ELSEVIER Estrogen and Progestin Components of Oral ContraceDtives: RelationshiD to Vascular Diseke Bruce R. Carr* and Howard Oryt Recently, new information has been published about: a) the relationship between combination oral contraceptives (OCs), estrogen dose, cigarette smoking, and the risk of myocardial infarction (MI) and stroke; and b) the effect of different progestins on the risk of venous thromboembo- lism (VTE). We review the epidemiologic data. Regardless of age, in the absence of smoking, use of sub-50 kg OCs is not associated with any meaningful increase in risk of MI or stroke. If the small, statistically nonsignificant eleva- tions in risk for these diseases are assumed (for the sake of argument) to be causal, then the incidence of MI and stroke associated with use of OCs containing less than 50 pg ethinyl estradiol (EE) would be approximately 2 per 100,000 per year. For women less than 35 years of age who do not smoke or do not have a history of hypertension, the risk would be even lower. Any woman over the age of 35 who smokes should be advised to use a non-estrogen or nonhormonal contraceptive. There are now two reports, from lick et al. and Lewis ef al., that demonstrate that the relative risk of MI is certainly no greater for users of OCs containing desogestrel or gestodene than for users of OCs containing older progestins. In fact, both show reduced relative risks for the newer progestins compared to the older ones. With respect to progestins, four recent epidemi- ologic studies have indicated a twofold increased risk of nonfatal VTE with use of OCs containing desogestrel or gestodene compared with levonorgestrel. A fifth report, which showed an increased relative risk for norgestimate, is based on use among only 19 cases and 31 controls and is not statistically significant. As the authors themselves caution and as subsequent follow-up analyses and editori- als conclude, these studies do not provide evidence for a cause-and-effect relationship between OCs containing desogestrel or gestodene, and VTE. The recommendation with respect to desogestrel- and gestodene-containing OCs *University of Texas Southwestern Medical Center at Dallas, Dallas, TX, and tEpidemiological Consultant, Atlanta, GA Name and address for correspondence: Bruce R. Carr, M.D., UT Southwest- ern Medical Center at Dallas, Department of Obstetrics and Gynecology, 5323 Harry Hines Blvd., Dallas, TX 75235-9032. Tel: 214/648-4747; Fax: 214/648- 8066 Submitted for publication November 1, 1996 Revised March 4,1997 Accepted for publication March 4, 1997 is that no change in prescribing practices is warranted for either current or new-start patients. There is a growing body of evidence demonstrating that OCs containing 30 or 35 pg of EE have lower risks of MI, stroke, and VTE than higher dose OCs. However, there is no epidemiologic study that demonstrates a greater risk of vascular events among women using OCs containing 30 or 35 pg EE compared with preparations containing 20 pg EE. Users of sub-50 pg OCs of any age have no clinically meaningful increase in incidence of MI or stroke compared with non-OC users. This is also true for smokers under the age of 35 years who use OCs. However, smokers over the age of 35 years who use OCs still have an unacceptably high incidence rate of MI and stroke and should not use combination OCs. Sub-50 kg OCs of all types are associated with a small excess risk of VTE, about 15 per 100,000 events per year. Until there is biologic explanation of the twofold greater risk of VTE in users of OCs containing desogestrel or gestodene compared with users of those containing older progestins, this association should not be accepted as one of cause and effect. CONTRACEPTION 1997$X:267-272 0 1997 Elsevier Science Inc. All rights reserved. KEY WORDS: oral contraception, smoking, myocardial in- farction, stroke, venous thromboembolism, coagulation system Introduction T he recognition that adverse vascular events associated with the use of oral contraceptives (OCs) are dose-related has led over the years to marked decreases in the amount of both estrogen and progestin contained in combination formulations.’ The last decade has also seen the introduction of less androgenic progestins, including norgestimate, deso- gestrel, and, in Europe, gestodene.2 The impact of lower doses of estrogen, and of different progestins, on the relative risk of myocardial infarction (MI), stroke, and venous thromboembolism (VTE) continues to be a focus of epidemiologic investigations. Still other studies have been directed at defining the effects of various formulations on metabolic factors that might 0 1997 Etsevier Science Inc. All rights reserved. 655 Avenue of the Americas, New York, NY 10010 ISSN OOlO-78241971$17.00 PII s0010-7824(97)00029-2