Oral Progestins in Hormonal Contraception: Importance and Future Perspectives of a New Progestin Only-Pill Containing 4 mg Drospirenone

 

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Abstract

Hormonal contraceptives are an effective and safe method for preventing pregnancy. Progestins used in contraception are either components of combined hormonal contraceptives (tablets, patches or vaginal rings) or are used as a single active ingredient in progestin mono-preparations (the progestin-only pill (POP), implants, intrauterine systems or depot preparations). Progestins are highly effective in long-term contraception when used properly, and have a very good safety profile with very few contraindications. A new oestrogen-free ovulation inhibitor (POP) has recently been authorised in the USA and the EU. This progestin mono-preparation contains 4 mg of drospirenone (DRSP), which has anti-gonadotropic, anti-mineralocorticoidic and anti-androgenic properties. The hormone administration regimen of 24 days followed by a 4-day hormone-free period was chosen to improve bleeding control and to maintain oestradiol concentrations at early follicular-phase levels, preventing oestrogen deficiency. Clinical trials have demonstrated a high contraceptive effectiveness, a very low risk of cardiovascular side effects and a favourable menstrual bleeding pattern. Due to the long half-life of DRSP (30 – 34 hours), the effectiveness of the preparation is maintained even if a woman forgets to take a pill on a single occasion. Studies involving deliberate 24-hour delays in taking a pill have demonstrated that ovulation inhibition is maintained if a single pill is missed. Following a summary of the current status of oestrogen-free contraception, this review article will describe the clinical development programme of the 4 mg DRSP mono-preparation and the resulting data on the effectiveness and safety of this new oestrogen-free oral hormonal contraceptive.

Publication History

Received: 04 February 2021

Accepted after revision: 28 March 2021

Article published online:
14 June 2021

© 2021. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commecial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/)

