gestodene and Thrombophlebitis

In October, 1995, the United Kingdom Committee on Safety of Medicines recommended that women should use oral contraceptives containing desogestrel or gestodene only if prepared to accept an increased risk of thromboembolism. This action was based on observational studies that indicated a 2-3-fold increase in the risk of thromboembolism when desogestrel and gestodene-containing contraceptives were compared to products with levonorgestrel. The fact that these studies point in the same direction is concerning, but it is possible that these observational studies, somewhat similar in design, are influenced by the same unrecognized biases. Furthermore, the case numbers are relatively small (20-40 cases), and, for example, preferential prescribing to women at greater risk could affect the results. It is difficult to reconcile the conclusions with the strong belief supported by good evidence that thrombosis is an estrogen dose-related complication, and that progestational agents have no impact on clotting parameters. In my view, these equivocal reports are not of sufficient strength to escape biases and to change our prescribing of oral contraceptives.

Topics: Clinical Trials as Topic; Contraceptives, Oral, Synthetic; Desogestrel; Female; Humans; Norpregnenes; Risk Factors; Thrombophlebitis; United Kingdom

Topics: Abortion, Legal; Adult; Cohort Studies; Contraceptives, Oral, Synthetic; Desogestrel; Female; Humans; Norpregnenes; Pregnancy; Pregnancy Rate; Risk Factors; Thrombophlebitis

The "attrition of susceptibles" was a plausible noncausal hypothesis (that sought to account for the observed association between current use of OCs containing desogestrel or gestodene and the incidence of VTE). However, there are now several pieces of evidence suggesting that this hypothesis can explain, at most, only a small part of the association. For the time being, when weighing the advantages and disadvantages of use of various types of OCs, it is probably prudent to assume that relative to the risk of VTE in users of levonorgestrel, there truly is a heightened risk in women who currently take desogestrel- or gestodene-containing OCs.

Topics: Adolescent; Adult; Age Factors; Bias; Case-Control Studies; Contraceptives, Oral, Synthetic; Desogestrel; Female; Humans; Levonorgestrel; Norpregnenes; Research Design; Thrombophlebitis

Epidemiological studies have shown that women who use third-generation oral contraceptives (OC) containing desogestrel, gestodene or norgestimate have a higher risk of venous thrombosis than women who use second-generation OC containing levonorgestrel. It is also known that a mutation in factor V (factor V(Leiden)), which results in resistance to activated protein C (APC) and which is the most common cause of hereditary thrombophilia, potentiates the prothrombotic effect of OC. Effects of APC on thrombin generation in the plasma of women using OC were compared to the response to APC in non-OC users and in individuals that were heterozygous or homozygous for factor V(Leiden). The response towards APC was evaluated on basis of the ratio (APC-sr) of the time integrals of thrombin formation determined in the presence and absence of APC. Compared with women not using OC, women who used OC exhibited a significantly decreased sensitivity to APC (P<0.001), independent of the kind of OC used. Women who used third-generation monophasic OC were significantly less sensitive to APC than women using second-generation OC (P<0.001) and had APC-sr that did not significantly differ from heterozygous female carriers of factor V(Leiden) who did not use OC. Women who were heterozygous for factor V(Leiden) and used OC had APC-sr in the range of homozygous carriers of factor V(Leiden). Two women who started OC therapy had significantly elevated APC-sr within 3 d. Acquired APC resistance may explain the epidemiological observation of increased risk for venous thrombosis in OC users, especially in women using third-generation OC.

Topics: Adolescent; Adult; Aged; Contraceptives, Oral, Combined; Desogestrel; Factor V; Female; Hemostasis; Heterozygote; Humans; Levonorgestrel; Male; Middle Aged; Norgestrel; Norpregnenes; Protein C; Thrombin; Thrombophlebitis

Topics: Adult; Contraceptives, Oral, Synthetic; Ethinyl Estradiol; Factor V; Female; Humans; Mutation; Norpregnenes; Thrombophlebitis

