[en] [en] OBJECTIVES: To evaluate the effect on endocrine and metabolic parameters of a new combined oral contraceptive (COC) containing estetrol (E4) and drospirenone (DRSP).
STUDY DESIGN: Randomized, open-label, controlled, 3-arm, parallel study. Healthy subjects received either E4 15 mg/DRSP 3 mg (E4/DRSP) (n = 38), or ethinylestradiol (EE) 30 µg/levonorgestrel (LNG) 150 µg (n = 29), or EE 20 µg/DRSP 3 mg (n = 31) for 6 treatment cycles. Median percentage change from baseline to cycle 3 and to cycle 6 were evaluated for endocrine parameters, liver proteins, lipid profile, and carbohydrate metabolism.
RESULTS: At cycle 6, E4/DRSP treatment had less effect on gonadotropins (follicle stimulating hormone [FSH] +30.5%, luteinizing hormone [LH] -7.5%) compared to EE/LNG (FSH -84.0%, LH -92.0%) and EE/DRSP (FSH -64.0%, LH -90.0%). With E4/DRSP increases in total cortisol (+26.0%) and cortisol binding globulin ([CBG] (+40.0%) were less compared to EE/LNG (cortisol +109.0%, CBG +152.0%) and EE/DRSP (cortisol +107.0%, CBG +140.0%). Liver proteins, except CRP, increased, but the effect was less pronounced with E4/DRSP for angiotensinogen (+75.0%) compared to EE/LNG (+170.0%) and EE/DRSP (+206.5%) and for sex hormone binding globulin ([SHBG] +55.0%), compared to EE/LNG (+74.0%) and EE/DRSP (+251.0%). E4/DRSP had minimal impact on lipid parameters; the largest effect was observed for triglycerides (+24.0%), which was less compared to EE/LNG (+28.0%) and EE/DRSP (+65.5%). E4/DRSP had no effect on carbohydrate metabolism.
CONCLUSIONS: E4/DRSP treatment has limited effects on endocrine and metabolic parameters. The effects on gonadotropins, cortisol, CBG, angiotensinogen, SHBG and triglycerides were less pronounced compared to EE-containing products.
IMPLICATIONS STATEMENT: Combining E4 15 mg with DRSP 3 mg resulted in a COC with a different metabolic profile in comparison to EE-containing products. The clinical relevance of these findings needs to be further assessed, using clinical endpoints to establish the safety profile of this new COC.
Disciplines :
Reproductive medicine (gynecology, andrology, obstetrics)
Author, co-author :
Klipping, Christine ; Dinox BV, Groningen, The Netherlands
Duijkers, Ingrid; Dinox BV, Groningen, The Netherlands
Mawet, Marie ; Centre Hospitalier Universitaire de Liège - CHU > > Service de gynécologie-obstétrique (CHR) ; Estetra SRL, An Affiliate's Company of Mithra Pharmaceuticals, Liège, Belgium
Maillard, Catherine ; Université de Liège - ULiège > Département des sciences cliniques > Labo de biologie des tumeurs et du développement ; Estetra SRL, An Affiliate's Company of Mithra Pharmaceuticals, Liège, Belgium
Bastidas, Adriana; Estetra SRL, An Affiliate's Company of Mithra Pharmaceuticals, Liège, Belgium
Jost, Maud ; Université de Liège - ULiège > Département des sciences cliniques > Labo de biologie des tumeurs et du développement ; Estetra SRL, An Affiliate's Company of Mithra Pharmaceuticals, Liège, Belgium. Electronic address: mjost@mithra.com
Foidart, Jean-Michel ; Université de Liège - ULiège > Département des sciences cliniques
Language :
English
Title :
Endocrine and metabolic effects of an oral contraceptive containing estetrol and drospirenone.
Bitzer, J., Pharmacological profile of estrogens in oral contraception. Minerva Ginecol 63 (2011), 299–304.
Fruzzetti, F, Tremollieres, F, Bitzer, J., An overview of the development of combined oral contraceptives containing estradiol: focus on estradiol valerate/dienogest. Gynecol Endocrinol 28 (2012), 400–408.
Agren, UM, Anttila, M, Maenpaa-Liukko, K, Rantala, M, Rautainen, H, Sommer, WF, et al. Effects of a monophasic combined oral contraceptive containing nomegestrol acetate and 17beta-oestradiol compared with one containing levonorgestrel and ethinylestradiol on haemostasis, lipids and carbohydrate metabolism. Eur J Contracept Reprod Health Care 16 (2011), 444–457.
Gaspard, U, Scheen, A, Endrikat, J, Buici, C, Lefebvre, P, Gerlinger, C, et al. A randomized study over 13 cycles to assess the influence of oral contraceptives containing ethinylestradiol combined with drospirenone or desogestrel on carbohydrate metabolism. Contraception 67 (2003), 423–429.
Grandi, G, Napolitano, A, Cagnacci, A., Metabolic impact of combined hormonal contraceptives containing estradiol. Expert Opin Drug Metab Toxicol 12 (2016), 779–787.
Dinger, J, Do Minh, T, Heinemann, K, Impact of estrogen type on cardiovascular safety of combined oral contraceptives. Contraception 94 (2016), 328–339.
