Elsevier

Contraception

Volume 80, Issue 5, November 2009, Pages 436-444
Contraception

Original research article
Bleeding pattern and cycle control with an estradiol-based oral contraceptive: a seven-cycle, randomized comparative trial of estradiol valerate/dienogest and ethinyl estradiol/levonorgestrel

https://doi.org/10.1016/j.contraception.2009.03.018Get rights and content

Abstract

Background

This study compared the bleeding pattern, cycle control and safety of an oral contraceptive (OC) comprising estradiol valerate/dienogest (E2V/DNG; administered using a dynamic dosing regimen) with a monophasic OC containing ethinyl estradiol 20 mcg/levonorgestrel 100 mcg (EE/LNG). E2V releases estradiol (E2), which is identical to endogenously produced 17β-estradiol.

Study design

This was a randomized, multicenter, double-blind, double-dummy trial lasting seven cycles in healthy women aged 18–50 years.

Results

Overall, 798 women were randomized and received allocated treatment (399 per group). There were significantly fewer bleeding/spotting days reported by women who received E2V/DNG than those who received EE/LNG [17.3±10.4 vs. 21.5±8.6, respectively, p<.0001, Reference Period 1 (Days 1–90); and 13.4±9.vs. 15.9±7.1, respectively, p<.0001, Reference Period 2 (Days 91–180)]. Through Cycles 1–7, the occurrence of scheduled withdrawal bleeding per cycle was 77.7–83.2% with E2V/DNG and 89.5–93.8% with EE/LNG (p<.0001 per cycle). The duration and intensity of scheduled withdrawal bleeding were reduced with E2V/DNG vs. EE/LNG. The incidence of intracyclic bleeding was similar with E2V/DNG (10.5%–18.6%) and EE/LNG (9.9%–17.1%) (p>.05 per cycle). No unintended pregnancies occurred with E2V/DNG, but there was one unintended pregnancy with EE/LNG. Adverse drug reactions occurred in 10.0% and 8.5% of women taking E2V/DNG and EE/LNG, respectively. Overall, 79.4% of women were satisfied with E2V/DNG and 79.9% with EE/LNG.

Conclusions

A novel OC composed of E2V/DNG is associated with an acceptable bleeding profile that is comparable to that of an EE-containing OC.

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.

References (30)

  • The safety and contraceptive efficacy of a 24-day low-dose oral contraceptive regimen containing gestodene 60 microg and ethinylestradiol 15 microg

    Eur J Contracept Reprod Health Care

    (1999)
  • Sitruk-WareR.

    New progestagens for contraceptive use

    Hum Reprod Update

    (2006)
  • KoetsawangS. et al.

    A randomized, double-blind study of two combined oral contraceptives containing the same progestogen, but different estrogens. World Health Organization Task Force on Oral Contraception

    Contraception

    (1980)
  • AstedtB. et al.

    Clinical trial of a new oral contraceptive pill containing the natural oestrogen 17 beta-oestradiol

    Br J Obstet Gynaecol

    (1979)
  • AstedtB. et al.

    The natural oestrogenic hormone oestradiol as a new component of combined oral contraceptives

    Br Med J

    (1977)
  • Cited by (126)

    • Contraception in autoimmune diseases

      2019, Best Practice and Research: Clinical Obstetrics and Gynaecology
    • Oral hormonal therapy as treatment option for abnormal uterine bleeding

      2023, European Journal of Contraception and Reproductive Health Care
    View all citing articles on Scopus

    The study was funded by Bayer Schering Pharma AG, Berlin, Germany.

    View full text