Background and Objective: The hormonal components of combined oral contraceptives (COCs) have various metabolic and haemostatic effects. The objective of this study was to compare the metabolic and haemostatic effects of a novel COC comprising estradiol valerate/dienogest (E2V/DNG) with ethinylestradiol/levonorgestrel (EE/LNG).
Methods: In a randomized, open-label study conducted in Germany over seven cycles, healthy women aged 18–50 years received E2V/DNG (E2V 3 mg on days 1–2, E2V 2 mg/DNG 2 mg on days 3–7, E2V 2 mg/DNG 3 mg on days 8–24, E2V 1 mg on days 25–26, placebo on days 27–28; n = 30) or EE/LNG (EE 0.03 mg/LNG 0.05 mg on days 1–6, EE 0.04 mg/LNG 0.075 mg on days 7–11, EE 0.03 mg/LNG 0.125 mg on days 12–21, placebo on days 22–28; n = 28). The primary variables were the mean intraindividual relative changes from baseline to cycle 7 in high-density lipoprotein (HDL) and low-density lipoprotein (LDL) cholesterol levels. Changes in other lipid parameters, haemostatic parameters, sex hormone-binding globulin (SHBG), cortisol-binding globulin (CBG), carbohydrate metabolism parameters, blood pressure and body weight were also assessed.
Results: Mean ± SD HDL cholesterol increased by 7.9%±21.8% with E2V/DNG and decreased by 2.3%±14.4% with EE/LNG. Mean ± SD LDL cholesterol decreased by 6.5% ±15.9% with E2V/DNG and by 3.0% ±17.4% with EE/LNG. Mean ± SD prothrombin fragment 1+2 and D-dimer levels remained essentially unchanged in the E2V/DNG group (−0.6% ± 30.3% and −2.1% ± 43.5%, respectively), but increased in the EE/LNG group (by 117.3% ± 358.0% and 62.9% ± 99.5%, respectively). Changes in other hepatic-induced arameters (SHBG, CBG) and carbohydrate metabolism were generally less pronounced with E2V/DNG versus EE/LNG. Body weight and blood pressure remained stable throughout the study in both treatment groups. Both formulations were well tolerated, with no serious adverse events reported.
Conclusion: E2V/DNG had a minimal impact on metabolic and haemostatic parameters, and a more favourable effect than EE/LNG on lipid markers.
Combine Oral Contraceptive Dienogest Prothrombin Fragment SHBG Level Drospirenone
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This study was funded by Bayer HealthCare Pharmaceuticals, Berlin, Germany, the manufacturer of estradiol valerate/dienogest. Medical writing services during the preparation of this manuscript were provided by Lyndal Staples and Danielle Turner (inScience Communications, a Wolters Kluwer business, Chester, UK). Funding for this editorial assistance was provided by Bayer HealthCare Pharmaceuticals.
Uwe Mellinger, Susanne Parke and Marco Serrani are current employees of Bayer HealthCare Pharmaceuticals. Wolfgang Junge is the Medical Director of Laboratorium fuer Klinische Forschung, the center at which all laboratory tests were performed.
World Health Organization Task Force on Oral Contraception. A randomized, double-blind study of two combined oral contraceptives containing the same progestogen, but different estrogens. Contraception 1980 May; 21(5): 445–59CrossRefGoogle Scholar
Astedt B, Jeppsson S, Liedholm P, et al. Clinical trial of a new oral contraceptive pill containing the natural oestrogen 17 beta-oestradiol. Br J Obstet Gynaecol 1979 Sep; 86(9): 732–6CrossRefPubMedGoogle Scholar
Astedt B, Svanberg L, Jeppsson S, et al. The natural oestrogenic hormone oestradiol as a new component of combined oral contraceptives. Br Med J 1977 Jan 29; 1(6056): 269CrossRefPubMedPubMedCentralGoogle Scholar
Csemiczky G, Dieben T, Coeling Bennink HJ, et al. The pharmacodynamic effects of an oral contraceptive containing 3mg micronized 17 beta-estradiol and 0.150mg desogestrel for 21 days, followed by 0.030 mg desogestrel only for 7 days. Contraception 1996 Dec; 54(6): 333–8CrossRefPubMedGoogle Scholar
Hirvonen E, Allonen H, Anttila M, et al. Oral contraceptive containing natural estradiol for premenopausal women. Maturitas 1995 Jan; 21(1): 27–32CrossRefPubMedGoogle Scholar
Hirvonen E, Stenman UH, Malkonen M, et al. New natural oestradiol/cyproterone acetate oral contraceptive for premenopausal women. Maturitas 1988 Oct; 10(3): 201–13CrossRefPubMedGoogle Scholar
Hirvonen E, Vartiainen E, Kulmala Y. A multicenter trial with a new OC using a natural estradiol and cyproterone acetate for women over 35 [abstract]. Advances Contraception 1990; 6(4): 248Google Scholar
