Effect of oral contraceptives containing 20 and 35 μg ethinyl estradiol on urinary prostacyclin and thromboxane levels in smokers and non-smokers

Abstract

Objective: Several observational epidemiological studies have shown an increased risk of myocardial infarction (MI) in oral contraceptive (OC) users who smoke cigarettes. Nearly a quarter of all OC users are smokers. The etiology of MI in OC users has been shown to be thrombotic, and the thrombogenic effect of OCs appears to be due to the estrogen component of the formulation. There are epidemiologic data that indicate that decreasing the estrogen dosage in OCs decreases the risk of thrombosis. Smoking may enhance thrombosis in OC users by decreasing prostacyclin levels. The objective of the present study was to investigate the interaction between smoking and OC use with respect to thrombogenesis by studying the effects of OCs and smoking on urinary levels of prostacyclin PGI and thromboxane A 2 TX in smokers and non-smokers. Study Design: A total of 60 healthy women, aged 19–32 years, who were not taking any hormonal treatment for at least 3 months prior to initiating the study were divided into three equal groups: A) OC users who smoked ( N = 20), B) OC users who did not smoke ( N = 20), and a control group of 10 smokers and 10 non-smokers. To be eligible to participate in the study, all smokers had to smoke at least one pack of cigarettes per day. Each OC treatment group was randomized to receive either norethindrone (NET) acetate (1 mg)/ethinyl estradiol (EE 2) (0.035 mg) ( N = 10) or NET acetate (1 mg)/EE 2 (0.02 mg) ( N = 10) daily for 3 months. Overnight urine collections and fasting blood samples were obtained at baseline and at 3 months prior to taking the last OC. Serum levels of NET and EE 2, as well as urinary levels of cotinine and the stable metabolites of prostacyclin and thromboxane A 2 (6-keto-prostaglandin F 1α and thromboxane B 2, respectively), were measured by specific immunoassays. Results: Study subjects showed compliance with respect to smoking and OC use as determined by the levels of serum NET, EE 2, and cotinine. Comparing mean levels of PGI metabolites in the two groups of OC smokers, those taking 35 μg EE 2 showed a significant decrease in PGI. Comparing the ratio of PGI/TX in all smokers, only the smokers on the 35 μg formulation showed a significant decrease in the ratio, while there was no change in the 20 μg group. No significant changes in the ratio PGI/TX during the same time interval in smoking and non-smoking controls and OC non-smokers were observed. Conclusions: Women smokers taking 20 μg EE 2 OC had no thrombophilic changes of PGI and TXA 2 metabolites. Women smokers taking 35μg EE 2 oral contraceptive had thrombophilic changes in PGI/TXA metabolite ratio. Women smokers who use oral contraceptives may have less thrombotic risk taking formulations with 20μg EE 2 than 35μg EE 2.