The serum steroid signature of PCOS hints at the involvement of novel pathways for excess androgen biosynthesis.

CONTEXT Polycystic ovary syndrome (PCOS) is defined by androgen excess and ovarian dysfunction in the absence of a specific physiological diagnosis. The best clinical marker of androgen excess is hirsutism, while the best biochemical parameter is still a matter of debate. Current consensus guidelines recommend, among other hormones, serum free testosterone as an important serum parameter to measure androgen excess. Recently, however, novel active androgens and androgen metabolic pathways have been discovered. OBJECTIVE To assess the contribution of novel androgens and related steroid biosynthetic pathways to the serum steroid pool in PCOS women in comparison to healthy controls. DESIGN This is a case control study, wherein PCOS was diagnosed according to the AE-PCOS 2009 criteria. Serum steroid profiling was performed by liquid chromatography high-resolution mass spectrometry. SETTING Yeditepe University and associated clinics in Istanbul, Turkey, together with Bern University Hospital Inselspital, Bern, Switzerland. PARTICIPANTS 42 PCOS women and 42 matched, healthy control women. MAIN OUTCOME MEASURES Assessment of 34 steroids compartmentalized in four androgen related pathways: the classic androgen pathway, the backdoor pathway, the C11-oxy backdoor pathway, and the C11-oxy (11β-hydroxyandrostenedione) pathway. RESULTS Metabolites of all four pathways were identified in healthy and PCOS women. Highest concentrations were found for progesterone in controls and androstenedione in PCOS. Lowest levels were found for 11-ketotestosterone in controls compared to PCOS, and for 20α-hydroxyprogesterone in PCOS compared to controls. PCOS also had higher serum testosterone levels compared to the controls. PCOS women had overall higher levels of steroid metabolites of all four androgen pathways compared to healthy controls. CONCLUSIONS Novel alternative pathways contribute to the androgen production in healthy and PCOS women. Hyperandrogenism in PCOS is characterized by an overall increase of serum androgens in the classic, backdoor and C11-oxy pathways. While monogenetic disorders of steroid biosynthesis can be recognized by a specific pattern in the steroid profile, no diagnostic pattern or classifier was found in the serum for PCOS

POTENTIAL PROTECTIVE ROLE OF SDF-1 AND CXCR4 GENE VARIANTS IN THE DEVELOPMENT OF DEMENTIA

Background: The aim of this study was to evaluate the role of polymorphisms of stromal cell-derived factor-1 (SDF-1) and chemokine receptor-4 (CXCR4) genes in dementia susceptibility in a Turkish population. Subjects and methods: The study group included 61 dementia patients, while the control group comprised 82 healthy individuals. Gene polymorphisms of SDF-1 3’A G801A (rs1801157) and CXCR4 C138T (rs2228014) were genotyped by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis. Results: A significantly reduced risk for developing dementia was found for the group bearing an A allele for SDF-1 3’A polymorphism (p=0.009; x2=6.812; OR=0.626; 95%CI= 0.429-0.913). The frequency of the CXCR4 TT and TC genotype was significantly lower in patients with dementia compared to controls (p=0.028; x2=5.583; OR=0.215; 95%CI=0.05-0.914); (p=0.027; x2=4.919; OR=0.484; 95% CI= 0.246-0.955). Additionally, combined genotype analysis showed that the frequency of SDF1 GACXCR4 CC was significantly lower in patients with dementia in comparison with those of controls (p=0.049; OR=0.560; 95% CI= 0.307±1.020). Conclusions: Our study provides new evidence that SDF1 A and CXCR4 T alleles may be associated with a decreased dementia risk. The present study is important because to our knowledge, it is the first one to be conducted in a Turkish population to date, but we believe that more patients and controls are needed to obtain statistically significant results

Mitochondrial dysfunction results in enhanced adrenal androgen production in H295R cells.

The role of mitochondria in steroidogenesis is well established. However, the specific effects of mitochondrial dysfunction on androgen synthesis are not fully understood. In this study, we investigate the effects of various mitochondrial and metabolic inhibitors in H295R adrenal cells and perform a comprehensive analysis of steroid and metabolite profiling. We report that mitochondrial complex I inhibition by rotenone shifts cells toward anaerobic metabolism with a concomitant hyperandrogenic phenotype characterized by rapid stimulation of dehydroepiandrosterone (DHEA, 2h) and slower accumulation of androstenedione and testosterone (24h). Screening of metabolic inhibitors confirmed DHEA stimulation, which included mitochondrial complex III and mitochondrial pyruvate carrier inhibition. Metabolomic studies revealed truncated tricarboxylic acid cycle with an inverse correlation between citric acid and DHEA production as a common metabolic marker of hyperandrogenic inhibitors. The current study sheds light on a direct interplay between energy metabolism and androgen biosynthesis that could be further explored to identify novel molecular targets for efficient treatment of androgen excess disorders

A Dynamic Model of the Firm: Structural Explanations of Key Empirical Findings

SSRN-id28380957We derive a dynamic model of the rm in the spirit of the trade-o¤ theory of capital structure that explains rm behavior in terms of rm characteristics. We show our model is consistent with many important ndings about the cross-section of rms, including the negative relations between pro tability and leverage, and between dividends and investment-cash ow sensitivities. The model also explains the existence of zero-debt rms and their observed characteristics. These results have been used to challenge the trade-o¤ theory and the assumption of perfect capital markets. We revisit these critiques and provide structural explanations for the regularities we replicate

Investigations on testicular blood flow in acute and chronic testicular diseases using imaging techniques

Die Farbduplexsonografie nimmt sowohl in den Fällen mit akuter intratestikulärer Perfusionsstörung des Hodens als auch bei chronischen testikulären Erkrankungen mit Durchblutungsstörung eine zentrale Rolle bei der Diagnostik ein. Klinisch gehört sie mittlerweile zu der routinemäßigen Untersuchung beim akuten Skrotum. Auch bei der Abklärung der chronischen testikulären Erkrankungen wie Varikozele und Azoospermie kann die Gefäßdarstellung des Hodens diagnostisch vorteilhaft sein