nach oben

Clinical Drug Investigation

Erschienen in:

01.08.2011 | Original Research Article

Metabolic and Haemostatic Effects of Estradiol Valerate/Dienogest, a Novel Oral Contraceptive

A Randomized, Open-Label, Single-Centre Study

verfasst von: Wolfgang Junge, Uwe Mellinger, Dr Susanne Parke, Marco Serrani

Erschienen in: Clinical Drug Investigation | Ausgabe 8/2011

Einloggen, um Zugang zu erhalten

Abstract

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.

Trial registration:} ClinicalTrials.gov Identifier: NCT00185224

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): 445–59CrossRef

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): 732–6CrossRefPubMed

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): 269CrossRefPubMedPubMedCentral

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): 333–8CrossRefPubMed

Hirvonen E, Allonen H, Anttila M, et al. Oral contraceptive containing natural estradiol for premenopausal women. Maturitas 1995 Jan; 21(1): 27–32CrossRefPubMed

Hirvonen E, Stenman UH, Malkonen M, et al. New natural oestradiol/cyproterone acetate oral contraceptive for premenopausal women. Maturitas 1988 Oct; 10(3): 201–13CrossRefPubMed

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): 248

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: 105–13CrossRef

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): 458–64CrossRefPubMed

10.

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: 183

11.

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: 39–44

12.

Schubert W, Cullberg G. Ovulation inhibition with 17 beta-estradiol cyclo-octyl acetate and desogestrel. Acta Obstet Gynecol Scand 1987; 66(6): 543–7CrossRefPubMed

13.

Serup J, Bostofte E, Larsen S, et al. Natural oestrogens for oral contraception. Lancet 1979 Sep 1; 2(8140): 471–2CrossRefPubMed

14.

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): 616–9CrossRefPubMed

15.

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): 218–25CrossRefPubMed

16.

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): 57–62CrossRefPubMed

17.

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): 221–32CrossRefPubMed

18.

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): 436–44CrossRefPubMed

19.

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): 409–16CrossRefPubMed

20.

Wiegratz I, Lee JH, Kutschera E, et al. Effect of four oral contraceptives on hemostatic parameters. Contraception 2004 Aug; 70(2): 97–106CrossRefPubMed

21.

European Medicines Agency: Committee for Medicinal products for human use (CHMP). Guideline on clinical investigation of steroid contraceptives in women. London: EMA 2005: 1–5

22.

Helgason S. Estrogen replacement therapy after the menopause: estrogenicity and metabolic effects. Acta Obstet Gynecol Scand 1982 Suppl.; 107: 1–29

23.

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): 65–9PubMed

24.

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): 511–8CrossRefPubMed

25.

Oettel M, Breitbarth H, Elger W, et al. The pharmacological profile of dienogest. Eur J Contracept Reprod Health Care 1999; 4Suppl. 1: 2–13CrossRef

26.

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): 193–8CrossRefPubMed

27.

Fotherby K. Oral contraceptives and lipids. BMJ 1989 Apr 22; 298(6680): 1049–50CrossRefPubMedPubMedCentral

28.

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): 1895–906PubMed

29.

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): 645–51PubMed

30.

Fleming TR. Surrogate endpoints and FDA’s accelerated approval process. Health Aff (Millwood) 2005 Jan–Feb; 24(1): 67–78CrossRef

31.

Grimes DA, Schulz KF, Raymond EG. Surrogate end points in women’s health research: science, protoscience, and pseudoscience. Fertil Steril 2010 Apr; 93(6): 1731–4CrossRefPubMed

32.

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): 1196–204CrossRefPubMed

33.

Wiegratz I, Lee JH, Kutschera E, et al. Effect of dienogest-containing oral contraceptives on lipid metabolism. Contraception 2002 Mar; 65(3): 223–9CrossRefPubMed

34.

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): 271–8CrossRefPubMed

35.

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): 1816–21PubMed

36.

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): 560–7CrossRefPubMed

37.

Gooren L. Hormone treatment of the adult transsexual patient. Horm Res 2005; 64Suppl. 2: 31–6PubMed

38.

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): 47–184

39.

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): 5723–9CrossRefPubMed

40.

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): 77–82CrossRefPubMed

41.

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): 573–4CrossRef

42.

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): 242–8CrossRefPubMed

43.

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): 468–77CrossRefPubMed

44.

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): 928–32PubMed

45.

Oettel M, Graeser T, Hoffmann H, et al. The preclinical and clinical profile of dienogest: a short overview. Drugs Today 1999; 35Suppl. C: 3–12

46.

Fleming TR, DeMets DL. Surrogate end points in clinical trials: are we being misled? Ann Intern Med 1996 Oct 1; 125(7): 605–13CrossRefPubMed

47.

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.): 15S

48.

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): 94

Titel: Metabolic and Haemostatic Effects of Estradiol Valerate/Dienogest, a Novel Oral Contraceptive
A Randomized, Open-Label, Single-Centre Study
verfasst von: Wolfgang Junge
Uwe Mellinger
Dr Susanne Parke
Marco Serrani
Publikationsdatum: 01.08.2011
Verlag: Springer International Publishing
Erschienen in: Clinical Drug Investigation / Ausgabe 8/2011
Print ISSN: 1173-2563
Elektronische ISSN: 1179-1918
DOI: https://doi.org/10.2165/11590220-000000000-00000

Live-Webinar "Chronische Unterbauch- und Viszeralschmerzen in der Praxis managen"

Springer Medizin

Metabolic and Haemostatic Effects of Estradiol Valerate/Dienogest, a Novel Oral Contraceptive

A Randomized, Open-Label, Single-Centre Study

Abstract

Live-Webinar "Chronische Unterbauch- und Viszeralschmerzen in der Praxis managen"

Springer Medizin

Abstract

Bitte loggen Sie sich ein, um Zugang zu diesem Inhalt zu erhalten

Weitere Artikel der Ausgabe 8/2011

Erratum to: Subjective effects and safety of whole and tampered morphine sulfate and naltrexone hydrochloride (ALO-01) extended-release capsules versus morphine solution and placebo in experienced non-dependent opioid users: a randomized, doubleblind, placebo-controlled, crossover study

Erratum to: Rationale for the use of a fixed-dose combination in the management of hypertension: efficacy and tolerability of lercanidipine/enalapril

Combination of Low- Dose Isotretinoin and Pulsed Oral Azithromycin in the Management of Moderate to Severe Acne

Clinical Utility of Maraviroc

Cycle Control and Bleeding Pattern of a 24/4 Regimen of Drospirenone 3 mg/Ethinylestradiol 20 μg Compared with a 21/7 Regimen of Desogestrel 150 μg/Ethinylestradiol 20 μg

The Role of Topical Moxifloxacin, a New Antibacterial in Europe, in the Treatment of Bacterial Conjunctivitis