional maturation of the transitional zone (the putative zona fasciculata), whereas EGF can act independently of the hypothalamic-pituitary axis to stimulate functional maturation of the DZ (the putative zona glomerulosa).

Acid-base homeostasis in children with growth hormone deficiency.

BACKGROUND: Although the primary use of growth hormone (GH) is to promote linear growth, it is also known to affect many metabolic processes and to influence renal function. In laboratory animals, growth hormone deficiency (GHD) causes a mild metabolic acidosis that is corrected by GH treatment. We observed a patient with GHD who initially presented with acidosis of unclear etiology and corrected the acidosis with GH treatment. OBJECTIVES: To determine: 1) whether children with GHD have lower mean serum bicarbonate concentrations than do children with short stature because of other causes; and 2) whether the presence of a low serum bicarbonate concentration increases the probability of GHD among children with short stature. METHODS: We collected data from the medical records of 143 children with short stature who had serum electrolyte concentrations measured as part of their initial evaluations, 66 with GHD and 77 with short stature as a result of other causes. We compared mean serum bicarbonate concentrations and bicarbonate standard deviation scores (SDS) between these two groups and determined the probability of GHD for patients according to bicarbonate SDS. RESULTS: The mean serum bicarbonate concentration was significantly lower in patients with GHD (mean standard deviation [SD]; 23.9 [0.4] mEq/L vs 25.2 [0.3] mEq/L) as was the bicarbonate SDS (-0.12 [0.14] SD vs 0.38 [0.10] SD). Twelve (75%) of 16 patients with bicarbonate SDS 1 SD. Patients with bicarbonate SDS between -1 SD and 1 SD had an intermediate probability of GHD, 46/102 (45%), similar to the overall prevalence of GHD in the study population (46%). Mean bicarbonate concentrations and bicarbonate SDS increased significantly in 9 patients who had repeat electrolyte measurements during treatment with GH (mean bicarbonate; 21.7 [1.1] mEq/L vs 26.9 [0.59] mEq/L, mean bicarbonate SDS; -1.24 [0.43] SD vs 0.55 [0.27] SD). CONCLUSIONS: Serum bicarbonate concentrations are lower in patients with GHD than in patients with short stature as a result of other causes. In addition, serum bicarbonate concentrations rise with GH treatment in patients with GHD. The probability of GHD is increased for patients with bicarbonate SDS 1 SD. These findings indicate a role for GH in maintaining normal acid-base homeostasis and suggest that GHD should be considered in children whose growth failure is attributed to other causes of acidosis.

Fetal growth.

Fetal growth requires the correct balance of nutrients, oxygen, and growth factors operating under the direction of a genetic plan modified by maternal factors. The classic hormones of postnatal growth play differing roles with alternative controls compared to those after birth. The study of conditions of abnormal fetal growth illuminates the mechanism of normal fetal growth. It is now apparent that abnormal birth weight leads to long-term consequences.

Variation in the management of pediatric diabetic ketoacidosis by specialty training.