Recent epidemiologic studies reported that the risk of venous thromboembolism (VTE) was higher with the use of the newer third generation oral contraceptives than with second generation agents. Although the overall findings of these studies are similar, the results, as they relate to patterns and duration of oral contraceptive use particularly among first-time users, are inconsistent. We reanalyzed data from the Transnational case-control study to assess the risk of VTE associated with first-time use of oral contraceptives as a function of its duration of use. Over the period 1993 to 1995, 471 cases of venous thromboembolism were identified in Germany and the United Kingdom. For each case, up to four controls were obtained, for a total of 1772 controls. Data on oral contraceptive use and confounding variables, including data on sociodemographic, lifestyle, medical history, and family history of disease, were obtained by interview. Data analysis was based on the 105 cases and 422 controls who were first-time users of second or third generation agents, or never users of oral contraception. Rate ratios, adjusted for confounders and approximated by odds ratios, were estimated as a continuous function of duration of oral contraceptive use by logistic regression and quadratic spline models. We found, for first-time users, that the adjusted rate ratio of VTE as a function of the duration of oral contraceptive use is essentially identical for second and third generation pills relative to never users. This rate ratio increases to around 10 in the first year of use and decreases to around two after 2 years of use, remaining at this risk level thereafter for both second and third generation agents. We conclude that second and third generation agents are associated with identical risks of venous thromboembolism when they are prescribed to women who are using oral contraceptives for the first time ever.. Recent epidemiologic studies reported that the risk of venous thromboembolism (VTE) was higher with the use of the newer third-generation oral contraceptives (OCs) than with second-generation agents. Although the overall findings of these studies are similar, the results, as they relate to patterns and duration of OC use, particularly among first-time users, are inconsistent. The authors reanalyzed data from the transnational case-control study to assess the risk of VTE associated with first-time use of OCs as a function of its duration of use. Over the period 1993-95, 471 cases of VTE were identified in Germany and the UK. For each case, up to 4 controls were obtained, for a total of 1772 controls. Data on OC use and confounding variables, including data on sociodemographic, lifestyle, medical history, and family history of disease, were obtained by interview. Data analysis was based on the 105 cases and 422 controls who were first-time users of second- or third-generation agents or never-users of OCs. Rate ratios, adjusted for confounders and approximated by odds ratios, were estimated as a continuous function of duration of OC use by logistic regression and quadratic spline models. The authors found, for first-time users, that the adjusted rate ratio of VTE as a function of the duration of OC use is essentially identical for second- and third-generation pills relative to never-users. This rate ratio increases to about 10 in the first year of use and decreases to about 2 after 2 years of use, remaining at this risk level thereafter for both second- and third-generation agents. The authors conclude that second- and third-generation agents are associated with identical risks of VTE when they are prescribed to women who are using OCs for the first time ever.

Topics: Adult; Austria; Case-Control Studies; Contraceptives, Oral; Desogestrel; Ethinyl Estradiol; Female; France; Germany; Humans; Logistic Models; Norpregnenes; Progesterone Congeners; Pulmonary Embolism; Risk Factors; Switzerland; Thrombophlebitis; United Kingdom; Veins

Topics: Contraceptives, Oral; Desogestrel; Female; Humans; Norpregnenes; Progesterone Congeners; Thrombophlebitis

Topics: Contraceptives, Oral; Desogestrel; Drug and Narcotic Control; Female; Humans; Norpregnenes; Progesterone Congeners; Thrombophlebitis

Topics: Adolescent; Adult; Contraceptives, Oral; Desogestrel; Female; Humans; Middle Aged; Norpregnenes; Thrombophlebitis; Thrombosis

Topics: Contraceptives, Oral, Combined; Desogestrel; Female; Humans; Norpregnenes; Progesterone Congeners; Thromboembolism; Thrombophlebitis

Previous reports speculated that vascular events could be related to the development of antibodies against synthetic steroids contained in oral contraceptives or other hormonal treatments. This study describes original immunoassays designed to detect antisynthetic steroid antibodies. In a first step, the assays were characterized and validated using animal-raised antisteroid antibodies. In a second step, a population of 88 oral contraceptive users, 47 of them having developed a vascular thrombosis during synthetic steroid use and 41 serving as healthy control users, were tested. Detection of antibodies against ethinylestradiol, levonorgestrel, norethisterone, cyproterone acetate, and gestodene showed that the values obtained in normal oral contraceptive users as well as thrombosis patients are very low, and show no statistically significant difference between the two groups tested. Taken together, these data indicate that the "immunological hypothesis" related to antisteroid antibodies is unlikely to explain the pathogenesis of vascular events in oral contraceptive users.

Topics: Adolescent; Adult; Androgen Antagonists; Antibodies; Contraceptives, Oral; Contraceptives, Oral, Synthetic; Cyproterone Acetate; Ethinyl Estradiol; Female; Humans; Immunoenzyme Techniques; Levonorgestrel; Middle Aged; Norethindrone; Norpregnenes; Progesterone Congeners; Thrombophlebitis