The effect of metformin on vitamin B12 level in pediatric patients.

PURPOSE: Metformin is a common medication for patients with hyperglycemia. In adults, one well-documented side effect of metformin is vitamin B12 deficiency. However, this side effect has rarely been studied in pediatric patients. This study examined the changes of vitamin B12 level in pediatric patients being treated with metformin. METHODS: Data were collected from pediatric patients (n=151) with at least 3 months of consecutive metformin intake. The effects of dose of metformin on the mean vitamin B12 level were investigated at 6, 12, 24, and 36 months. The effect of compliance of metformin intake on vitamin B12 level also was studied. RESULTS: There was no significant decrease in mean vitamin B12 level at 6, 12, 24, or 36 months in patients treated with metformin. Mean vitamin B12 decrease was only noticeable (p<0.05) in patients taking a high dose of metformin with good compliance. Despite this change, the mean vitamin B12 remained well within the normal reference range. Furthermore, of the 151 patients studied, only 1 demonstrated vitamin B12 deficiency after 12 months of treatment. However, his B12 level was normal at 24 and 36 months without any vitamin B12 supplements. CONCLUSION: Our findings suggest that metformin treatment in children does not cause vitamin B12 deficiency; however, the effect of long-term consistent high-dose treatment on vitamin B12 level remains unknown.

Quality of Life in Adolescent Boys with Idiopathic Short Stature: Positive Impact of Growth Hormone and Aromatase Inhibitors.

BACKGROUND: The combination of growth hormone (GH) and aromatase inhibitors (AI) improves linear growth in severely short adolescent boys; however, the effects of this intervention on quality of life (QoL) are unknown. This study assesses whether GH, AI, or their combination impacts the QoL of adolescent males with idiopathic short stature (ISS) from both the adolescent and the parent perspective. METHOD: A randomized open-label comparator trial was conducted in 76 pubertal males with ISS who received AI, GH, or AI/GH for 24 months. The condition-specific Quality of Life in Short Stature Youth questionnaire was used to assess QoL. RESULTS: QoL scores were low at baseline in the children's and parents' reports. Within-group testing showed that total QoL scores increased significantly at 24 months in the GH and AI/GH group but not the AI group in the children's report, whereas it increased in all of the groups in the parents' report. Increases in QoL scores were associated with an increase in height SDS. CONCLUSIONS: Treatment with GH and AI/GH was associated with improved QoL scores as measured from both the patients' and the parents' perspectives, suggesting that the improved growth resulting from the use of these growth-promoting therapies has beneficial psychosocial effects in adolescent males with ISS followed for 24 months.

Repulsive separation of the cytoplasmic ends of transmembrane helices 3 and 6 is linked to receptor activation in a novel thyrotropin receptor mutant (M626I).

Ligand-dependent activation of G protein-coupled receptors (GPCRs) involves repositioning of the juxtacytoplasmic ends of transmembrane helices TM3 and TM6. This concept, inferred from site-directed spin labeling studies, is supported by chemical cross-linking of the cytoplasmic ends of TM3 and TM6 blocking GPCR activation. Here we report a novel constitutive active mutation (M626I) in TM6 of the TSH receptor (TSHR), identified in affected members of a family with nonautoimmune hyperthyroidism. The specific constitutive activity of M626I, measured by its basal cAMP generation corrected for cell surface expression, was 13-fold higher than that of wild-type TSHR. Homology modeling of the TSHR serpentine domain based on the rhodopsin crystal structure suggests that M626 faces the side chain of I515 of TM3 near the membrane-cytoplasmic junction. Steric hindrance of the introduced isoleucine by I515 is consistent with the fact that shorter or more flexible side chains at position 626 did not increase constitutivity. Furthermore, a reciprocal mutation at position 515 (I515M), when introduced into the M626I background, acts as revertant mutation by allowing accommodation of the isoleucine sidechain at position 626 and fully restoring the constitutive activity to the level of wild-type TSHR. Thus, repulsive separation of the juxtacytoplasmic TM6 and TM3 in the M626I model conclusively demonstrates a direct link between the opening of this cytoplasmic face of the receptor structure and G protein coupling.

Randomized Trial of Aromatase Inhibitors, Growth Hormone, or Combination in Pubertal Boys with Idiopathic, Short Stature.

CONTEXT: Growth of short children in puberty is limited by the effect of estrogen on epiphyseal fusion. OBJECTIVES: To compare: 1) the efficacy and safety of aromatase inhibitors (AIs) vs GH vs AI/GH on increasing adult height potential in pubertal boys with severe idiopathic short stature (ISS); and 2) differences in body composition among groups. DESIGN: Randomized three-arm open-label comparator. SETTING: Outpatient clinical research. PATIENTS: Seventy-six pubertal boys [mean (SE) age, 14.1 (0.1) years] with ISS [height SD score (SDS), -2.3 (0.0)]. INTERVENTION: Daily AIs (anastrozole or letrozole), GH, or AI/GH for 24-36 months. OUTCOMES: Anthropometry, bone ages, dual x-ray absorptiometry, spine x-rays, hormones, safety labs. RESULTS: Height gain [mean (SE)] at 24 months was: AI, +14.0 (0.8) cm; GH, +17.1 (0.9) cm; AI/GH, +18.9 (0.8) cm (P < .0006, analysis of covariance). Height SDS was: AI, -1.73 (0.12); GH, -1.43 (0.14); AI/GH, -1.25 (0.12) (P < .0012). Those treated through 36 months grew more. Regardless of treatment duration, height SDS at near-final height [n = 71; age, 17.4 (0.2) years; bone age, 15.3 (0.1) years; height achieved, ∼97.6%] was: AI, -1.4 (0.1); GH, -1.4 (0.2); AI/GH, -1.0 (0.1) (P = .06). Absolute height change was: AI, +18.2 (1.6) cm; GH, +20.6 (1.5) cm; AI/GH, +22.5 (1.4) cm (P = .01) (expected height gain at -2.0 height SDS, +13.0 cm). AI/GH had higher fat free mass accrual. Measures of bone health, safety labs, and adverse events were similar in all groups. Letrozole caused higher T and lower estradiol than anastrozole. CONCLUSIONS: Combination therapy with AI/GH increases height potential in pubertal boys with ISS more than GH and AI alone treated for 24-36 months with a strong safety profile.