Hoffmann H, Moore C, Kovacs L, et al. Alternatives of the replacement of ethinylestradiol by natural 17beta-estradiol in dienogest-containing oral contraceptives. Drugs Today 1999; 35: 105–13CrossRefGoogle Scholar
Hoffmann H, Moore C, Zimmermann H, et al. Approaches to the replacement of ethinylestradiol by natural 17beta-estradiol in combined oral contraceptives. Exp Toxicol Pathol 1998 Sep; 50(4-6): 458–64CrossRefPubMedGoogle Scholar
Kivinen S, Saure A. Efficacy and tolerability of a combined oral contraceptive containing 17 beta-estradiol and desogestrel [abstract]. Eur J Contracept Reprod Health Care 1996; 1: 183Google Scholar
Kovacs L, Hoffmann H. A new low-dose oral contraceptive containing ethinylestradiol, estradiol and dienogest: first experience of its clinical use. In: Elstein M, editor. Extra-genital effects of contraceptives: 4th Congress of the European Society of Contraception, Barcelona, Spain, June 1996. Pearl River: The Parthenon Publishing Group Inc., 1997: 39–44Google Scholar
Schubert W, Cullberg G. Ovulation inhibition with 17 beta-estradiol cyclo-octyl acetate and desogestrel. Acta Obstet Gynecol Scand 1987; 66(6): 543–7CrossRefPubMedGoogle Scholar
Serup J, Bostofte E, Larsen S, et al. Natural oestrogens for oral contraception. Lancet 1979 Sep 1; 2(8140): 471–2CrossRefPubMedGoogle Scholar
Wenzl R, Bennink HC, van Beek A, et al. Ovulation inhibition with a combined oral contraceptive containing 1mg micronized 17 beta-estradiol. Fertil Steril 1993 Oct; 60(4): 616–9CrossRefPubMedGoogle Scholar
Endrikat J, Parke S, Trummer D, et al. Ovulation inhibition with four variations of a four-phasic estradiol valerate/ dienogest combined oral contraceptive: results of two prospective, randomized, open-label studies. Contraception 2008 Sep; 78(3): 218–25CrossRefPubMedGoogle Scholar
Palacios S, Wildt L, Parke S, et al. Efficacy and safety of a novel oral contraceptive based on oestradiol (oestradiol valerate/dienogest): a phase III trial. Eur J Obstet Gynecol Reprod Biol 2010 Mar; 149(1): 57–62CrossRefPubMedGoogle Scholar
Zeun S, Lu M, Uddin A, et al. Pharmacokinetics of an oral contraceptive containing oestradiol valerate and dienogest. Eur J Contracept Reprod Health Care 2009 Jun; 14(3): 221–32CrossRefPubMedGoogle Scholar
Ahrendt HJ, Makalova D, Parke S, et al. 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. Contraception 2009 Nov; 80(5): 436–44CrossRefPubMedGoogle Scholar
Klipping C, Marr J. Effects of two combined oral contraceptives containing ethinyl estradiol 20 microg combined with either drospirenone or desogestrel on lipids, hemostatic parameters and carbohydrate metabolism. Contraception 2005 Jun; 71(6): 409–16CrossRefPubMedGoogle Scholar
Wiegratz I, Lee JH, Kutschera E, et al. Effect of four oral contraceptives on hemostatic parameters. Contraception 2004 Aug; 70(2): 97–106CrossRefPubMedGoogle Scholar
European Medicines Agency: Committee for Medicinal products for human use (CHMP). Guideline on clinical investigation of steroid contraceptives in women. London: EMA 2005: 1–5Google Scholar
Helgason S. Estrogen replacement therapy after the menopause: estrogenicity and metabolic effects. Acta Obstet Gynecol Scand 1982 Suppl.; 107: 1–29Google Scholar
Lindberg UB, Crona N, Stigendal L, et al. A comparison between effects of estradiol valerate and low dose ethinyl estradiol on haemostasis parameters. Thromb Haemost 1989 Feb 28; 61(1): 65–9PubMedGoogle Scholar
Mashchak CA, Lobo RA, Dozono-Takano R, et al. Comparison of pharmacodynamic properties of various estrogen formulations. Am J Obstet Gynecol 1982 Nov 1; 144(5): 511–8CrossRefPubMedGoogle Scholar
Oettel M, Breitbarth H, Elger W, et al. The pharmacological profile of dienogest. Eur J Contracept Reprod Health Care 1999; 4Suppl. 1: 2–13CrossRefGoogle Scholar
Strowitzki T, Faustmann T, Gerlinger C, et al. Dienogest in the treatment of endometriosis-associated pelvic pain: a 12-week, randomized, double-blind, placebo-controlled study. Eur J Obstet Gynecol Reprod Biol 2010 Aug; 151(2): 193–8CrossRefPubMedGoogle Scholar
Applebaum-Bowden D, McLean P, Steinmetz A, et al. Lipoprotein, apolipoprotein, and lipolytic enzyme changes following estrogen administration in postmenopausal women. J Lipid Res 1989 Dec; 30(12): 1895–906PubMedGoogle Scholar
