Anti-Müllerian hormone and letrozole levels in boys with constitutional delay of growth and puberty treated with letrozole or testosterone.

STUDY QUESTION: Does treatment of constitutional delay of growth and puberty (CDGP) in boys with aromatase inhibitor letrozole (Lz) or conventional low-dose testosterone (T) have differing effects on developing seminiferous epithelium? SUMMARY ANSWER: Anti-Müllerian hormone (AMH) declined similarly in both treatment groups, and the two Sertoli cell-derived markers (AMH and inhibin B (iB)) exhibited differing responses to changes in gonadotrophin milieu. WHAT IS KNOWN ALREADY: Boys with CDGP may benefit from puberty-inducing medication. Peroral Lz activates gonadotrophin secretion, whereas intramuscular low-dose T may transiently suppress gonadotrophins and iB. STUDY DESIGN, SIZE, DURATION: Sera of 28 boys with CDGP who participated in a randomised, controlled, open-label trial at four paediatric centres in Finland between August 2013 and January 2017 were analysed. The patients were randomly assigned to receive either Lz (2.5 mg/day) (n = 15) or T (1 mg/kg/month) (n = 13) for 6 months. PARTICIPANTS/MATERIALS, SETTING, METHODS: The 28 patients were at least 14 years of age, showed first signs of puberty, wanted medical attention for CDGP and were evaluated at 0, 3, 6 and 12 months of visits. AMH levels were measured with an electrochemiluminescence immunoassay and Lz levels with liquid chromatography coupled with tandem mass spectrometry. MAIN RESULTS AND THE ROLE OF CHANCE: AMH levels decreased in both treatment groups during the 12-month follow-up (P < 0.0001). Between 0 and 3 months, the changes in gonadotrophin levels (increase in the Lz group, decrease in the T group) correlated strongly with the changes in levels of iB (FSH vs iB, r = 0.55, P = 0.002; LH vs iB, r = 0.72, P < 0.0001), but not with the changes in AMH (P = NS). At 12 months, AMH levels did not differ between the groups (P = NS). Serum Lz levels (range, 124-1262 nmol/L) were largely explained by the Lz dose per weight (at 3 months r = 0.62, P = 0.01; at 6 months r = 0.52, P = 0.05). Lz levels did not associate with changes in indices of hypothalamic-pituitary-gonadal axis activity or Sertoli cell markers (in all, P = NS). LIMITATIONS, REASONS FOR CAUTION: The original trial was not blinded for practical reasons and included a limited number of participants. WIDER IMPLICATIONS OF THE FINDINGS: In early puberty, treatment-induced gonadotrophin stimulus was unable to counteract the androgen-mediated decrease in AMH, while changes in iB levels were associated with changes in gonadotrophin levels. AMH decreased similarly in both groups during the treatment, reassuring safety of developing seminiferous epithelium in both treatment approaches. Since a fixed dose of Lz induced variable serum Lz levels with a desired puberty-promoting effect in all boys, more research is needed to aim at a minimal efficient dose per weight. STUDY FUNDING/COMPETING INTEREST(S): This study was supported by the Academy of Finland, the Foundation for Pediatric Research, the Emil Aaltonen Foundation, Sigrid Juselius Foundation and Helsinki University Hospital Research Funds. The authors have nothing to disclose. TRIAL REGISTRATION NUMBER: NCT01797718.

Serum glucocorticoids and adiponectin associate with insulin resistance in children born small for gestational age.

OBJECTIVES: Altered glucocorticoid activity is one possible mechanism linking fetal growth restriction with later insulin resistance (IR) and type 2 diabetes. We aimed to investigate whether serum glucocorticoid parameters are related to IR in children born small for gestational age (SGA). DESIGN: A total of 110 children (55 age- and gender-matched pairs born SGA or appropriate for gestational age (AGA) in a case-control setting) were studied at the mean age of 12.2 (s.d. 0.2) years. METHODS: Serum cortisol, corticosteroid-binding globulin (CBG), free cortisol index (FCI=cortisol/CBG), and glucocorticoid bioactivity (GBA, transactivation assay) were analyzed and related to serum adiponectin and insulin-like growth factor-binding protein 1 (IGFBP1) concentrations and homeostasis model assessment for IR (HOMA-IR) and QUICKI indices. RESULTS: In the pooled study population, GBA correlated well with cortisol and FCI (r=0.681 and 0.586 respectively; P<0.001 for both). Serum cortisol, CBG, FCI, GBA, HOMA-IR, or QUICKI did not differ between the SGA and AGA subjects, but the SGA children had lower body mass index (P=0.005) and waist circumference (WC) (P=0.001). The mean GBA in the highest GBA quartile was higher among the SGA subjects than among the AGA subjects (138.6 vs 96.4 nmol/l cortisol equivalents, P<0.001). In the SGA children, GBA correlated positively with HOMA-IR (r=0.522, P<0.001) and inversely with adiponectin (r=-0.278, P=0.042) (WC/height ratio adjustments), and in logistic regression analysis, higher GBA (odds ratio (OR) 1.3; P=0.013), lower adiponectin (OR 1.4; P=0.038), and lower IGFBP1 (OR 1.9; P=0.010) associated independently with higher HOMA-IR. CONCLUSIONS: These findings suggest that increased glucocorticoid activity and low serum adiponectin concentrations associate with IR in SGA children.