OBJECTIVE: To compare management strategies for pediatric diabetic ketoacidosis (DKA) among physicians with different specialty training. METHODS: We conducted a mail survey of 1000 randomly selected physicians, including 200 pediatric endocrinologists, 200 general emergency physicians, 200 pediatric emergency physicians, 200 pediatric intensivists, and 200 pediatric chief residents. We posed questions regarding a hypothetical 10-year-old patient with new onset of diabetes mellitus who is approximately 10% dehydrated but alert, with venous pH of 7.1 and serum glucose concentration of 34.7 mmol/L (625 mg/dL). Questions involved the rate of rehydration, content of intravenous fluids, insulin therapy, potassium replacement, use of sodium bicarbonate, and adjustments in therapy for decreasing serum glucose concentration. We compared responses of physicians in each specialty and used multiple regression analysis to adjust for potential confounding variables, including number of years in practice, number of children with DKA seen per month, and practice setting. RESULTS: Five hundred eighty-one physicians (58.1%) completed the survey, with responses demonstrating significant, consistent differences between specialties. Extremes of responses included the following: (1) 59% of endocrinologists vs 11% of general emergency physicians would give an initial fluid bolus of less than 20 mL/kg (odds ratio [OR], 11.7; 95% confidence interval [CI], 5.0-27.7) (P < .001); (2) 83.5% of general emergency physicians vs 42.5% of pediatric intensivists would administer an initial insulin bolus (OR, 4.1; 95% CI, 2.0-8.7) (P < .001); (3) 58.2% of pediatric intensivists vs 9% of general emergency physicians would replace fluids over a period of greater than 24 hours (OR, 14.1; 95% CI, 5.5-37.5) (P < .001); and (4) 54.3% of general emergency physicians vs 7.3% of pediatric intensivists would use potassium chloride alone for potassium replacement (OR, 10.8; 95% CI, 5.0-23.8) (P < .001). All of these differences persisted after adjusting for the potential confounding variables. CONCLUSIONS: Substantial differences exist in the management of pediatric DKA among physicians of different specialties, presumably due to differences in specialty training. These differences obscure our ability to evaluate the treatment of DKA and highlight the necessity for further studies comparing the outcomes of different treatment strategies.

Predictors of early remission of hyperthyroidism in children.

Children with hyperthyroidism often require prolonged courses of antithyroid medication to achieve remission, and long-term compliance is problematic. To determine which clinical and laboratory features predict early remission, we reviewed the records of 191 patients less than 19 yr old with Graves' disease. We compared patients achieving remission within 2 yr (group 1, n = 27) with those who completed more than 2 yr of medical therapy but did not achieve a remission (group 2, n = 79). Patients who were in neither of the above categories (n = 85) were excluded from the statistical analysis. Variables that were measurable at the time of diagnosis, recorded in more than 50% of the study population and associated with early remission in the univariate analysis (P < or = 0.05), were entered into a stepwise multiple logistic regression analysis. Variables retaining a significant association with early remission (P < 0.05) were considered independent predictors of early remission. Patients achieving early remission were older (mean, 12.5 vs. 10.9 yr, P = 0.039) and had higher body mass indexes (BMI, 19.0 vs. 16.6, P = 0.002), higher BMI SD scores (-0.03 vs. -0.60, P = 0.004), lower heart rates (110 vs. 121, P = 0.023), smaller goiters (group 1: 60% with moderate/large goiter; group 2: 83%, P = 0.050), lower platelet counts (272 vs. 339 K/microL, P = 0.006), lower serum T4 and T3 concentrations at presentation (T4: 18.3 vs. 22.5 microg/dL, P = 0.015; T3: 439 vs. 613 ng/dL, P = 0.008), and were less likely to have a positive test for thyroid stimulating Igs (group 1: 50% vs. group 2: 93%, P = 0.008). Regression analysis identified BMI SD score and goiter size as independent predictors of early remission (P < 0.05). Eighty-six percent of patients with BMI SD score above -0.5 SD and minimal/small goiters achieved early remission, compared with 13% of those with BMI SD score below -0.5 SD and moderate/large goiters. We conclude that, of multiple clinical and laboratory variables associated with early remission, BMI SD score and goiter size are independent predictors. Algorithms employing these two variables can be used to facilitate counseling of patients and expedite therapeutic decisions.

New aspects in the diagnosis and treatment of pubertal disorders.

Recent developments in biochemistry, genetics, and clinical research have produced a profound effect on the understanding of normal and abnormal puberty. This article is intended to point out selected new developments that affect the understanding of puberty and clinical practice in disorders of puberty.

Growth retardation in premenarchial female rhesus monkeys during chronic administration of GnRH agonist (leuprolide acetate).