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

• References/Literatur

• 1 Schindler AE. Non-contraceptive benefits of oral hormonal contraceptives. Int J Endocrinol Metab 2013; 11: 41-47 DOI: 10.5812/ijem.4158.
  CrossrefPubMedGoogle Scholar
• 2 World Health Organization. Medical eligibility criteria for contraceptive use. 5th ed.. Geneva: WHO; 2015. Accessed March 08, 2021 at: https://www.who.int/publications/i/item/9789241549158
  Google Scholar
• 3 Khialani D, Rosendaal F, van Hylckama Vlieg A. Hormonal Contraceptives and the Risk of Venous Thrombosis. Semin Thromb Hemost 2020; 46: 865-871 DOI: 10.1055/s-0040-1715793.
  Article in Thieme ConnectPubMedGoogle Scholar
• 4 Lidegaard Ø, Nielsen LH, Skovlund CW. et al. Risk of venous thromboembolism from use of oral contraceptives containing different progestogens and oestrogen doses. BMJ 2011; 343: d6423 DOI: 10.1136/bmj.d6423.
  CrossrefPubMedGoogle Scholar
• 5 Lidegaard O, Nielsen LH, Skovlund CW. et al. Venous thrombosis in users of non-oral hormonal contraception: follow-up study, Denmark 2001–10. BMJ 2012; 344: e2990 DOI: 10.1136/bmj.e2990.
  CrossrefPubMedGoogle Scholar
• 6 Bundesinstitut für Arzneimittel und Medizinprodukte. Rote-Hand-Brief zu den kombinierten hormonalen Kontrazeptiva. Accessed December 13, 2020 at: http://www.bfarm.de/SharedDocs/Risikoinformationen/Pharmakovigilanz/DE/RHB/2014/rhb-khk.html
  PubMedGoogle Scholar
• 7 European Medicines Agency. Combined hormonal contraceptives. Accessed May 31, 2021 at: http://www.ema.europa.eu/en/medicines/human/referrals/combined-hormonal-contraceptives
  PubMedGoogle Scholar
• 8 Schindler AE, Campagnoli C, Druckmann R. et al. Classification and pharmacology of progestins. Maturitas 2008; 61: 171-180 DOI: 10.1016/j.maturitas.2008.11.013.
  CrossrefPubMedGoogle Scholar
• 9 Regidor PA, Schindler AE. Antiandrogenic and antimineralocorticoid health benefits of COC containing newer progestins: dienogest and drospirenone. Oncotarget 2017; 8: 83334-83342 DOI: 10.18632/oncotarget.19833.
  CrossrefPubMedGoogle Scholar
• 10 Römer T, Göretzlehner G. Kontrazeption mit OC in 238 Problemsituationen. 3rd ed.. ed. Berlin: De Gruyter; 2017: 3-320
  Google Scholar
• 11 Ahrendt HJ, Bühling KJ. Estrogen Free Contraception: progestin-only systems. J Reprod Med Endocrinol 2010; 7 (Sonderheft 1): 97-105
  PubMedGoogle Scholar
• 12 World Health Organization, Johns Hopkins Bloomberg School of Public Health. Family Planning: A Global Handbook for Providers. 3rd ed.. 2018. Accessed May 31, 2021 at: https://apps.who.int/iris/bitstream/handle/10665/260156/9780999203705-eng.pdf?s
  Google Scholar
• 13 van Hylckama Vlieg A, Helmerhorst FM, Rosendaal FR. The risk of deep venous thrombosis associated with injectable depot-medroxyprogesterone acetate contraceptives or a levonorgestrel intrauterine device. Arterioscler Thromb Vasc Biol 2010; 30: 2297-2300 DOI: 10.1161/ATVBAHA.110.211482.
  CrossrefPubMedGoogle Scholar
• 14 AWMF. AWMF guideline hormonal contraception 2020. Accessed July 06, 2020 at: https://www.awmf.org/leitlinien/detail/ll/015-015.html
  PubMedGoogle Scholar
• 15 Bachmann G, Korner P. Bleeding patterns associated with non-oral hormonal contraceptives: a review of the literature. Contraception 2009; 7: 247-258 DOI: 10.1016/j.contraception.2008.10.012.
  CrossrefPubMedGoogle Scholar
• 16 Hsia JK, Creinin MD. Intrauterine Contraception. Semin Reprod Med 2016; 34: 175-182 DOI: 10.1055/s-0036-1571438.
  Article in Thieme ConnectPubMedGoogle Scholar
• 17 World Health Organization. WHO Pharmaceuticals Newsletter No. 6, 2019. Licence: CC BY-NC-SA 3.0 IGO. Geneva: World Health Organization; 2019
  Google Scholar
• 18 Fachinformation 28 mini^®; November 2019.
  PubMedGoogle Scholar
• 19 Cerazette® Summary of product characteristics 2020. May 2020. Accessed May 31, 2021 at: https://www.medicines.org.uk/emc/product/1698/smpc#gref
  PubMedGoogle Scholar
• 20 Lidegaard Ø, Løkkegaard E, Jensen A. et al. Thrombotic stroke and myocardial infarction with hormonal contraception. N Engl J Med 2012; 366: 2257-2266 DOI: 10.1056/NEJMoa1111840.
  CrossrefPubMedGoogle Scholar
