Increased oxidative stress is associated with hyperandrogenemia in polycystic ovary syndrome evidenced by oxidized lipoproteins stimulating rat ovarian androgen synthesis in vitro.

PURPOSE: To determine the relationship between serum total testosterone (TT) levels and oxidative stress indices in patients with polycystic ovary syndrome (PCOS), and to investigate the effect of oxidative stress on androgen synthesis and its mechanism in rat ovarian theca-interstitial (T-I) cells. METHODS: Clinical, hormonal, metabolic, and oxidative stress parameters were analyzed in a cross-sectional case-control study including 626 patients with PCOS and 296 controls. The effects of oxidized low-density lipoprotein (ox-LDL) and oxidized high-density lipoprotein (ox-HDL) on cell proliferation, TT secretion, and expression of key enzymes involved in testosterone synthesis were evaluated in T-I cells. RESULTS: Serum TT levels were elevated with an increase in ox-LDL levels, whereas glutathione concentrations were lower in the high-TT subgroup than in the low-TT subgroup. The average ovarian volume and ox-LDL and malondialdehyde levels were significant predictors of TT levels in the multivariate regression models. In a rat ovarian T-I cell model, lipoprotein and oxidized lipoprotein treatments stimulated proliferation and promoted testosterone secretion. The mRNA and protein levels of 17α-hydroxylase were significantly higher in oxidized lipoprotein-treated cells than those in lipoprotein-treated cells. The mRNA levels of cholesterol side chain cleavage enzyme and steroidogenic acute regulatory protein were also significantly higher in ox-HDL-treated cells than in HDL-treated cells. CONCLUSIONS: Oxidative stress can promote androgen production by up-regulating the expression of testosterone synthesis-related enzymes in vitro and may be an essential factor in elevating serum TT levels in patients with PCOS.

Circulating vitamin D concentration and risk of 14 cancers: a bidirectional Mendelian randomization study.

BACKGROUND: Observational studies have revealed relationships between circulating vitamin D concentrations and the risk of different types of cancer, although the potential causal relationship remains controversial. This study aims to investigate the presence of a causal relationship between circulating vitamin D concentrations and the risk of different types of cancer. METHODS: Summary statistics from corresponding genome-wide association studies (GWASs) were used to investigate the causal relationship between circulating vitamin D concentrations and the risk of 14 cancers. A two-sample Mendelian randomization (MR) analysis using inverse-variance weighting (IVW) as the primary method was performed. Additionally, the results were verified using four other methods, including MR-Egger, weighted median, weighted mode, and simple mode. Multiple sensitivity analyses were conducted to ensure the robustness of our MR findings. RESULTS: The MR analysis showed no causal relationship between circulating vitamin D concentrations and most types of cancer, except for a causal relationship with melanoma skin cancer (MSC) (odds ratio [OR]IVW = 1.003, 95% confidence intervals [CI] 1.001-1.005, P = 0.004). Conversely, reverse MR revealed a causal relationship between circulating vitamin D concentration and colorectal cancer (ORIVW = 0.398, 95% CI 0.195-0.813, P = 0.01; ORweighted median = 0.352, 95% CI 0.135-0.917, P = 0.03). CONCLUSIONS: Our findings provide support for a causal relationship between circulating vitamin D concentration and risk of MSC. Additionally, we found a causal relationship between circulating vitamin D concentration and risk of colorectal cancer in reverse-MR analysis. This evidence indicate that vitamin D is of great significance in the prevention and treatment of MSC and the prognosis of colorectal cancer.

CYP2E1 C-1054T and 96-bp I/D genetic variations and risk of gestational diabetes mellitus in chinese women: a case-control study.

BACKGROUND: Cytochrome P450 2E1 (CYP2E1) plays a key role in the metabolism of xenobiotic and endogenous low-molecular-weight compounds. This study aimed to determine if the genetic variations of 96-bp insertion/deletion (I/D) and C-1054T (rs2031920) in CYP2E1 were associated with the risk of gestational diabetes mellitus (GDM). METHODS: CYP2E1 polymorphisms were genotyped in a case-control study of 1,134 women with uncomplicated pregnancies and 723 women with GDM. The effects of genotype on the clinical, metabolic, and oxidative stress indices were assessed. RESULTS: The CYP2E1 C-1054T variant was associated with an increased risk of GDM based on the genotype, recessive, dominant, and allele genetic models (P < 0.05). The TT + CT genotype remained a significant predictive factor for GDM risk after correcting for maternal age and pre-pregnancy body mass index (OR = 1.277, 95% CI: 1.042-1.563, P = 0.018). Moreover, fasting insulin concentrations and homeostatic model assessment of insulin resistance were significantly higher in GDM patients carrying the T allele than in those with the CC genotype (P < 0.05). Furthermore, the combined genotype II + ID/TT + CT of the 96-bp I/D and C-1054T polymorphisms further increased the risk of GDM when the combined genotype DD/CC was set as the reference category (OR = 1.676, 95% CI: 1.182-2.376, P = 0.004). CONCLUSIONS: The T allele of the C-1054T polymorphism and its combination with the I allele of the 96-bp I/D variation in CYP2E1 are associated with an increased risk of GDM in the Chinese population. The - 1054T allele may be associated with more serious insulin resistance in patients.