Second-Generation Combined Oral Contraceptives Induce Early Cardiovascular Risk Through Inflammatory and Oxidative...

Second-generation combined oral contraceptive pills (COCPs), particularly formulations containing ethinylestradiol and levonorgestrel, remain widely used because of their effectiveness and affordability in middle and low-income countries. However, concerns persist about their cardiovascular safety. This study investigated the dose-dependent effects of a second-generation COCP on systolic blood pressure (SBP), inflammatory biomarkers, oxidative stress, vascular mediators, and vascular histology in female Sprague-Dawley rats. Twenty-four female Sprague-Dawley rats were acclimatized and randomly assigned to control, low-dose (1.1 µg/kg/day), and high-dose COCP (11 µg/kg/day) groups. Treatments were administered orally for six weeks. SBP and body weight were monitored before and after treatment. Serum C-reactive protein (CRP), tumour necrosis factor-alpha (TNF-α), and lipid profile were measured. Renal vascular homogenates were analyzed for nuclear factor kappa B (NF-κB), endothelin-1 (ET-1), nitric oxide (NO), malondialdehyde (MDA), superoxide dismutase, catalase (CAT), and glutathione. Histological examination was performed on the renal and thoracic arteries. The SBP increased by 4.6% in the low dose and 21.8% in the high dose (p < 0.05). High-dose treatment significantly increased CRP, TNF-α, and NF-κB levels, indicating enhanced systemic and vascular inflammation. Vascular MDA and CAT increased in both treated groups, suggesting oxidative stress with compensatory antioxidant activation. Low-dose COCP increased ET-1 levels, while the NO and lipid profiles showed no significant changes across the treated groups. Both doses produced marked structural alterations in the renal and thoracic arteries. The dose-dependent rise in vascular inflammation, oxidative stress, and SBP suggests early cardiovascular risk is mediated primarily by inflammatory vascular remodeling rather than by overt dyslipidemia.