Control of side effects in strategy for increasing adherence to combined oral contraceptives. The role for a three-phase desogestrel-containing drug

Introduction. The frequency of side effects when taking combined oral contraceptives (COCs) is still high, which is the reason for refusal to take COCs by women worldwide with a frequency of 30 to 81 %. Management of side effects will help increase the user's adherence to the chosen method of contraception.

Aim: to identify approaches to prevent users from refusing to take COCs due to side effects and increase adherence to their use.

Materials and Мethods. The search for foreign literary sources in English was carried out in the international bases PubMed/MEDLINE, Google Scholar, Cochrane Library, in Russian in еLibrary database, by keywords: «hormonal contraception», «combined oral contraceptives», «side effects», «adherence». Search depth was 30 years (1992–2022). 437 and 74 articles were identified, respectively, of which the review included 44 manuscripts that satisfied the criteria for inclusion on the topic studied: full-text manuscripts with the results of original studies, systematic reviews and meta-analyses.

Results. In the literature, there is a lower incidence of side effects of COCs containing 30–35 µg of ethinylestradiol (tri- and monophasic) compared with 20 micrograms of ethinylestradiol. It was found that the risk of intermenstrual bleeding is 30 % lower when using COCs containing thirdgeneration progestogens compared with second-generation progestogens (relative risk (RR) = 0.71; 95 % confidence interval (CI) = 0.55–0.91) using monophasic combinations as an example. The use of a three-phase COC containing desogestrel (DSG) was characterized by a low incidence of irregular bleeding (3.3 % in the first cycle and a decrease to 2.3 % by the 12^th cycle), no effect on physiological parameters, a decrease in blood androgens content and a positive effect on seborrhea and acne, excellent tolerance (2.6% failures due to adverse events). Three-phase COCs are characterized by a lower frequency of intermenstrual bleeding (by 2 times) and amenorrhea (by 3 times) compared with other COCs. A positive effect on reducing the frequency of irregular spotting and breakthrough bleeding was shown when switching from a COC of another composition to a three-phase one containing DSG, and continuing to use it.

Conclusion. A three-phase COC containing DSG continues to be a topical hormonal contraceptive for women both for the first time and when switching from another COC due to side effects, including those associated with menstrual irregularities.

1. Schindler A.E., Campagnoli C., Druckmann R. et al. Classification and pharmacology of progestins. Maturitas. 2008;61(1):171–80. https://doi.org/10.1016/j.maturitas.2003.09.014.

2. Kulier R., Helmerhorst F.M., Maitra N., Gülmezoglu A.M. Effectiveness and acceptability of progestogens in combined oral contraceptives – a systematic review. Reprod Health. 2004;1(1):1–9. https://doi.org/10.1186/1742-4755-1-1.

3. Hooper D.J. Attitudes, awareness, compliance and preferences among hormonal contraception users: a global, cross-sectional, selfadministered, online survey. Clin Drug Investig. 2010;30(11):749–63. https://doi.org/10.2165/11538900-000000000-00000.

4. Prilepskaya V.N., Nazarova N.M., Tarasova M.A., Letunovskaya A.B. International project "CHOICE": a brief review of study results. [Mezhdunarodnyj proekt «CHOICE»: kratkij obzor rezul'tatov issledovaniya]. Ginekologiya. 2010;12(4):26–8. (In Russ.).

5. Zhuk S.I., Zakhurdaeva L.D. Features of modern counseling on contraception. [Osobennosti sovremennogo konsul'tirovaniya po voprosam kontracepcii]. Medicinskie aspekty zdorov'ya zhenshchiny. 2011;4(43):29–32. (In Russ.).

6. Moreau C., Cleland K., Trussell J. Contraceptive discontinuation attributed to method dissatisfaction in the United States. Contraception. 2007;76(4):267–72. https://doi.org/10.1016/j.contraception.2007.06.008.

7. Fait T., Buryak D., Cirstoiu M.-M. et al. Needs and preferences of women users of oral contraceptives in selected countries in Central and Eastern Europe. Drugs Context. 2018;7:212510. https://doi.org/10.7573/dic.212510.

8. Bahamondes L., Pinho F., de Melo N.R. et al. Associated factors with discontinuation use of combined oral contraceptives. Rev Bras Ginecol Obstet. 2011;33(6):303–9. [Article in Portuguese]. https://doi.org/10.1590/s0100-72032011000600007.

9. Pustotina O.A., Gereybekova E.R. Side effects of modern combined oral contraceptives. [Pobochnye effekty sovremennyh kombinirovannyh oral'nyh kontraceptivov]. Akusherstvo i ginekologiya. Novosti. Mneniya. Obuchenie. 2016;(3):96–102. (In Russ.).

