Vitamin D3 supplementation for 16 weeks improves flow-mediated dilation in overweight African-American adults.

BACKGROUND: A growing body of evidence has linked vitamin D deficiency to increased risk of cardiovascular disease. Vitamin D deficiency is also more common in African Americans for whom an increased cardiovascular disease risk exists. This study sought to test the hypothesis that 16 weeks of 60,000 IU monthly supplementation of oral vitamin D(3) would improve flow-mediated dilation (FMD) in African Americans, whereas no change would be observed in the placebo group. METHODS: A randomized, double-blind, placebo-controlled clinical trial was conducted. Fifty-seven African-American adults were randomly assigned to either the placebo group or vitamin D group. RESULTS: Following 16 weeks of placebo (n = 23; mean age 31 ± 2 years) or 60,000 IU monthly oral vitamin D(3) (n = 22; mean age 29 ± 2 years), serum concentrations of 25-hydroxyvitamin D (25(OH)D) increased from 38.2 ± 3.0 to 48.7 ± 3.2 nmol/l and 34.3 ± 2.2 to 100.9 ± 6.6 nmol/l, respectively. No changes in serum parathyroid hormone (PTH), serum calcium, or urine calcium/creatinine were observed following either treatment. Following 16 weeks of treatment, significant improvements in FMD were only observed in the vitamin D group (1.8 ± 1.3%), whereas the placebo group had no change (-1.3 ± 0.6%). Similarly, the vitamin D group exhibited an increase in absolute change in diameter (0.005 ± 0.004 cm) and FMD/shear (0.08 ± 0.04 %/s(-1), area under the curve (AUC) × 10(3)) following treatment, whereas no change (-0.005 ± 0.002 cm and -0.02 ± 0.02 %/s(-1), AUC, respectively) was observed following placebo. CONCLUSION: Supplementation of 60,000 IU monthly oral vitamin D(3) (~2,000 IU/day) for 16 weeks is effective at improving vascular endothelial function in African-American adults.

Genotype and phenotype of patients with gonadotropin-releasing hormone receptor mutations.

Human mutations in the gonadotropin-releasing hormone receptor (GNRHR) gene cause autosomal recessive, normosmic idiopathic hypogonadotropic hypogonadism (IHH). At least 19 different mutations have been identified in this G-protein-coupled receptor, which consist mostly of missense mutations. The Gln106Arg and Arg262Gln mutations comprise nearly half of the identified alleles. Most mutations impair ligand binding and all compromise cell signaling events. Some of the mutations also adversely affect activation of gonadotropin subunit or Gnrhr gene promoters. Interestingly, a number of the mutant GnRHRs can be rescued in vitro from misfolding and degradation within the cell by the addition of a GnRHR antagonist IN3. Most affected patients have compound heterozygous GNRHR mutations that may cause either complete IHH (no evidence of puberty) or incomplete IHH (partial evidence of puberty), although some genotypes are associated with mild disease in some families and severe disease in others. GNRHR mutations also appear to cause constitutional delay of puberty, and one genotype (homozygosity for Gln106Arg) may be reversible in patients with IHH. Mutations in the human GNRHR gene have contributed greatly to the understanding of normosmic IHH, as well as the structure and function of the GnRHR.

The prevalence of intragenic deletions in patients with idiopathic hypogonadotropic hypogonadism and Kallmann syndrome.

Idiopathic hypogonadotropic hypogonadism (IHH) and Kallmann syndrome (KS) are clinically and genetically heterogeneous disorders caused by a deficiency of gonadotrophin-releasing hormone (GnRH). Mutations in three genes--KAL1, GNRHR and FGFR1--account for 15-20% of all causes of IHH/KS. Nearly all mutations are point mutations identified by traditional PCR-based DNA sequencing. The relatively new method of multiplex ligation-dependent probe amplification (MLPA) has been successful for detecting intragenic deletions in other genetic diseases. We hypothesized that MLPA would detect intragenic deletions in approximately 15-20% of our cohort of IHH/KS patients. Fifty-four IHH/KS patients were studied for KAL1 deletions and 100 were studied for an autosomal panel of FGFR1, GNRH1, GNRHR, GPR54 and NELF gene deletions. Of all male and female subjects screened, 4/54 (7.4%) had KAL1 deletions. If only anosmic males were considered, 4/33 (12.1%) had KAL1 deletions. No deletions were identified in any of the autosomal genes in 100 IHH/KS patients. We believe this to be the first study to use MLPA to identify intragenic deletions in IHH/KS patients. Our results indicate approximately 12% of KS males have KAL1 deletions, but intragenic deletions of the FGFR1, GNRH1, GNRHR, GPR54 and NELF genes are uncommon in IHH/KS.