• 21 de Melo NR. Estrogen-free oral hormonal contraception: benefits of the progestin-only pill. Womens Health (Lond) 2010; 6: 721-735 DOI: 10.2217/whe.10.36.
  CrossrefPubMedGoogle Scholar
• 22 Smith OP, Critchley HO. Progestogen only contraception and endometrial break through bleeding. Angiogenesis 2005; 8: 117-126 DOI: 10.1007/s10456-005-9003-z.
  CrossrefPubMedGoogle Scholar
• 23 Villavicencio J, Allen RH. Unscheduled bleeding and contraceptive choice: increasing satisfaction and continuation rates. Open Access J Contracept 2016; 7: 43-52 DOI: 10.2147/OAJC.S85565.
  CrossrefPubMedGoogle Scholar
• 24 Skovlund CW, Mørch LS, Kessing LV. et al. Association of Hormonal Contraception With Depression. JAMA Psychiatry 2016; 73: 1154-1162 DOI: 10.1001/jamapsychiatry.2016.2387. Erratum in: JAMA Psychiatry 2017; 74: 764
  CrossrefPubMedGoogle Scholar
• 25 Mitchell VE, Welling LLM. Not All Progestins are Created Equally: Considering Unique Progestins Individually in Psychobehavioral Research. Adaptive Human Behavior and Physiology 2020; 6: 381-412 DOI: 10.1007/s40750-020-00137-1.
  CrossrefPubMedGoogle Scholar
• 26 Hadji P, Colli E, Regidor PA. Bone health in estrogen-free contraception. Osteoporos Int 2019; 30: 2391-2400 DOI: 10.1007/s00198-019-05103-6.
  CrossrefPubMedGoogle Scholar
• 27 Jenapharm GmbH & Co KG. Yaz. Summary of product characteristics. July 2020. Accessed May 31, 2021 at: https://db.cbg-meb.nl/mri/spc/nlh-1269-001.pdf
  PubMedGoogle Scholar
• 28 Theramex Ireland Limited. Zoely. Summary of product characteristics. June 2020. Accessed May 31, 2021 at: http://www.medicines.org.uk/emc/product/3038/smpc
  PubMedGoogle Scholar
• 29 Regidor PA. The clinical relevance of progestins in hormonal contraception: present status and future developments. Oncotarget 2018; 9: 34628-34638 DOI: 10.18632/oncotarget.26015.
  CrossrefPubMedGoogle Scholar
• 30 Fuhrmann U, Krattenmacher R, Slater EP. et al. The novel progestin drospirenone and its natural counterpart progesterone: biochemical profile and antiandrogenic potential. Contraception 1996; 54: 243-251 DOI: 10.1016/s0010-7824(96)00195-3.
  CrossrefPubMedGoogle Scholar
• 31 Krattenmacher R. Drospirenone: pharmacology and pharmacokinetics of a unique progestin. Contraception 2000; 62: 29-38 DOI: 10.1016/s0010-7824(00)00133-5.
  CrossrefPubMedGoogle Scholar
• 32 Richter WH, Koytchev R, Kirkov V. et al. Comparative pharmacokinetic estimates of drospirenone alone and in combination with ethinyl estradiol after single and repeated oral administration in healthy females. Contraception 2020; 101: 137-143 DOI: 10.1016/j.contraception.2019.10.005.
  CrossrefPubMedGoogle Scholar
• 33 Rohn KJ, Cook IT, Leyh TS. et al. Potent inhibition of human sulfotransferase 1A1 by 17α-ethinylestradiol: role of 3′-phosphoadenosine 5′-phosphosulfate binding and structural rearrangements in regulating inhibition and activity. Drug Metab Dispos 2012; 40: 1588-1595 DOI: 10.1124/dmd.112.045583.
  CrossrefPubMedGoogle Scholar
• 34 Duijkers IJ, Heger-Mahn D, Drouin D. et al. A randomised study comparing the effect on ovarian activity of a progestogen-only pill (POP) containing desogestrel and a new POP containing drospirenone in a 24/4 regimen. Eur J Contracept Reprod Health Care 2015; 20: 419-427 DOI: 10.3109/13625187.2015.1044082.
  CrossrefPubMedGoogle Scholar
• 35 Duijkers IJM, Heger-Mahn D, Drouin D. et al. Maintenance of ovulation inhibition with a new progestogen-only pill containing drospirenone after scheduled 24-h delays in pill intake. Contraception 2016; 93: 303-309 DOI: 10.1016/j.contraception.2015.12.007.
  CrossrefPubMedGoogle Scholar
• 36 Rice CF, Killick SR, Dieben T. et al. A comparison of the inhibition of ovulation achieved by desogestrel 75 mg and levonorgestrel 30 mg daily. Hum Reprod 1999; 14: 982-985 DOI: 10.1093/humrep/14.4.982.
  CrossrefPubMedGoogle Scholar
• 37 Archer DF, Ahrendt HJ, Drouin D. Drospirenone-only oral contraceptive: results from a multicenter noncomparative trial of efficacy, safety and tolerability. Contraception 2015; 92: 439-444
  CrossrefPubMedGoogle Scholar
