Occlusive Vascular Diseases in Oral Contraceptive Users

Abstract

Despite being an unprecedented departure from normal physiology, the combined oral contraceptive is not only highly effective, but it also has a remarkably good safety record. Concerns over safety persist, though, particularly with regard to venous thromboembolism (VTE), stroke and myocardial infarction (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 published studies of the epidemiology and pathology of the occlusive vascular diseases 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 haemostasis is likely to be important in oral contraceptive-induced VTE. The complexity of the changes involved and the difficulty of ascribing clinical significance 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 exposed 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 regard to arterial disease risk, epidemiological information relating to dose effects and joint effects with other risk factors, and studies of pathology and changes in risk factors, suggests that oral contraceptive use per se does not cause arterial disease. It can, nevertheless, synergise very powerfully with subclinical endothelial damage to promote arterial occlusion. Accordingly, the prothrombotic effects of the oral contraceptive estrogen intervene in a cycle of endothelial damage and repair which would otherwise remain 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 established risk factors by oral contraceptive use rather than modification of the supposed risk of oral contraceptive use by established risk factors. Attempts to understand vascular occlusion in oral contraceptive users in terms of the general features of VTE or with reference to atherosclerosis may be limiting, and future work needs to acknowledge that such occlusions may have unique features. Unequivocal identification of the mechanisms involved would contribute considerably to the alleviation of fears over vascular disease and to the development of even safer formulations.

Association between C-reactive protein, metabolic cardiovascular risk factors, obesity and oral contraceptive use in young adults

“…Although oral contraceptive use does not appear to cause arterial disease, it may synergize with endothelial dysfunction to promote arterial occlusions resulting in cardiovascular events. 29 This study also confirms previous findings that CRP levels are associated with elevated triglyceride concentrations, low concentrations of HDL cholesterol and high concentrations of apolipoprotein B. In this combination of risk factors, plasma concentrations of low-density lipoprotein cholesterol are often normal, but there is an increased proportion of atherogenic small, dense low-density lipoprotein particles.…”

Dexamethasone Increased Plasminogen Activator Inhibitor-1 Expression on Human Umbilical Vein Endothelial Cells: An Additive Effect to Tumor Necrosis Factor-α

“…Dex further increased the expression of PAI-1 gene in the cells stimulated by TNF-·, and did not reduce the effect on cell proliferation induced by TNF-·. Since proliferation of vascular endothelial cells may also be associated with thrombogenesis [21,22], these findings suggest that the balance of blood coagulation versus fibrinolysis may incline to coagulation when TNF-· and Dex cooperate on vascular endothelial cells. This possibility is worthy of further consideration, because thromboembolism of microvasculature may be associated with a part of the side effects of GC, including aseptic necrosis of the head of femoral bone [23], which occurs when the drugs are administered to patients with autoimmune diseases [24].…”

Misconceptions about gene-environment interactions in psychiatry

“…We would rarely expect to observe additivity between risk factors as it is very unlikely that risk factors never co-participate in any causal models of disease. 1 Indeed, empirical evidence shows that where combined effects of established risk factors on disease have been examined, fi ndings support greater than additive patterns of joint risk 2 that is also refl ected by fi ndings in other fi elds of medicine [11][12][13] as well as psychiatry. 14 15 Indeed, the programme of interventions aimed at reducing cardiovascular disease by specifi c targeting of high-risk groups is based on the assumption of multiplicative (greater than additive) models of combined effects on risk.…”