Leuprolide acetate in depot form (0.75 mg/kg body weight/month, i.m.) was administered to four female rhesus monkeys from 18-30 months of age, a period that includes the premenarchial growth spurt. They were compared to eight age matched controls. As anticipated, sexual maturation was blocked in the Leuprolide group and menarche did not occur. Growth was also severely retarded; no weight gain occurred during the study in the Leuprolide group as compared to a 25% weight gain (P = .044) in the control group. The Leuprolide group also lost muscle mass. Food intake normalized for body weight was not affected. Linear growth averaged 35% less in the Leuprolide group. Serum IGF-1 concentrations increased from 486 +/- 84 to 965 +/- 47 ng/mL (P = .0025) in the Leuprolide group and from 838 +/- 139 to 3,006 +/- 545 ng/mL (P = .0016) in the control group. These data suggest that premenarchial pituitary/gonadal suppression results in a distinctive pattern of growth retardation in monkeys.

Adolescent growth and maturation in zinc-deprived rhesus monkeys [see comment].

Growth retardation has been associated with zinc deficiency in adolescent human populations, but animal models were not available previously to explore this syndrome. Moderate dietary zinc deprivation (2 micrograms Zn/g diet) was introduced in female rhesus monkeys (Macaca mulatta; n = 10) from the beginning of puberty through menarche. Subgroups of animals (n = 4) continued to be fed the zinc-deficient diet through 45 mo of age (sexual maturity). Reduced weight gain and linear growth and lower plasma zinc concentrations (11.8 +/- 0.6 and 9.2 +/- 0.8 mumol/L in control and zinc-deficient monkeys, respectively) were evident during the premenarcheal growth spurt. Slower skeletal growth, maturation, and mineralization were recorded in the postmenarcheal period and some indicators of sexual maturation were delayed. Food intake was slightly higher in the zinc-deficient group than in controls. These data confirm that adolescent growth and maturation are vulnerable to disruption by moderate dietary zinc deprivation in nonhuman primates.

A role for epidermal growth factor in the morphological and functional maturation of the adrenal gland in the fetal rhesus monkey in vivo.

We determined the effects of epidermal growth factor (EGF) and beta-methasone on the growth and development of the adrenal gland of the fetal rhesus monkey in vivo between 121-128 days of gestation. The adrenal to body weight ratio was significantly greater (P < 0.05) in EGF-treated fetuses (0.988 +/- 0.046 x 10(-3) g/g) and significantly reduced (P < 0.05) in beta-methasone-treated fetuses (0.401 +/- 0.056 x 10(-3) g/g) compared with that in control fetuses (0.689 +/- 0.050 x 10(-3) g/g). The increase in adrenal weight with EGF administration was due to hypertrophy of definitive zone cells of the adrenal cortex, whereas the reduction in adrenal weight after beta-methasone treatment was due to a decrease in the size of definitive and fetal zone cells of the adrenal cortex. By Western analysis, EGF treatment induced a significant (P < 0.05) 2.8-fold increase in the amount of protein for 3 beta-hydroxysteroid dehydrogenase/isomerase (3 beta HSD) in the fetal adrenal. EGF also stimulated the induction of immunocytochemical staining for 3 beta HSD in transitional zone cells of the adrenal cortex. In contrast, beta-methasone resulted in 2.6-, 4.5-, and 6.6-fold significant decreases (P < 0.05) in the amount of protein for cytochrome P450 cholesterol side-chain cleavage, cytochrome P450 17 alpha-hydroxylase/17,20-lyase, and 3 beta HSD in the fetal adrenal. After beta-methasone treatment. 3 beta HSD staining was detected in some of the definitive zone cells, with no 3 beta HSD staining in the transitional zone. In conclusion, growth and functional differentiation of fetal primate adrenal gland can be accelerated prematurely by EGF and inhibited by glucocorticoid negative feedback.

Adrenocortical function in the very low birth weight infant: improved testing sensitivity and association with neonatal outcome.