10. Mynko O.I., Ashrafzyanova D.R., Lobanova V.V. Combined oral contraceptives: frequency of use and occurrence of side effects in women of reproductive age. [Kombinirovannye oral'nye kontraceptivy: chastota primeneniya i vozniknoveniya pobochnyh effektov u zhenshchin reproduktivnogo vozrasta]. ENIGMA. 2020;(26):105–14. (In Russ.).

11. Mack N., Crawford T.J., Guise J.M. et al. Strategies to improve adherence and continuation of shorter-term hormonal methods of contraception. Cochrane Database Syst Rev. 2019;4(4):CD004317. https://doi.org/10.1002/14651858.CD004317.pub5.

12. Poindexter A. The emerging use of the 20-microg oral contraceptive. Fertil Steril. 2001;75(3):457–6. https://doi.org/10.1016/s0015-0282(00)01747-7.

13. Edelman A., Micks E., Gallo M.F. et al. Continuous or extended cycle vs. cyclic use of combined hormonal contraceptives for contraception. Cochrane Database Syst Rev. 2014;2014(7):CD004695. https://doi.org/10.1002/14651858.CD004695.pub3.

14. Gallo M.F., Nanda K., Grimes D.A. et al. 20 µg versus >20 µg estrogen combined oral contraceptives for contraception. Cochrane Database Syst Rev. 2013;2013(8):CD003989. https://doi.org/10.1002/14651858.CD003989.pub5.

15. Carr B.R. Cycle control with desogestrel-containing oral contraceptives comparison of a monophasic and triphasic regimen. Int J Fertil Menopausal Stud. 1993;38(5):274–9.

16. Darney P. Safety and efficacy of a triphasic oral contraceptive containing desogestrel: results of three multicenter trials. Contraception. 1993;48(4):323–37. https://doi.org/10.1016/0010-7824(93)90078-l.

17. Ferguson H., Vree M.L., Wilpshaar J., Eskes T.K. Multicenter study of the efficacy, cycle control and tolerability of a phasic desogestrel-containing oral contraceptive. Eur J Contracept Reprod Health Care. 2000;5(1):35– 45. https://doi.org/10.1080/13625180008500378.

18. Coenen C.M., Thomas C.M., Borm G.F. et al. Changes in androgens during treatment with four low-dose contraceptives. Contraception. 1996;53(3):171–6. https://doi.org/10.1016/0010-7824(96)00006-6.

19. Katz H.I., Kempers S., Akin M.D. et al. Effect of a desogestrel-containing oral contraceptive on the skin. Eur J ContraceptReprod Health Care. 2000;5(4):248–55. https://doi.org/10.1080/13625180008500411.

20. Prilepskaya V.N., Serov V.N., Zharov E.V. et al. Effects of a phasic oral contraceptive containing desogestrel on facial seborrhea and acne. Contraception. 2003;68(4):239–45. https://doi.org/10.1016/s0010-7824(03)00167-7.

21. Kränzlin H.T., Nap M.A. The effect of a phasic oral contraceptive containing Desogestrel on seborrhea and acne. Eur J Contracept Reprod Health Care. 2006;11(1):6–13. https://doi.org/10.1080/13625180500252638.

22. Vartiainen M., de Gezelle H., Broekmeulen C.J. Comparison of the effect on acne with a combiphasicdesogestrel-containing oral contraceptive and a preparation containing cyproterone acetate. Eur J Contracept Reprod Health Care. 2001;6(1):46–53.

23. van Vloten W.A., van Haselen C.W., van Zuuren E.J. et al. The effect of 2 combined oral Contraceptives containing either drospirenone or cyproterone acetate on acne and seborrhea. Cutis. 2002;69(4 Suppl):2–15.

24. De Leo V., Di Sabatino A., Musacchio M.C. et al. Effect of oral contraceptives on markers of hyperandrogenism and SHBG in women with polycystic ovary syndrome. Contraception. 2010;82(3):276–80. https://doi.org/10.1016/j.contraception.2010.04.002.

25. van Vliet H.A., Grimes D.A., Lopez L.M. et al. Triphasic versus monophasic oral contraceptives for contraception. Cochrane Database Syst Rev. 2011; 2011(11):CD003553. https://doi.org/10.1002/14651858.CD003553.pub2.

