gestodene and Thrombosis

In some studies third-generation oral contraceptives have been reported to be associated with a higher risk of venous thromboembolism than are second-generation oral contraceptives, whereas recent, more refined studies have not confirmed this. The reasons for the alleged differences are under discussion, and differential effects on hemostasis have been proposed. Eighteen studies comparing second- and third-generation oral contraceptives with respect to their effects on hemostasis were analyzed. Significant changes from baseline were reported for many variables with both second- and third-generation oral contraceptives without significant between-group differences. Also, in a combined analysis of nonsignificant changes, no consistent pattern of change emerged for any marker, with the exception of higher factor VII levels associated with third-generation oral contraceptives. However, factor VII is not related to venous thromboembolism risk. In addition, 1 cross-sectional study with an unvalidated assay reported a higher ratio of activated protein C sensitivity with third-generation oral contraceptives. Only 2 components of the hemostatic system (factor VII and activated protein C sensitivity ratio) emerged as potentially differentially affected by second- and third-generation oral contraceptives; the association with venous thromboembolism risk is questionable in the former case and unknown in the latter.. The initial finding of an increased risk of venous thromboembolism in users of third-generation oral contraceptives (OCs) has not been confirmed in recent, more methodologically refined studies. This article reviews 17 prospective studies with healthy volunteers and one cross-sectional study that compared second- and third-generation OCs in terms of their effects on markers of hemostasis. Significant changes from baseline were reported for many variables with both second- and third-generation OCs. For example, activated partial prothrombin clotting time, protein S, and tissue plasminogen activator and its inhibitor were reduced during OC treatment. However, none of the studies reported statistically significant differences between treatment groups for any of these markers. In a combined analysis of nonsignificant changes, no consistent pattern emerged for any coagulation or fibrinolysis parameter with the exception of higher factor VII levels (not related to venous thromboembolism risk) associated with third-generation formulations. The cross-sectional study with an unvalidated assay found a higher ratio of activated C protein sensitivity with third-generation OCs. Only two components of the hemostatic system--factor VII and activated protein C sensitivity ratio--emerged as potentially differentially affected by second- and third-generation OCs. The association with venous thromboembolism risk is questionable in the former cases and unknown in the latter.

Topics: Contraceptives, Oral, Hormonal; Contraceptives, Oral, Synthetic; Desogestrel; Female; Hemostasis; Humans; Norpregnenes; Progesterone Congeners; Protein C; Risk; Thrombosis

Oral contraceptives (OCs) are, or perhaps more correctly, were, until recently, being taken by approximately 65 million women worldwide, which corresponds to approximately 6% of all women of reproductive age. OCs have been available since the early 1960s, and there is substantial evidence to suggest that no single medication has had such a profound impact on our reproductive and social life than the pill. In the Scandinavian countries, 30-50% of young women have been reported to be using OCs. Its widespread use throughout the world for several decades indicates that women and their doctors have considered that the benefits of OCs outweigh potential side effects. On October 18, 1995, the Committee on Safety of Medicines in the United Kingdom sent a warning to all British doctors and pharmacists about OCs containing desogestrel or gestodene. A similar warning was subsequently distributed by the German and Norwegian health authorities. As these OC types dominate the market in Northern Europe, many gynaecologists, general practitioners, women of reproductive age, different national bodies on drug safety, and people in general have been asking: * What was the background for these actions? * How do we interpret the new studies? * What do we do now concerning prescription of OCs? * What is the moral of this story?

Topics: Contraceptives, Oral; Desogestrel; Female; Humans; Norpregnenes; Risk Factors; Thrombosis

