Original research articleEffects of conventional or extended-cycle regimen of an oral contraceptive containing 30 mcg ethinylestradiol and 2 mg dienogest on various hemostasis parameters
Introduction
The conventional regimen of combined oral contraceptives (COCs) which typically consists of 21 days of administration of an estrogen/progestogen combination and a subsequent hormone-free interval of 7 days was introduced about 45 years ago and is still the standard of hormonal control of fertility. However, there is no medical reason for the regular withdrawal bleeding associated with the rapid decline of serum levels of contraceptive steroids during the pill-free week. This regimen was chosen to simulate normal cyclic events and to facilitate the general acceptance of this new contraceptive method [1].
On the other hand, the regular cyclic fluctuations in the serum concentrations of the contraceptive steroids, i.e., an increase during the first days of administration up to a steady-state followed by a rapid fall to baseline levels in the hormone-free week [2], are associated not only with changes in many metabolic parameters, particularly hepatic proteins, but also with possible somatic and psychic complaints [1], [3].
Therefore, omission of the hormone-free interval and continuous use of COCs for several weeks or months has been individually practiced for many years by women suffering from cycle-dependent symptoms or menses-related disorders. Various international surveys have indeed revealed that the majority of women prefer the extended regimen to the conventional use [1], [4].
To replace this off-label use of COCs by treatment with approved COC regimens, extended-cycle preparations have been developed to reduce the frequent regular bleeding during conventional use of COCs. Clinical studies have been carried out to investigate the effect of continuous use of COCs for 6, 9, 12 or 24 weeks without any hormone-free interval [5], [6], [7], [8], [9], [10], [11], [12], [13], [14], [15], [16], [17]. After these time-periods, most regimens included a 7-day hormone-free break as a compromise in order to cause withdrawal bleeding [1].
Although many advantages of the extended COC cycles are obvious or probable, no data are available concerning the risks associated with extended-cycle regimens. One of the most important complications of COC use are thromboembolic diseases, and the relative risk of deep vein thrombosis (DVT) rises particularly during the first months of use, suggesting a major role of predisposition and risk factors [18], [19], [20], [21]. However, in young women, DVT is a rare event, and consequently, fairly reliable epidemiological findings cannot be expected before new formulations have been used by a large number of women for a sufficient period of time. As a surrogate, regulatory authorities demand controlled studies on the effect of new COC formulations or regimens on hemostasis parameters, even though no causal relationship has so far been established between COC-induced changes in distinct hemostasis parameters and the risk of venous thromboembolic disease.
In a comparative, prospective, randomized study at the center of Obstetrics and Gynecology, University Hospital of Frankfurt, the effects of conventional treatment (21+7 days) with a monophasic combination of 30 mcg ethinylestradiol and 2 mg dienogest (EE/DNG) on various procoagulatory, anticoagulatory, profibrinolytic factors, antifibrinolytic factors, markers of thrombin and fibrin turnover and clotting tests were compared with those of an extended-cycle regimen (84+7 days) with EE/DNG. The time points were 3 and 12 months.
Section snippets
Design of the study
After screening of 66 healthy women between 18 and 40 years of age seeking contraception, 60 volunteers with regular menstrual cycles and without contraindications for the use of COCs were included in this prospective randomized study. The remaining 6 women were screening failures. The following reasons were identified: obesity (body mass index >30 kg/m2), thalassemia minor, post-traumatic syndrome, Hashimoto's thyroiditis, laboratory values outside of inclusion range and withdrawal of consent.
Results
Sixty volunteers were randomized to be treated with EE/DNG either for 13 conventional cycles (21+7 days) or 4 extended cycles (84+7 days) as a subgroup for the measurement of hemostasis parameters within the frame of a larger efficacy and safety study. One volunteer became pregnant in the control cycle and dropped out before the first medication, reducing the conventional group to n=29. Two women discontinued the study prematurely during the first extended-cycle because of irregular bleeding
Discussion
The most important finding of this randomized study was the lack of any significant differences between the conventional (21+7 days) and extended-cycle regimen (84+7 days) at 12 months. In both groups, there was a significant rise in fibrinogen, factor VII and factor VIII, protein C, plasminogen and t-PA activity and a reduction in antithrombin, protein S, t-PA antigen and PAI-1 antigen. In parallel, the timeover means of prothrombin fragment 1+2, D-dimers, and PAP increased.
There are two other
Acknowledgments
The study was financially supported by Jenapharm (Jena, Germany). The support of Dr. E. Palombo-Kinne (Jenapharm) for critical review, and Bodo Kirsch (Jenapharm) who did the statistical evaluation of the results, is gratefully acknowledged.
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2013, Best Practice and Research: Clinical Endocrinology and MetabolismCitation Excerpt :Acceleration of baseline procoagulation and fibrinolysis processes is seen with different oral combinations. Oral contraceptives are found to cause an increase in levels of fibrinogen, prothrombin fragment 1 + 2, d-dimer, plasminogen, plasmin–antiplasmin complex, protein C activity and a decrease in antithrombin activity, tissue-plasminogen activator (t-PA) and plasminogen activator inhibitor (PAI).56,57 Once again this effect is modulated by the progestin's androgenicity.
Effect of extended-cycle regimen with an oral contraceptive containing 30 mcg ethinylestradiol and 2 mg dienogest on bleeding patterns, safety, acceptance and contraceptive efficacy
2011, ContraceptionCitation Excerpt :Therefore, the daily dose of contraceptive steroids, rather than the duration of continuous intake, impacts the risk of venous thrombosis [38]. Direct comparisons between conventional and extended-cycle use of EE/DNG revealed no relevant difference of the effects on various metabolic variables including hemostasis, carbohydrate metabolism and lipid metabolism [40–43]. In the present study, three thrombotic events were reported during extended-cycle treatment, all of them at an early stage of treatment (first, sixth and seventh week of treatment, respectively).
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2010, ContraceptionCitation Excerpt :This finding confirms that the changes in liver proteins are related to the EE component of the OC rather than to the progestin as previously suggested [52,53]. Another clinical trial on a monophasic COC containing 30 mcg EE and 2 mg DNG (EE/DNG) demonstrated significant increases in fibrinogen (20%), factor VII antigen (50–60%), factor VII activity (45%), activated factor VII (30–45%) and factor VIII activity (10–20%) after 3 and 12 months of treatment [57]. In contrast, when DNG is associated with E2V, no or little changes in clotting factors were noted, indicating that the hemostatic changes reported with OCs are likely related to the EE and not to the progestin component.
Effect of a continuous regimen of contraceptive combination of ethinylestradiol and drospirenone on lipid, carbohydrate and coagulation profiles
2010, ContraceptionCitation Excerpt :On the other hand, a non-significant increase in fibrinogen levels was found, while total activated thromboplastin time remained unchanged and thrombin time decreased. These results are comparable to findings reported by Klipping et al. [17], who used a combination of a lower dose of ethinylestradiol (20 mcg) and drospirenone (3 mg) in the traditional cyclic regimen with a hormone-free interval, and similar to data published by Wiegratz et al. [14], who evaluated a combination of ethinylestradiol (30 mcg) and dienogest (2 mg), both in a continuous regimen and in the traditional cyclic regimen. In contrast, Machado et al. [13] evaluated a combination of ethinylestradiol (30 mcg) and gestodene (75 mcg) in a continuous regimen and reported an increase in antithrombin III and an increase in PAI-1 and fibrinogen levels.
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