Berr F, Eckel RH, Kern Jr F. Contraceptive steroids increase hepatic uptake of chylomicron remnants in healthy young women. J Lipid Res 1986 Jun; 27(6): 645–51PubMedGoogle Scholar
Fleming TR. Surrogate endpoints and FDA’s accelerated approval process. Health Aff (Millwood) 2005 Jan–Feb; 24(1): 67–78CrossRefGoogle Scholar
Grimes DA, Schulz KF, Raymond EG. Surrogate end points in women’s health research: science, protoscience, and pseudoscience. Fertil Steril 2010 Apr; 93(6): 1731–4CrossRefPubMedGoogle Scholar
Walsh BW, Schiff I, Rosner B, et al. Effects of postmenopausal estrogen replacement on the concentrations and metabolism of plasma lipoproteins. N Engl J Med 1991 Oct 24; 325(17): 1196–204CrossRefPubMedGoogle Scholar
Wiegratz I, Lee JH, Kutschera E, et al. Effect of dienogest-containing oral contraceptives on lipid metabolism. Contraception 2002 Mar; 65(3): 223–9CrossRefPubMedGoogle Scholar
Gaspard U, Endrikat J, Desager JP, et al. A randomized study on the influence of oral contraceptives containing ethinylestradiol combined with drospirenone or desogestrel on lipid and lipoprotein metabolism over a period of 13 cycles. Contraception 2004 Apr; 69(4): 271–8CrossRefPubMedGoogle Scholar
Oelkers W, Foidart JM, Dombrovicz N, et al. Effects of a new oral contraceptive containing an antimineralocorticoid progestogen, drospirenone, on the renin-aldosterone system, body weight, blood pressure, glucose tolerance, and lipid metabolism. J Clin Endocrinol Metab 1995 Jun; 80(6): 1816–21PubMedGoogle Scholar
Gaussem P, Alhenc-Gelas M, Thomas JL, et al. Haemostatic effects of a new combined oral contraceptive, nomegestrol acetate/17beta-estradiol, compared with those of levonorgestrel/ethinyl estradiol: a double-blind, randomised study. Thromb Haemost 2011 Jan 12; 105(3): 560–7CrossRefPubMedGoogle Scholar
Gooren L. Hormone treatment of the adult transsexual patient. Horm Res 2005; 64Suppl. 2: 31–6PubMedGoogle Scholar
Klipping C, Junge W, Mellinger U, et al. Haemostatic effects of a novel four-phasic combined oral contraceptive containing estradiol valerate and dienogest [poster no. 090: 96-7]. Eur J Contracept Reprod Health Care 2008; 13(s2): 47–184Google Scholar
Toorians AW, Thomassen MC, Zweegman S, et al. Venous thrombosis and changes of hemostatic variables during cross-sex hormone treatment in transsexual people. J Clin Endocrinol Metab 2003 Dec; 88(12): 5723–9CrossRefPubMedGoogle Scholar
Olofsson BO, Dahlen G, Nilsson TK. Evidence for increased levels of plasminogen activator inhibitor and tissue plasminogen activator in plasma of patients with angiographically verified coronary artery disease. Eur Heart J 1989 Jan; 10(1): 77–82CrossRefPubMedGoogle Scholar
Paramo JA, Colucci M, Collen D, et al. Plasminogen activator inhibitor in the blood of patients with coronary artery disease. Br Med J (Clin Res Ed) 1985 Aug 31; 291(6495): 573–4CrossRefGoogle Scholar
Meltzer ME, Doggen CJ, de Groot PG, et al. Fibrinolysis and the risk of venous and arterial thrombosis. Curr Opin Hematol 2007 May; 14(3): 242–8CrossRefPubMedGoogle Scholar
Meltzer ME, Doggen CJ, de Groot PG, et al. The impact of the fibrinolytic system on the risk of venous and arterial thrombosis. Semin Thromb Hemost 2009 Jul; 35(5): 468–77CrossRefPubMedGoogle Scholar
Scarabin PY, Plu-Bureau G, Zitoun D, et al. Changes in haemostatic variables induced by oral contraceptives containing 50 micrograms or 30 micrograms oestrogen: absence of dose-dependent effect on PAI-1 activity. Thromb Haemost 1995 Sep; 74(3): 928–32PubMedGoogle Scholar
Oettel M, Graeser T, Hoffmann H, et al. The preclinical and clinical profile of dienogest: a short overview. Drugs Today 1999; 35Suppl. C: 3–12Google Scholar
Fleming TR, DeMets DL. Surrogate end points in clinical trials: are we being misled? Ann Intern Med 1996 Oct 1; 125(7): 605–13CrossRefPubMedGoogle Scholar
Parke S, Nahum GG, Wildt L, et al. Efficacy and tolerability of a new oral contraceptive containing estradiol and dienogest [abstract]. Obstet Gynecol 2008; 111(4 Suppl.): 15SGoogle Scholar
Parke S, Makalová D, Ahrendt H-J, et al. Bleeding patterns and cycle control with a novel four-phasic combined oral contraceptive containing estradiol valerate and dienogest [abstract]. Eur J Contracept Reprod Health Care 2008; 13(1): 94Google Scholar