Oral contraceptives increase the natural incidence of venous thrombosis of 1-2/10,000 women per year 3- to 4-fold. Recent studies have shown that desogestrel or gestodene containing formulations bear twice the risk of older low-dose ovulation inhibitors. During pregnancy, the incidence of thrombosis rises to 10/10,000 women-years and post partum up to 40/ 10,000. For 60% of thromboses no causal explanation can be found. In approximately 40% of the patients an inherited thrombophilia can be presumed. Among the hereditary types of thrombophilia, a resistance to activated protein C (APC-resistance) represents nearly 50%, while in 15 to 20% a deficiency of antithrombin III, protein C or protein S is found. APC-resistance, with a prevalence of 3-5% in the general population, increases the risk of thrombosis 8-fold and in users of oral contraceptives 35-fold. Antithrombin III-deficiency carries a comparable risk. Protein C-deficiency increases the risk of thrombosis 9-fold and in users of oral contraceptives 15-fold. Ovulation inhibitors do not influence the risk of thrombosis in women with protein S-deficiency. Anti-phospholipid-antibodies increase during treatment with oral contraceptives and represent a considerably enhanced risk of thrombosis. Inherent thrombophilia is suspected in a patient with a positive history or family history of thrombosis, especially with thrombosis before the age of 40 or with atypical localisation. Even in these risk groups, the cost-benefit ratio of selective screening is unfavorable, as today at most 70% of the hereditary thrombophilias can be diagnosed by laboratory analysis, and only very few of the patients will actually experience a thrombotic event: only 3 of 1000 carriers of APC-resistance will suffer from thrombosis during oral contraception. On the other hand, a negative result of laboratory tests does not exclude a hereditary thrombophilic disorder. At present, it is unclear whether a selective screening process is superior to a careful assessment of individual and family history. A general screening, however, cannot be justified because of the unfavorable cost/benefit ratio. If the individual or family history or pathological laboratory parameters indicate an increased risk of thrombosis, this risk has to be carefully weighed against the consequences of discontinuation of pill use. Those few individuals with risk factors who will experience a thrombo-embolic event, cannot be identified in advance. If oral contraceptive

Topics: Adult; Blood Coagulation Tests; Contraceptives, Oral, Hormonal; Contraceptives, Oral, Synthetic; Cost-Benefit Analysis; Desogestrel; Female; Humans; Mass Screening; Norpregnenes; Pregnancy; Risk Factors; Thrombosis

There are several possible mechanisms by which combined oral contraceptives (COC) use increase venous thromboembolism (VTE) risk. Melodene® is a monophasic COC containing the third-generation progestin Gestodene (GSD), which is associated with increased risk of VTE. Therefore, the aim of this study was to investigate the possible alterations in viscoelastic parameters of whole blood and plasma clots along with the biophysical characteristics of erythrocytes and specifically fibrin fibers in females using a COC containing GSD. GSD appeared to have a significant impact on the biophysical characteristics of fibrin fiber networks. When GSD is combined with ethinylestradiol the viscoelastic properties of whole blood clots tend to become more prothrombotic. The alterations to and aggregation of erythrocytes accompanied with spontaneous formation of a fibrin "blanket" provides a possible mechanism for the increased occurrence of "red" clots, which can lead to occlusions in the vascular system. Thus, the increased risk of VTE associated with these COCs can be attributed to these erythrocyte-and-fibrin-rich-clots occluding venous vessels. However, our findings also propose that these changes to the biophysical properties of both erythrocytes and fibrin, specifically spontaneous expansion of deformed fibrin networks, can also occlude vessels in the microcirculation, which could have lasting, subclinical complications for female users. We recommend that a thorough risk assessment, with specific focus on coagulation and other factors affecting fibrin formation, be done for each female before prescribing a GSD-containing COC. Females that "qualify" then need to be monitored on a regular basis to lower the risk of thrombotic events. RESEARCH HIGHLIGHTS: Gestodene in combination with ethinyl estradiol significantly impacts the biophysical characteristics of erythrocytes and fibrin fiber networks. These changes, specifically spontaneous expansion of deformed fibrin networks, can occlude vessels in the microcirculation, which could have lasting, subclinical complications for the female user. The changes observed for specifically erythrocytes and fibrin show that the hormone formulation investigated contribute to a thrombogenic profile for female users.