Serum lipid concentrations and growth characteristics in 12-year-old children born small for gestational age.

According to Barker's hypothesis, children born small for gestational age (SGA) are at increased risk for cardiovascular diseases in adulthood. The aim of our study was to determine whether retarded fetal growth is associated with dyslipidemia in childhood and, if so, to find predictive factors in the growth characteristics of SGA children. We studied the serum lipid concentrations of 55 SGA children and their 55 appropriate for gestational age control subjects at the age of 12 y. Growth variables were recorded at birth, 5 y, and 12 y of age. The study group consisted of all full-term SGA children born at our university hospital during a 22-mo period in 1984-1986. Nearly half of the SGA children (47.3%) were in the highest quartile for serum total cholesterol of the appropriate for gestational age children (p = 0.038). In multiple logistic regression analysis, poor catch-up growth in height (odds ratio, 13. 8; 95% confidence interval, 2.0-97.5), female sex (odds ratio, 8.1; 95% confidence interval, 1.3-48.9), and early stage of puberty (odds ratio, 7.5; 95% confidence interval, 1.2-46.5) predicted high cholesterol level in the SGA children. By the age of 5 y, 20 (36.4%) SGA children showed catch-up growth of > or =2 SD scores in height, and 21 (38.2%) SGA children showed catch-up growth of > or =2 SD scores in weight from birth. At the age of 12 y, the SGA children were still significantly shorter (p<0.001) and lighter (p< 0.05) than the appropriate for gestational age children, even though their pubertal development was similarly advanced. In conclusion, to be born SGA has long-term consequences for later growth and may already influence the level of serum total cholesterol before the teens. SGA children with poor catch-up growth in height may be at the highest risk for hypercholesterolemia.

The clinical efficacy of nebulized racemic epinephrine and albuterol in acute bronchiolitis.

OBJECTIVE: To investigate whether nebulized racemic epinephrine or albuterol improves respiratory distress in infants with acute bronchiolitis. DESIGN: A randomized, placebo-controlled, double-blind study. SETTING: A university hospital providing primary hospital care for all pediatric patients in a defined area. PATIENTS: One hundred consecutive infants younger than 24 months treated in the hospital for acute bronchiolitis. INTERVENTION: The patients received two inhalations at 30-minute intervals: racemic epinephrine followed by physiologic saline (REP group; n = 24), albuterol followed by physiologic saline (AP group; n = 27), physiologic saline followed by racemic epinephrine (PRE group; n = 24), and physiologic saline followed by albuterol (PA group; n = 25). All patients received intramuscular epinephrine 60 minutes after the beginning of the study. MAIN OUTCOME MEASURES: Oxygen saturation, respiratory rate, and two clinical scores were used: one based on wheezing and retractions (Respiratory Distress Assessment Instrument) and the other based on changes in wheezing, retractions, and respiratory rate (Respiratory Assessment Change Score). MAIN RESULTS: During the study, there were no significant differences among the four groups in clinical scores, oxygen saturations, and respiratory rates. Mean Respiratory Distress Assessment Instrument scores improved significantly within the REP, PRE, and AP groups 15 minutes after the first inhalation. In only the REP group, which received racemic epinephrine, the confidence limits did not overlap. A comparison of paired data of each patient revealed that the difference in Respiratory Assessment Change Score was significant between racemic epinephrine and physiologic saline, but not between albuterol and physiologic saline. Intramuscular epinephrine significantly improved Respiratory Distress Assessment Index scores in those groups treated earlier with racemic epinephrine (REP and PRE groups). No significant adverse effects were seen in any group or at any phase of the study. CONCLUSIONS: Elimination of hypoxia by supplemental oxygen and moistening of inspired air relieve the symptoms of acute bronchiolitis. Nebulized racemic epinephrine and albuterol are safe and useful in the treatment of acute bronchiolitis. Improvements in symptom scores at 15 minutes favor the use of racemic epinephrine. As the action of epinephrine is short, the effect can be increased by repeated inhalations.

Mucha-Habermann disease: a diagnostic possibility for prolonged fever associated with systemic and skin symptoms.

The severe form of Mucha-Habermann disease with systemic symptoms is a rarely diagnosed disease which should be considered for children with prolonged fever, impaired general condition, skin manifestations and elevated C-reactive protein concentration and/or erythrocyte sedimentation rate. Eleven cases have been described previously in children. We describe two acute episodes of this syndrome in a three-year-old child; the diagnosis was based on clinical, dermatological and histological findings. During both episodes, the fever lasted for more than one week, C-reactive protein concentration increased to more than 150 mg/l, and there was extensive lymph node enlargement. Skin eruption was initially maculopapulous, then vesiculous and finally pustulous. On skin biopsy, vasculitic changes were observed. We treated the second attack of our patient with high-dose gamma globulin; the first attack appeared to resolve itself spontaneously.