Elsevier

Contraception

Volume 78, Issue 5, November 2008, Pages 384-391
Contraception

Original research article
Effects of conventional or extended-cycle regimen of an oral contraceptive containing 30 mcg ethinylestradiol and 2 mg dienogest on various hemostasis parameters

https://doi.org/10.1016/j.contraception.2008.06.015Get rights and content

Abstract

Background

The study was conducted to investigate the effect of a combined oral contraceptive (COC) containing 30 mcg ethinylestradiol and 2 mg dienogest with two different regimens on various hemostasis variables.

Study Design

Hemostatic parameters were measured in 59 women treated with a monophasic COC containing 30 mcg ethinylestradiol and 2 mg dienogest (EE/DNG) either conventionally (13 cycles with 21 days of treatment+7 days without hormones) or with an extended-cycle regimen (4 extended cycles with 84 days of continuous administration of EE/DNG, followed by a hormone-free interval of 7 days). Blood samples were taken on Days 21–26 of the preceding control cycle and on Days 19–21 of the 3rd and 13th conventional cycle or on Days 82–84 of the first and fourth extended cycle.

Results

After 3 and 12 months, 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%) occurred in both treatment regimens. In both groups, there was a small but significant decrease in the level and activity of antithrombin, a 20–25% decrease in total and free protein S and a 15–20% rise in the level and activity of protein C, but no significant change of the thrombin-antithrombin complex. A significant over-time rise by about 25% of prothrombin fragment 1+2 occurred only in the extended-cycle group, but this effect did not differ significantly from that observed during conventional treatment. Plasminogen was elevated by 50% in both groups, while tissue-plasminogen activator (t-PA) activity rose by 15% in the conventional group and by 25–30% in the extended-cycle group. In both groups, t-PA antigen was reduced by about 30% and plasminogen activator inhibitor-1 by 40–60%. The levels of the plasmin-antiplasmin complex rose by 30–40% and those of D-dimers by 20–55%. The prothrombin time was slightly increased and the activated partial thromboplastin time was slightly decreased.

Conclusion

In general, these results were in agreement with those observed during treatment with other COCs. The study demonstrated that during conventional and extended-cycle treatment with EE/DNG, a steady-state in the effects on hemostasis variables was reached within 3 months, and that the effects observed after 3 and 12 months of treatment did not substantially differ between conventional and extended-cycle regimen.

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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