MicroRNAs 223-3p and 93-5p in patients with chronic kidney disease before and after renal transplantation.

Chronic kidney disease (CKD) is associated with a multifactorial dysregulation of bone and vascular calcification and closely linked to increased cardiovascular mortality and concomitant bone disease. We aimed to investigate specific microRNA (miRNA) signatures in CKD patients to find indicators for vascular calcification and/or bone mineralization changes during CKD and after kidney transplantation (KT). A miRNA array was used to investigate serum miRNA profiles in CKD patients, then selected miRNAs were quantified in a validation cohort comprising 73 patients in CKD stages 3 to 5, 67 CKD patients after KT, and 36 healthy controls. A spectrum of biochemical parameters including markers for kidney function, inflammation, glucose, and mineral metabolism was determined. The relative expression of miR-223-3p and miR-93-5p was down-regulated in patients with CKD stage 4 and 5 compared to healthy controls. This down-regulation disappeared after kidney transplantation even when lower glomerular filtration rates (eGFR) persisted. MiR-223-3p and miR-93-5p were associated with interleukin-6 (IL-6) and eGFR levels, and by trend with interleukin-8 (IL-8), C-peptide, hematocrit, and parathyroid hormone (PTH). This study contributes new knowledge of serum miRNA expression profiles in CKD, potentially reflecting pathophysiological changes of bone and calcification pathways associated with inflammation, vascular calcification, mineral and glucose metabolism. Identified miRNA signatures can contribute to future risk markers or future therapeutic targets in bone and kidney disease.

Testosterone to dihydrotestosterone ratio as a new biomarker for an adverse metabolic phenotype in the polycystic ovary syndrome.

CONTEXT: Polycystic ovary syndrome (PCOS) is a heterogeneous disease with many different aspects, including hyperandrogenism and metabolic disturbances. Clinical phenotypes show different patterns of steroid hormones that have been investigated to some extent. OBJECTIVE: This study intended to determine the role of the testosterone (TT) to dihydrotestosterone (DHT) ratio (TT/DHT ratio) in PCOS patients and to further assess the correlation of this ratio with hormonal, anthropometric, and metabolic parameters. DESIGN AND SETTING: Serum samples of 275 premenopausal PCOS patients fulfilling Rotterdam criteria and 35 BMI-matched, premenopausal, healthy controls were analyzed for testosterone, DHT, dehydroepiandrosterone (DHEA), and androstenedione using liquid chromatography/mass spectrometry. MAIN OUTCOME MEASURES: We measured total levels of testosterone and DHT and calculated unbound hormone levels as well as the ratio of testosterone to DHT. Further, impaired glucose tolerance, basal and stimulated serum insulin levels, metabolic syndrome and insulin resistance according to the homeostatic model assessment (HOMA-IR) were assessed. RESULTS: PCOS patients showed significantly higher levels of TT (P < .001), free testosterone (P < .001), and free DHT (P < .001) compared to healthy controls. The TT/DHT ratio was significantly higher in PCOS patients (P < .001). No difference was found for total DHT levels (P = .072). In PCOS patients alone, the TT/DHT ratio was significantly higher in obese patients (P < .001) and patients with metabolic syndrome (P < .001), impaired glucose tolerance (IGT) (P < .001) or insulin resistance (P < .001). Significant correlations of the TT/DHT ratio with various adverse anthropometric, hormonal, lipid and liver parameters and parameters of glucose metabolism were found. CONCLUSION: Our data provide evidence for a strong link between a high TT/DHT ratio and an adverse metabolic phenotype in PCOS patients. This correlation was only found in PCOS patients, suggesting the TT/DHT ratio to be a new biomarker for an adverse metabolic phenotype in PCOS patients.

Testicular synthesis and vitamin D action.

CONTEXT: The vitamin D system has pleiotropic effects not only in bone metabolism. Its role in testicular steroidogenesis is new and deserves intensive research. OBJECTIVE: We hypothesize that vitamin D, especially 1,25 dihydroxyvitamin D3 [1,25(OH)2D3 (calcitriol)] induces male steroidogenesis and intend to identify its impact on genes and pathways in testicular androgen regulation. METHODS: Human adult primary testicular cells were isolated, treated with 1,25(OH)2D3, and their gene expression levels profiled by microarray analysis. Highly regulated genes were confirmed by real-time quantitative PCR. In addition, the effects of 1,25(OH)2D3 in combination with LH and IGF-I on the gene expression level of androgens were assessed. T levels in the culture media were determined by a high-resolution ELISA. The expression of vitamin D receptor was confirmed at baseline and after 1,25(OH)2D3 stimulation using immunocytochemistry. RESULTS: Microarrays depicted 63 genes significantly regulated by 1,25(OH)2D3, including genes related to male androgen and vitamin D metabolism, mainly triggered by the vitamin D receptor/retinoid X receptor activation. 1,25(OH)2D3 led to significant changes in the expression profiles of reproductive genes and significantly increased T synthesis in human testicular cell cultures. CONCLUSIONS: Data from our human primary testicular cell culture model suggest that vitamin D plays a major role in male steroidogenesis in vitro.