OBJECTIVE: To evaluate adrenocortical function in ill preterm infants and investigate potential relationships between plasma cortisol concentrations and major neonatal outcomes. STUDY DESIGN: Randomized trial of adrenocorticotropic hormone (1-24ACTH) stimulation testing, followed by a chart review. SETTING: Two level III neonatal intensive care units, Sacramento, Calif. PARTICIPANTS: Sixty-seven very low birth weight infants, born at 32 weeks of gestation or earlier weighing 1500 gm or less, who had endotracheal intubation and indwelling arterial access. RESULTS: Most infants (76%) had baseline cortisol concentrations < 414 nmol/L (15.0 micrograms/dl), and of those, only 36% responded to stimulation with 1-24ACTH, 0.1 microgram/kg. Raising the 1-24ACTH dose to 0.2 microgram/kg resulted in a response rate of 67% (p = 0.09) but decreased the sensitivity of the test. An elevated mean 11-deoxycortisol/cortisol ratio indicated that decreased 11 beta-hydroxylase activity may limit cortisol production in some infants. Infants with baseline cortisol concentrations less than 414 nmol/L (15.0 micrograms/dl) were more likely to have chronic lung disease (p < 0.002) and less likely to have severe intraventricular hemorrhage (p < 0.02). Response to 1-24ACTH was not associated with a detectable difference in outcome. CONCLUSION: Many very low birth weight infants have low cortisol and ACTH concentrations and are unable to mount a cortisol response to physiologic doses (0.1 microgram/kg) of 1-24ACTH. These findings suggest that delayed maturation of adrenal response may result in physiologically inadequate cortisol concentrations in stressed very low birth weight infants. This delayed maturation may contribute to the development of chronic lung disease.

Thyroid dysfunction: an adolescent gynecologic perspective.

Abnormalities of thyroid function may cause irregularity or absence of the menstrual period, inhibit pubertal development and linear growth, and suppress reproductive function. Furthermore, pregnancy may itself affect thyroid function. New information is presented about the diagnosis and treatment of various forms of congenital and acquired thyroid disease. Issues ranging from the molecular biology of thyroid hormone resistance to public health measures developed to eliminate endemic goiter are addressed.

Comparison of the distinct effects of epidermal growth factor and betamethasone on the morphogenesis of the gas exchange region and differentiation of alveolar type II cells in lungs of fetal rhesus monkeys.

To compare the effects of epidermal growth factor (EGF) and betamethasone on the morphogenesis of the gas exchange region and the differentiation of the alveolar type II cell during fetal lung development, fetal rhesus monkeys (78% gestation) were treated in utero with EGF (5.33 mg/kg total dose), beta-methasone (2.6 mg/kg total dose) or the carrier, saline (control), every other day for 7 days. EGF-treated monkeys had significantly increased body and adrenal weights. Betamethasone-treated monkeys had significantly decreased body and adrenal weights. Exogenous EGF reduced cytoplasmic glycogen and increased the cytoplasmic organelle and SP-A content within alveolar type II cells. In contrast, exogenous betamethasone did not alter alveolar type II cell cytodifferentiation. Neither EGF nor betamethasone treatment significantly altered the structure of the gas exchange region as shown by a lack of change from controls in alveolar airspace size or in the fraction of the gas exchange region that was potential airspace. We conclude that at clinically relevant doses, EGF greatly accelerates the maturation of alveolar type II cells, whereas betamethasone does not. Exogenous EGF may act directly on alveolar type II cells because these cells contain EGF receptor. Neither EGF nor betamethasone had dramatic effects on the morphogenesis of the gas exchange region.

Physiology of puberty.

