Occlusive vascular diseases in oral contraceptive users - Epidemiology, pathology and mechanisms

Despite being an unprecedented departure from normal physiology, the combin ed oral contraceptive is not only highly effective, but it also has a remar kably good safety record. Concerns over safety persist, though, particularl y with regard to venous thromboembolism (VTE), stroke and myocardial infarc tion (MI). Epidemiological studies consistently show an increase in risk of VTE, but the results are more contentious with regard to arterial diseases . Despite 40 years of research, the mechanisms behind these adverse effects are not understood. In this review, we integrate information from publishe d studies of the epidemiology and pathology of the occlusive vascular disea ses and their risk factors to identify likely explanations for pathogenesis in oral contraceptive users. Oral contraceptives induce both prothrombotic and fibrinolytic changes in haemostatic factors and an imbalance in haemos tasis is likely to be important in oral contraceptive-induced VTE. The comp lexity of the changes involved and the difficulty of ascribing clinical sig nificance has meant that uncertainty persists. A seriously under-researched area concerns vascular changes in oral contraceptive users. Histologically , endothelial and intimal proliferation have been identified in women expos ed to high plasma estrogen concentrations and these lesions are associated with thrombotic occlusion. Other structural changes may result in increased vascular permeability, loss of vascular tone and venous stasis. With regar d to arterial disease risk, epidemiological information relating to dose ef fects and joint effects with other risk factors, and studies of pathology a nd changes in risk factors, suggests that oral contraceptive use per se doe s not cause arterial disease. It can, nevertheless, synergise very powerful ly with subclinical endothelial damage to promote arterial occlusion. Accor dingly, the prothrombotic effects of the oral contraceptive estrogen interv ene in a cycle of endothelial damage and repair which would otherwise ge re main clinically silent or would ultimately progress - in, for example, the presence of cigarette smoking or hypertension - to atherosclerosis. Future work in this area should focus on modification of the effects of establishe d risk factors by oral contraceptive use rather than modification of the su pposed risk of oral contraceptive use by established risk factors. Attempts to understand vascular occlusion in oral contraceptive users in terms of t he general features of VTE or with reference to atherosclerosis may be limi ting, and future work needs to acknowledge that such occlusions may have un ique features. Unequivocal identification of the mechanisms involved would contribute considerably to the alleviation of fears over vascular disease a nd to the development of even safer formulations.