Topics: Adult; Blood Coagulation; Contraceptives, Oral, Combined; Erythrocytes; Female; Fibrin; Humans; Norpregnenes; Thrombosis; Young Adult

The effects of a combined oral contraceptive (COC) containing 20 microg ethinyl estradiol (EE) and 75 microg gestodene (GSD) on prothrombin activity (PA), activated partial thromboplastin time (APTT), thrombin time (TT), platelet number, fibrinogen, antithrombin III (ATIII), protein C, protein S and D-dimer were evaluated over 6 months in 23 young, healthy women. Laboratory assessments were performed prior to initiation of COC use (pretreatment) and after 3 and 6 months of use. Results showed no significant changes in fibrinogen, protein C, ATIII or D-dimer during COC use, compared with pretreatment values. The increase in platelet count, decreases in protein S level, PA and APTT, and the prolongation of TT were significant. In conclusion, the use of a COC containing 20 microg EE and 75 microg GSD did not cause any significant changes in the hemostatic parameters studied that could be suggestive of a higher prothrombotic risk. Further studies with a larger sample size are necessary in order to obtain conclusive data.

Topics: Adolescent; Adult; Blood Coagulation Tests; Contraceptives, Oral, Combined; Ethinyl Estradiol; Female; Hemostasis; Humans; Norpregnenes; Risk Factors; Thrombosis

Epidemiological studies have shown an increased risk of venous thrombosis in women taking third-generation oral contraceptives, ie, those containing the progestogens desogestrel or gestodene. This study assesses the risk of ischemic stroke with several types of oral contraceptives.. A multicenter, population-based, case-control study was performed in 9 Dutch centers in women aged 18 to 49 years. Women with a first ischemic stroke were compared with control women without vascular diseases. The control subjects were recruited by random-digit dialing and were stratified by age, area of residence, and year of stroke. All patients and control subjects filled in a questionnaire about the use of oral contraceptives and risk factors for ischemic stroke. Odds ratios were adjusted for the stratification factors.. Two hundred three women with an ischemic stroke and 925 control women were included. The risk of stroke in women using any type of oral contraceptives versus none was 2.3 (95% CI 1.6 to 3.3). Current users of first-generation oral contraceptives had an odds ratio of 1.7 (95% CI 0.7 to 4.4). Low-dose second-generation oral contraceptives increased the risk of stroke 2.4 times (95% CI 1.6 to 3.7), and third-generation oral contraceptives increased the risk of stroke 2.0 times (95% CI 1.2 to 3.5). The risk of stroke in women using third-generation oral contraceptives was not different from that in women using second-generation oral contraceptives (odds ratio 1.0, 95% CI 0.6 to 1.8).. Third-generation oral contraceptives (containing desogestrel or gestodene) confer the same risk of first ischemic stroke as second-generation oral contraceptives (containing levonorgestrel).

Topics: Adolescent; Adult; Arterial Occlusive Diseases; Brain Ischemia; Case-Control Studies; Comorbidity; Contraceptives, Oral; Desogestrel; Dose-Response Relationship, Drug; Female; Humans; Levonorgestrel; Middle Aged; Netherlands; Norpregnenes; Odds Ratio; Risk Assessment; Risk Factors; Stroke; Surveys and Questionnaires; Thrombosis

A 26-year-old woman suffered concomitant inferior vena cava, iliac, and femoral vein thrombosis and cerebral venous thrombosis. Ten days before symptom onset she had started using an oral contraceptive that contained low-dose ethynilestradiol and gestodene. Both protein C deficiency and protein C activated resistance were detected. To our knowledge, the association of cerebral, caval, and ilio-femoral-popliteal venous thrombosis has not been described previously. The severity of the clinical features could be a consequence of the two combined thrombophilic mechanisms and of the continuation of the oral contraceptive. A thrombophilic disorder should be considered in young patients with thromboembolic disease. Because of the high prevalence of the genetic deficiency causing protein C activated resistance, it is probably worthwhile to perform general screening before prescription of oral contraceptives.

Topics: Adult; Anticoagulants; Cerebral Hemorrhage; Cerebral Veins; Contraceptives, Oral, Hormonal; Contraceptives, Oral, Synthetic; Drug Resistance; Estradiol Congeners; Ethinyl Estradiol; Female; Femoral Vein; Follow-Up Studies; Humans; Iliac Vein; Intracranial Embolism and Thrombosis; Norpregnenes; Popliteal Vein; Prevalence; Progesterone Congeners; Protein C; Protein C Deficiency; Thrombosis; Vena Cava, Inferior; Warfarin

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

Topics: Contraceptives, Oral, Combined; Desogestrel; Female; Humans; Norpregnenes; Risk Factors; Thrombosis