Original research articleBleeding pattern and cycle control with an estradiol-based oral contraceptive: a seven-cycle, randomized comparative trial of estradiol valerate/dienogest and ethinyl estradiol/levonorgestrel☆
Introduction
Since their introduction in the 1960s, oral contraceptives (OCs) have become a well-accepted and widely used method of contraception. Despite their undoubted popularity, some women experience side effects while taking OCs, including breast tenderness, headache, nausea and altered libido. In addition, epidemiological studies have suggested an association between the use of OCs and an increased risk of arterial and venous thrombotic events [1]. However, these events are very rare and occur at a rate far less than that associated with pregnancy.
In order to improve their tolerability and to broaden the choice for women using OCs as their method of contraception, OCs have undergone considerable development over the past four decades, including reductions in the dose of synthetic estrogen [i.e., ethinyl estradiol (EE)] [2], [3], [4] and the incorporation of progestins with more favorable clinical profiles [5]. Additional efforts have included the replacement of synthetic estrogens with 17β-estradiol (E2) [6], [7], [8], [9], [10], [11], [12], [13], [14], [15], [16], [17], [18], [19], [20].
Although E2-containing OCs have been shown to effectively inhibit ovulation and provide excellent contraceptive efficacy [6], [7], [8], [9], [10], [11], [12], [15], [18], [19], [20], monophasic and biphasic regimens have proved unacceptable in terms of cycle control in clinical trials [6], [15], [18], [19], [20], often resulting in higher rates of premature discontinuation compared with preparations containing EE. Problems identified have included prolonged bleeding [20] an increased number of bleeding/spotting days per cycle [15], spotting and breakthrough bleeding [18], [19], and menstrual irregularities [6]. Potential reasons for the bleeding irregularities observed with E2-containing OCs have included an inappropriate estrogen/progestin ratio [6], [15], [18], [20] and suboptimal doses of estrogen [6], [19].
In order to improve the unacceptable cycle control observed in clinical studies of E2-containing OCs, an innovative OC has been developed in which estradiol valerate (E2V) has been combined with the progestin, dienogest (DNG), using a dynamic dosing regimen (with an estrogen step-down and a progestin step-up). This regimen provides reliable contraceptive efficacy [21], [22] and has been shown to be well tolerated [22], with stable serum E2 levels maintained throughout the cycle [23]. E2V releases E2, which is identical to endogenously produced 17β-estradiol; 1 mg of E2V is equivalent to 0.76 mg of E2, based on molecular weight.
The current study was carried out to compare the bleeding pattern, cycle control and safety of a dynamic dosing regimen of E2V/DNG with that of a monophasic regimen of EE/levonorgestrel (LNG).
Section snippets
Study design
This was a multicenter, double-blind, double-dummy, randomized study conducted in 34 centers in Germany, the Czech Republic and France, between March 2005 and September 2006 (Protocol No. 304004; ClinicalTrials.gov identifier NCT00185367). The study was conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki and the International Conference on Harmonization-Good Clinical Practice. The study protocol was approved by the local ethics committees in
Study population
Of the 846 women screened, 804 were randomized to E2V/DNG (n=402) and EE/LNG (n=402). Reasons for nonrandomization were withdrawal of consent (n=18), inclusion/exclusion criteria not met (n=21), loss to follow-up (n=1) and other (n=2). A total of six women did not receive treatment, meaning that the FAS comprised 798 women. Forty-four women prematurely discontinued treatment because of withdrawal of consent (n=11), protocol deviation (n=2), adverse events (n=26), pregnancy (n=1) and other (n=4)
Discussion
The bleeding pattern and cycle control achieved with the novel combination of E2V and DNG in a dynamic dosing regimen is comparable to that of a monophasic OC containing EE/LNG. Moreover, this E2V/DNG OC appears to be associated with shorter and lighter bleeding compared with EE/LNG and with overall fewer bleeding/spotting days per reference period. Scheduled withdrawal bleeding was more often absent in women who received E2V/DNG vs. EE/LNG, whereas intracyclic bleeding occurred in a similar
Acknowledgments
Medical writing assistance for the preparation of the manuscript was provided by Nicola Ryan and Lyndal McMillan of Wolters Kluwer Health. This assistance was funded by Bayer Schering Pharma AG. The authors would also like to thank Andrea Machlitt for editorial assistance during the preparation of the manuscript.
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The study was funded by Bayer Schering Pharma AG, Berlin, Germany.