• 38 Palacios S, Colli E, Regidor PA. Multicenter, phase III trials on the contraceptive efficacy, tolerability and safety of a new drospirenone-only pill. Acta Obstet Gynecol Scand 2019; 98: 1549-1557 DOI: 10.1016/j.contraception.2015.07.014.
  CrossrefPubMedGoogle Scholar
• 39 Kimble T, Burke AE, Barnhart KT. et al. A 1-year prospective, open-label, single-arm, multicenter, phase 3 trial of the contra- ceptive efficacy and safety of the oral progestin-only pill drospirenone 4 mg, using a 24/4-day regimen. Contraception 2020; 2: 100020 DOI: 10.1016/j.conx.2020.100020.
  CrossrefPubMedGoogle Scholar
• 40 Regidor PA, Colli E, Schindler AE. Drospirenone as estrogen-free pill and hemostasis: coagulatory study results comparing a novel 4 mg formulation in a 24 + 4 cycle with desogestrel 75 µg per day. Gynecol Endocrinol 2016; 32: 749-751 DOI: 10.3109/09513590.2016.1161743.
  CrossrefPubMedGoogle Scholar
• 41 Palacios S, Colli E, Regidor PA. Efficacy and cardiovascular safety of the new estrogen-free contraceptive pill containing 4 mg drospirenone alone in a 24/4 regime. BMC Womens Health 2020; 20: 218 DOI: 10.1186/s12905-020-01080-9.
  CrossrefPubMedGoogle Scholar
• 42 Oelkers W, Foidart JM, Dombrovicz N. et al. Effects of a new oral contraceptive containing an antimineralocorticoid progestin, drospirenone, on the renin–aldosterone system, body weight, blood pressure, glucose tolerance, and lipid metabolism. J Clin Endocrinol Metab 1995; 80: 1816-1821 DOI: 10.1210/jcem.80.6.7775629.
  CrossrefPubMedGoogle Scholar
• 43 Gaspard U, Scheen A, Endrikat J. 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 2003; 67: 423-429 DOI: 10.1016/s0010-7824(02)00537-1.
  CrossrefPubMedGoogle Scholar
• 44 Doran PM, Riggs BL, Atkinson EJ. et al. Effects of raloxifene, a selective estrogen receptor modulator, on bone turnover markers and serum sex steroid and lipid levels in elderly men. J Bone Miner Res 2001; 16: 2118-2125 DOI: 10.1359/jbmr.2001.16.11.2118.
  CrossrefPubMedGoogle Scholar
• 45 Foidart JM, Faustmann T. Advances in hormone replacement therapy: weight benefits of drospirenone, a 17a-spirolactone- derived progestogen. Gynecol Endocrinol 2007; 23: 692-699 DOI: 10.1080/09513590701582323.
  CrossrefPubMedGoogle Scholar
• 46 Palacios S, Colli E, Regidor PA. A multicenter, double-blind, randomized trial on the bleeding profile of a drospirenone-only pill 4 mg over nine cycles in comparison with desogestrel 0.075 mg. Arch Gynecol Obstet 2019; 300: 1805-1812 DOI: 10.1007/s00404-019-05340-4.
  CrossrefPubMedGoogle Scholar
• 47 Palacios S, Colli E, Regidor PA. Bleeding profile of women using a drospirenone-only pill 4 mg over nine cycles in comparison with desogestrel 0.075 mg. PLoS One 2020; 15: e0231856 DOI: 10.1371/journal.pone.0231856.
  CrossrefPubMedGoogle Scholar
• 48 Regidor PA, Colli E, Georgiev D. et al. Safety, influence on the endometrium, sonographic changes and bleeding profile after 13 cycles with the new drospirenone only pill (DOP) for contraception. Horm Mol Biol Clin Investig 2020; DOI: 10.1515/hmbci-2019-0061.
  CrossrefPubMedGoogle Scholar
• 49 Apter D, Colli E, Gemzell-Danielsson K. et al. Multicenter, open-label trial to assess the safety and tolerability of drospirenone 4.0 mg over 6 cycles in female adolescents, with a 7-cycle extension phase. Contraception 2020; 101: 412-419 DOI: 10.1016/j.contraception.2020.02.004.
  CrossrefPubMedGoogle Scholar
• 50 Ng M, Fleming T, Robinson M. et al. Global, regional, and national prevalence of overweight and obesity in children and adults during 1980–2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet 2014; 384: 766-781 DOI: 10.1016/S0140-6736(14)60460-8.
  CrossrefPubMedGoogle Scholar
• 51 Melka D, Kask K, Colli E. et al. A single-arm study to evaluate the transfer of drospirenone to breast milk after reaching steady state, following oral administration of 4 mg drospirenone in healthy lactating female volunteers. Womens Health (Lond) 2020; 16: 1745506520957192 DOI: 10.1177/1745506520957192.
  CrossrefPubMedGoogle Scholar
• 52 Exeltis. Slynd. 2019. Accessed at: http://www.drugs.com/pro/slynd.html
  PubMedGoogle Scholar