Puberty is not a single event but one stage in development. The endocrine events of puberty in many ways recapitulate previous changes in the fetus. It is currently not known what triggers puberty at an appropriate time. It appears that puberty is restrained by higher central nervous system controls, but the restraint can be eliminated by injury or tumor growth resulting in premature puberty. The first endocrine event of puberty is an increase in the amplitude of gonadotropin pulses at night due to increased pulsatile release of hypothalamic gonadotropin-releasing hormone (GnRH) into the hypothalamic-pituitary portal system. This is reflected by an increase in luteinizing hormone secretion after a bolus of exogenous GnRH. Gonadal steroids are produced due to increased gonadotropin stimulation, and secondary sexual development follows a well-described pattern of changes. The pubertal growth spurt results from an increase in growth hormone secretion induced by sex steroids as well as from local production of growth factors. Positive feedback leads to the onset of menses and ovulation in girls by mid-puberty or later. This physical and reproductive maturity occurs in an orderly pattern, of which the physiology is described and in large part understood.

Prenatal exposure to epidermal growth factor attenuates respiratory distress syndrome in rhesus infants.

Treatment of nonhuman primate fetuses with epidermal growth factor (EGF) results in histologic and biochemical maturation of their lungs. To determine whether these effects improve lung function postnatally, we studied premature rhesus infants delivered at 78% of gestation after in utero treatment with EGF (n = 5) or placebo (n = 5). Indices of lung function during the 4 d of postnatal care included fractional concentration of inspired oxygen, peak inspiratory pressure, ventilator rate, mean airway pressure, arterial to alveolar oxygen tension ratio, and ventilation index. Statistically significant differences were noted in the time courses of these variables between EGF- and placebo-treated infants. The direction of the differences indicated that the EGF-treated infants had less severe lung disease. Surfactant apoprotein A concentration and lecithin to sphingomyelin ratio were both significantly higher in the amniotic fluid of the EGF-treated group, indicating advanced biochemical maturation in this group of animals. Whereas birth weight was not affected by EGF exposure, adrenal and gut weights, standardized for body weight, were increased significantly. Histologic studies showed advanced cellular maturation with increased parenchymal airspace and decreased parenchymal tissue space in the EGF-treated group compared with the control group. We conclude that prenatal exposure to EGF stimulates biochemical and histologic maturation of the lung and markedly attenuates the clinical severity of respiratory disease in this model of simian respiratory distress syndrome.

The therapy for hypothalamic-pituitary tumors.

Pituitary-hypothalamic tumors may profoundly affect endocrine functions. Although these are generally rare tumors of the central nervous system, they prominently figure into the differential diagnosis of children and adolescents with disorders of growth or puberty.

The evolution of stature in humans.

There is significant evidence that a positive secular trend, apparently due to improved socioeconomic conditions, has led to taller stature today compared with 150-200 years ago. However, study of fossil remains of our hominid ancestors demonstrates the stature of individuals living during the last million years reached the range of heights seen today. Furthermore, data from recent prehistory and the last 2,000 years also reveal adult height in many groups to be equal to modern humans of the same region. Optimal conditions for growth appear to predate the advent of modern civilization and public health measures.

Serum insulin-like growth factor 1 concentrations in the developing rhesus monkey.

We studied the developmental pattern of serum IGF-1 concentrations in the rhesus monkey in cross-sectional and longitudinal manners. Values were lower in infants with a significant rise at the onset of puberty. Females values were lower than males except for pregnant females. There was a correlation of IGF-1 values with body weight in the males. Longitudinal study of six animals proved this age dependence of IGF-1 values. The rhesus monkey has a pattern of serum IGF-1 concentrations similar to that of the human being.

The growth hormone secretory response to growth hormone releasing factor in the developing rhesus monkey.

We studied the development of the GH response to growth hormone releasing hormone (GHRH) using two doses of GHRH. The newborns demonstrated higher baseline GH and responses to GHRH than animals of any older age. There was no difference noted between the rise in GH in male and female subjects with 10 mcg/kg vs 1 mcg/kg. Serum cortisol concentrations did not correlate with serum GH concentrations. These developmental patterns of serum GH are similar to those known in the human being.