Bastianelli, C, Farris, M, Rosato, E, Brosens, I, Benagiano, G., Pharmacodynamics of combined estrogen-progestin oral contraceptives: 1. Effects on metabolism. Expert Rev Clin Pharmacol 10 (2017), 315–326.
Holinka, CF, Diczfalusy, E, Coelingh Bennink, HJ, Estetrol: a unique steroid in human pregnancy. J Steroid Biochem Mol Biol 110 (2008), 138–143.
Apter, D, Zimmerman, Y, Beekman, L, Mawet, M, Maillard, C, Foidart, JM, et al. Bleeding pattern and cycle control with estetrol-containing combined oral contraceptives: results from a phase II, randomised, dose-finding study (FIESTA). Contraception 94 (2016), 366–373.
Gaspard, U, Taziaux, M, Mawet, M, Jost, M, Gordenne, V, Coelingh Bennink, H, et al. A multicenter, randomized study to select the minimum effective dose of estetrol (E4) in postmenopausal women (E4Relief): part 1. Vasomotor symptoms and overall safety. Menopause 27 (2020), 848–857.
Singer, CF, Bennink, HJ, Natter, C, Steurer, C, Rudas, M, Moinfar, F, et al. Antiestrogenic effects of the fetal estrogen estetrol in women with estrogen-receptor positive early breast cancer. Carcinogenesis 35 (2014), 2447–2451.
Duijkers, IJ, Klipping, C, Zimmerman, Y, Appels, N, Jost, M, Maillard, C, et al. Inhibition of ovulation by administration of estetrol in combination with drospirenone or levonorgestrel: results of a phase II dose-finding pilot study. Eur J Contracept Reprod Health Care 20 (2015), 476–489.
Apter, D, Zimmerman, Y, Beekman, L, Mawet, M, Maillard, C, Foidart, JM, et al. Estetrol combined with drospirenone: an oral contraceptive with high acceptability, user satisfaction, well-being and favourable body weight control. Eur J Contracept Reprod Health Care 22 (2017), 260–267.
Mawet, M, Maillard, C, Klipping, C, Zimmerman, Y, Foidart, JM, Coelingh Bennink, HJ, Unique effects on hepatic function, lipid metabolism, bone and growth endocrine parameters of estetrol in combined oral contraceptives. Eur J Contracept Reprod Health Care 20 (2015), 463–475.
Kluft, C, Zimmerman, Y, Mawet, M, Klipping, C, Duijkers, I, Neuteboom, J, et al. Reduced haemostatic effects with drospirenone-based oral contraceptives containing estetrol versus ethinyl estradiol. Contraception 95 (2017), 140–147.
Coelingh Bennink, HJT, Verhoeven, C, Zimmerman, Y, Visser, M, Foidart, JM, Gemzell-Danielsson, K, Pharmacodynamic effects of the fetal estrogen estetrol in postmenopausal women: results from a multiple-rising-dose study. Menopause 24 (2017), 677–685.
EudraCT 2016-004267-40. https://www.clinicaltrialsregister.eu/ctr-search/trial/2016-004267-40/results (accessed on November 24, 2020).
E4FREEDOM EU/Russia Study. ClinicalTrials.gov NCT02817828). https://www.clinicaltrials.gov/ct2/show/NCT02817828?term=estetrol&phase=2&draw=2&rank=3 (accessed on November 24, 2020).
E4FREEDOM United States/Canada Study (ClinicalTrials.gov NCT02817841) https://www.clinicaltrials.gov/ct2/show/NCT02817841?term=estetrol&phase=2&draw=2&rank=4 (accessed on November 24, 2020).
Hammond, GL, Hogeveen, KN, Visser, M, Coelingh Bennink, HJ, Estetrol does not bind sex hormone binding globulin or increase its production by human HepG2 cells. Climacteric 11:suppl 1 (2008), 41–46.
Douxfils, J, Klipping, C, Duijkers, I, Kinet, V, Mawet, M, Maillard, C, et al. Evaluation of the effect of a new oral contraceptive containing estetrol and drospirenone on hemostasis parameters. Contraception 102 (2020), 396–402.
Chen, L, Xu, J, Cai, S., The effect of dose-reduced combination oral contraceptives containing 20 µg of ethinyl estradiol and 100 µg of levonorgestrel on lipid metabolism: A meta-analysis. Am J Intern Med 4 (2016), 49–59.
Godsland, IF, Crook, D, Simpson, R, Proudler, T, Felton, C, Lees, B, et al. The effects of different formulations of oral contraceptive agents on lipid and carbohydrate metabolism. N Engl J Med 323 (1990), 1375–1381.
Sitruk-Ware, R, Nath, A., Metabolic effects of contraceptive steroids. Rev Endocr Metab Disord 12 (2011), 63–75.
Sitruk-Ware, R, Nath, A., Characteristics and metabolic effects of estrogen and progestins contained in oral contraceptive pills. Best Pract Res Clin Endocrinol Metab 27 (2013), 13–24.
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 71 (2005), 409–416.
Breech, LL, Braverman, PK., Safety, efficacy, actions, and patient acceptability of drospirenone/ethinyl estradiol contraceptive pills in the treatment of premenstrual dysphoric disorder. Int J Womens Health 1 (2010), 85–95.
