Treatment of central precocious puberty, comparison between the leuprorelin 1-month (3.75 mg) and 3-month depot (11.25 mg) formulations

Objective: A new 3-month depot formulation of 11.25 mg leuprorelin, has been developed recently. The aim of this study was to evaluate the therapeutic bioequivalence of this new formulation compared with that currently used of 3.75 mg leuprorelin 1-month depot for the treatment of central precocious puberty (CPP). Patients and methods: 18 children (17F, 1M) affected by CPP, with onset of pubertal development before the age of 8 yrs in girls and 9 in boys, were included in the trial. At the time of the inclusion the patients were under treatment with montly depot 3.75 mg leuprorelin for 3- 12 months and showed an adequate gonadotropin suppression (peak LH <3IU/L after GnRH test). Seven patients were randomly selected for continuing the therapy with 3.75 mg every 4 weeks and 11 children for therapy with 11.25 mg every 12 weeks, for 1 year period. Results: In patients treated with the 3-month depot formulation the mean peak LH and FSH levels after GnRH test tended to be higher, but not significantly, at 3 months as compared with those obtained with the previous montly formulation in the same patients (LH: 1.69±0.95 IU/L vs 1.29±0.72 IU/L; FSH: 3.30± 1.88 vs 1.73±0.88 IU/L) and in those children continuing the montly formulation (LH 1.06±0.85IU/L; FSH 1.77±0.76 IU/L). The peak FSH and LH decreased thereafter at 6 and 12 months of therapy. Breast stage was unchanged in 7/11 girls treated with the 3-month depot formulation and progressed from the stage B2 to B3 in the remaining 4 cases. No modifications in uterine and ovarian volumes were observed during the study in all patients. Predicted adult height, CA/BA and HA/BA ratios remained unchanged respect to those observed during the previous montly injection treatment in both groups of patients. Conclusion: The 3-month depot formulation of 11.25 mg leuprorelin, efficiently maintains the gonadal suppression induced by 1-month depot formulation. The FSH and LH levels tended to be higher in the first months of therapy compared with those observed during the montly injection regimen but they do not seem influence negatively the patients bone age and predicted adult height in the first year of therapy

Immunochip analyses identify a novel risk locus for primary biliary cirrhosis at 13q14, multiple independent associations at four established risk loci and epistasis between 1p31 and 7q32 risk variants.

To further characterize the genetic basis of primary biliary cirrhosis (PBC), we genotyped 2426 PBC patients and 5731 unaffected controls from three independent cohorts using a single nucleotide polymorphism (SNP) array (Immunochip) enriched for autoimmune disease risk loci. Meta-analysis of the genotype data sets identified a novel disease-associated locus near the TNFSF11 gene at 13q14, provided evidence for association at six additional immune-related loci not previously implicated in PBC and confirmed associations at 19 of 22 established risk loci. Results of conditional analyses also provided evidence for multiple independent association signals at four risk loci, with haplotype analyses suggesting independent SNP effects at the 2q32 and 16p13 loci, but complex haplotype driven effects at the 3q25 and 6p21 loci. By imputing classical HLA alleles from this data set, four class II alleles independently contributing to the association signal from this region were identified. Imputation of genotypes at the non-HLA loci also provided additional associations, but none with stronger effects than the genotyped variants. An epistatic interaction between the IL12RB2 risk locus at 1p31and the IRF5 risk locus at 7q32 was also identified and suggests a complementary effect of these loci in predisposing to disease. These data expand the repertoire of genes with potential roles in PBC pathogenesis that need to be explored by follow-up biological studies