Oxidative Stress in Polycystic Ovary Syndrome: Impact of Combined Oral Contraceptives

Abstract

Polycystic Ovary Syndrome (PCOS) is a complex hormonal disorder that is associated with heightened metabolic risks. While oxidative stress (OS) is known to play a role in PCOS, the precise nature of the relationship between PCOS and increased OS remains not entirely understood. Combined oral contraceptives (COCs) are the first-line treatment to regulate menstrual cycles and androgen levels, but their impact on oxidative stress requires further study. We conducted a transcriptomic analysis using RNAseq and assessed the levels of various oxidative stress (OS) markers in serum samples from women with PCOS and controls and whether they were using combined oral contraceptives (COCs), including enzymatic activities, FRAP, and 8-isoprostane (8-iso). A total of 359 genes were differentially expressed in women with PCOS compared to control women. Genes differentially expressed were enriched in functions related to inflammation and, interestingly, oxidative stress response. In controls, 8-iso levels were increased in women using COCs, whereas in women with PCOS, 8-iso levels were reduced in those using oral contraceptives (191.1 ± 97 vs. 26.4 ± 21 pg/mL, p: <0.0001). Correlation analyses showed a trend for a negative correlation between 8-iso and Ferriman score in women with PCOS consuming COCs (r = -0.86, p = 0.06) and a negative correlation between GSH and hyperandrogenism in women with PCOS (r = -0.89, p = 0.01). These results reveal the presence of lipid peroxidation in women with PCOS, which was modified by the use of COCs, providing new insights into the pathophysiology of PCOS in the Chilean population.

Keywords: cardiovascular risk; contraception; hormones; metabolism.

Figure 1

Transcriptomic profiling of PBMCs from women with PCOS and controls. (A) General differences between control and PCOS samples at the transcriptomic level are shown in PCA and Volcano plot. Statistical significance is determined by DESeq2. (B) Gene Set Expression Analysis reveals enrichment of terms associated with redox signaling in PCOS samples. (C) Heatmap showing PCOS-upregulated genes involved in the oxidative stress response. Color scale indicates z-score of expression levels.

Figure 2

Antioxidant capacity in plasma samples from women with PCOS and controls, with or without COCs. (a) Superoxide dismutase (SOD) activity in plasma, (b) glutathione peroxidase (GPX) activity in plasma, and (c) catalase (CAT) activity in plasma. (d) Transcriptional profiling of antioxidant enzymes. Data expressed as mean ± S.E.M. and compared using a two-way ANOVA testing the effect of the condition (control/PCOS) and oral contraceptive usage (none/COCs). Significant interaction (p ≤ 0.05) control vs. PCOS. # p < 0.05.

Figure 3

Stress oxidative markers. (a) Ferric reducing ability of plasma (FRAP) and (b) 8-isoprostane in woman plasma. Data expressed as mean ± S.E.M. and compared using a two-way ANOVA. Significant difference (p ≤ 0.05). * p < 0.05.

Figure 4

Glutathione metabolism. (a) Total glutathione in plasma. Data expressed as mean ± S.E.M. and compared using a two-way ANOVA. Significant differences (p ≤ 0.05). (b) Transcriptional profiling of glutathione metabolism enzymes. Differentially expressed enzymes in PCOS women are highlighted with dotted rectangles. Significant interaction (p ≤ 0.05) control vs. PCOS. # p < 0.05.

Figure 5

Correlation analysis between oxidative stress and hyperandrogenism (Ferriman index). (a) Correlation analysis between oxidative stress markers, antioxidant activity, Ferriman index, and (b) table of correlation coefficients and p-value of correlation. Abbreviations: FRAP: ferric reducing ability of plasma; Total GSH: total glutathione; GPX activity: glutathione peroxidase; r: Pearson’s correlation coefficient; p-values < 0.05 were considered statistically significant.