Gonadotropin receptor variants are linked to cumulative live birth rate after in vitro fertilization.

PURPOSE: The objective was to investigate if the gonadotropin receptor variants N680S (N: asparagine, S: serine, rs6166) in the follicle-stimulating hormone receptor (FSHR) and N312S (rs2293275) in the luteinizing hormone/human chorionic gonadotropin receptor (LHCGR) predicted cumulative live birth rate after in vitro fertilization (IVF). METHODS: A total of 665 women were consecutively enrolled for IVF during the period 2007-2016. Inclusion criteria were < 40 years of age, body mass index < 30 kg/m2, non-smoking, regular menstruation cycle of 21-35 days, and bilateral ovaries. A blood sample was drawn for endocrine hormonal analysis and for DNA extraction with subsequent genotyping of the FSHR N680S and LHCGR N312S polymorphisms. Statistical analyses were done on all completed IVF cycles. RESULTS: Women homozygous for S in both receptors combined (4S) had significantly higher live birth rate compared to those with other receptor variants when combining the first three IVF cycles (OR = 2.00, 95% CI [1.02, 3.92], p = 0.043). Cumulatively higher chance of live birth rate, during all IVF cycles, was also evident (HR = 1.89, 95% CI [1.00, 3.57], p = 0.049). CONCLUSIONS: Gonadotropin receptor variants are promising candidates for the prediction of the possibility to have a baby to take home after IVF treatment.

Non-linear association between androgen receptor CAG repeat length and risk of male subfertility--a meta-analysis.

The CAG repeat in the androgen receptor (AR) has been widely studied in association with male infertility, but the results are conflicting. In a recent meta-analysis, infertile men had <1 repeat longer CAG stretch than fertile men when analysed in a linear regression model assuming that AR function diminishes with increasing CAG length. However, in vitro, a non-linear activity pattern was recently demonstrated so that ARs containing short and long stretches, respectively, displayed lower activity than the AR of median length. These results prompted us to explore the possible association between CAG number and male infertility risk in a stratified manner on the basis of data from the mentioned meta-analysis and subjects from our clinical unit. The study population included 3915 men, 1831 fertile and 2084 infertile. Data were divided into three categories: CAG<22, CAG 22-23 (reference) and CAG>23 and analysed in a binary logistic regression model. Men with CAG<22 and CAG>23 had 20% increased odds ratio of infertility compared with carriers of the median lengths [for CAG<22: p=0.03, 95% confidence interval (CI): 1.02-1.39; for CAG>23: p=0.02, 95% CI: 1.03-1.44]. These results show that an alternative model to a linear one for the genotype-phenotype association in relation to AR CAG repeats is likely, as lengths close to the median confine lowest risk of infertility.

CAG repeat number is not inversely associated with androgen receptor activity in vitro.

A negative linear association between androgen receptor (AR) function and the CAG repeat numbers is generally assumed. However, in vivo data concerning the association between CAG number and androgenic effects have been conflicting. Since former in vitro studies mostly have been based on extreme CAG lengths and reporter-systems containing viral promoters, the objective of this study was to investigate ARs with CAG lengths within normal range (16, 22 and 28) in a reporter-assay with the human prostate specific antigen promoter as target. We also wished to elucidate whether the interpretation of the results was depending on the methods used for adjustment of transfection efficiency and protein content. With beta-galactosidase as transfection control, 22CAG had the highest activity (set to 100%) compared with 16CAG [mean 78% (range 41-132), P = 0.005] and 28CAG [68% (26-162), P = 0.006], whereas renilla-luciferase resulted in 16CAG behaving similar to 22CAG [104% (56-165), P = 0.7] and 28CAG having lower activity [59% (33-101), P = 0.004]. In these experiments, also the empty vector displayed considerable background activity. When adjusting for AR protein, the 22CAG genotype had the highest activity; 16CAG and 28CAG displaying 20% (10-47, P < 0.0001) and 12% (5-21, P < 0.0001) thereof. Similar results were obtained with adjustment for total protein. Thus, by normalizing for AR-content, contrary to various control vectors, the highest AR activity was confined to the 22CAG and not 16 CAG, which may at least partly explain the discrepancy in data aiming to link physiological conditions to CAG repeat length.

Sox5 regulates beta-cell phenotype and is reduced in type 2 diabetes.

Type 2 diabetes (T2D) is characterized by insulin resistance and impaired insulin secretion, but the mechanisms underlying insulin secretion failure are not completely understood. Here, we show that a set of co-expressed genes, which is enriched for genes with islet-selective open chromatin, is associated with T2D. These genes are perturbed in T2D and have a similar expression pattern to that of dedifferentiated islets. We identify Sox5 as a regulator of the module. Sox5 knockdown induces gene expression changes similar to those observed in T2D and diabetic animals and has profound effects on insulin secretion, including reduced depolarization-evoked Ca2+-influx and ß-cell exocytosis. SOX5 overexpression reverses the expression perturbations observed in a mouse model of T2D, increases the expression of key ß-cell genes and improves glucose-stimulated insulin secretion in human islets from donors with T2D. We suggest that human islets in T2D display changes reminiscent of dedifferentiation and highlight SOX5 as a regulator of ß-cell phenotype and function.

High-dose vitamin D supplementation in children with cerebral palsy or neuromuscular disorder.

Adequate vitamin D levels are essential for normal skeletal development and mineralization. This is particularly important in children with cerebral palsy or other neuromuscular disorders who are at an increased risk of osteoporosis. The aim of this study was to evaluate the effect of high-dose vitamin D3 supplementation on vitamin D status in 44 disabled children. Vitamin D was administered during school days (1000 IU vitamin D3 per orally five days per week for 10 weeks) to half of the children (N=21) while the others (N=23) continued without supplementation. At baseline the median serum 25-hydroxyvitamin D was 44 nmol/L (range 26-82 nmol/L). The concentration increased significantly during the 10 weeks intervention in the supplemented group (median 56 nmol/L, range 39-88 nmol/L; p=0.012 for the difference from baseline) and decreased in the control group (median 37 nmol/L, range 24-74 nmol/L; p=0.038). No significant changes in any of the other measured parameters were observed. Hypovitaminosis D is prevalent in disabled children. Supplementation with 1000 IU vitamin D3 perorally five days per week results in a significant increase in vitamin D level and is not associated with hypercalcemia or other adverse effects.