26. American College of Obstetricians and Gynecologists’ Committee on Health Care for Underserved Women, Contraceptive Equity Expert Work Group, and Committee on Ethic. Patient-Centered Contraceptive Counseling. ACOG Committee Statement Number 1. Obstet Gynecol. 2022;139(2):350–3. https://doi.org/10.1097/AOG.0000000000004659.

27. Dinger J., Bardenheuer K., Heinemann K. Cardiovascular and general safety of a 24-day regimen of drospirenone-containing combined oral contraceptives: final results from the International Active Surveillance Study of Women Taking Oral Contraceptives. Contraception. 2014;89(4):253–63. https://doi.org/10.1016/j.contraception.2014.01.023.

28. Kashanian M., Shahpourian F., Zare O. A comparison between monophasic levonorgestrel-ethinyl estradiol 150/30 and triphasic levonorgestrel-ethinyl estradiol 50-75-125/30-40-30 contraceptive pills for side effects and patient satisfaction: a study in Iran. Eur J Obstet Gynecol Reprod Biol. 2010;150(1):47–51. https://doi.org/10.1016/j.ejogrb.2010.01.010.

29. Roumen F.J. Review of the combined contraceptive vaginal ring, NuvaRing. Ther Clin Risk Manag. 2008;4(2):441–51. https://doi.org/10.2147/tcrm.s1964.

30. Lawrie T.A., Helmerhorst F.M., Maitra N.K. et al. Types of progestogens in combined oral contraception: effectiveness and side-effects. Cochrane Database Syst Rev. 2011;(5):CD004861. https://doi.org/10.1002/14651858.CD004861.pub2.

31. Grossman BN. Managing adverse effects of hormonal contraceptives. Am Fam Physician. 2010;82(12):1499–506.

32. Foran T. The management of irregular bleeding in women using contraception. Aust Fam Physician. 2017;46(10):717–2

33. Oral contraceptive-related uterine bleeding management. Family Practice Notebook. Available at: https://fpnotebook.com/Gyn/Pharm/OrlCntrcptvRltdUtrnBldngMngmnt.htm.

34. Vree M.L., Schmidt J. A large observational clinical evaluation of a desogestrel-containing combiphasic oral contraceptive in Germany. Eur J Contracept Reprod Health Care. 2001;6(2):108–14.

35. Dikke G.B. Five steps to successful contraception: a guide for physicians. [Pyat' shagov k uspeshnoj kontracepcii. Rukovodstvo dlya vrachej]. Moscow, 2017. 379 p. (In Russ.).

36. Kuznetsova I.V. Metabolic effects of combined hormonal contraception and a risk for thrombotic events. [Metabolicheskie effekty kombinirovannoj gormonal'noj kontracepcii i risk tromboticheskih oslozhnenij]. Akusherstvo i ginekologiya. 2016;(6):108–14. (In Russ.). https://doi.org/10.18565/aig.2016.6.108-114.

37. Baerwald A.R., Pierson R.A. Ovarian follicular development during the use of oral contraception: a review. J Obstet Gynaecol Can. 2004;26(1):19–24. https://doi.org/10.1016/s1701-2163(16)30692-2/

38. Bastianelli C., Farris M., Rosato E. et al. Pharmacodynamics of combined estrogen-progestin oral contraceptives: 1. Effects on metabolism. Expert Rev Clin Pharmacol. 2017;10(3):315–26. https://doi.org/10.1080/17512433.2017.1271708.

39. Lobo R.A., Skinner J.B., Lippman J.S., Cirillo S.J. Plasma lipids and desogestrel and ethinyl estradiol: a meta-analysis. Fertil Steril. 1996;65(6):1100–9.

40. Silva-Bermudez L.S., Toloza F.J.K., Perez-Matos M.C. et al. Effects of oral contraceptives on metabolic parameters in adult premenopausal women: a meta-analysis. Endocr Connect. 2020;9(10):978–98. https://doi.org/10.1530/EC-20-0423.

41. Godsland I.F., Walton C., Felton C. et al. Insulin resistance, secretion, and metabolism in users of oral contraceptives. J Clin Endocrinol Metab. 1992;74(1):6470. https://doi.org/10.1210/jcem.74.1.1530790.

42. Gaspard U., Endrikat J., Desager J.P. 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;69(4):271–8. https://doi.org/10.1016/j.contraception.2003.11.003.

43. Adeyanju O.A., Olatunji L.A. Drospirenone-containing oral contraceptives do not affect glucose regulation and circulating corticosterone. J Bas Clinic Physiol Pharm. 2019;30(5):20180184. https://doi.org/10.1515/jbcpp-2018-0184.

44. Radzinskiy V.E., Khamoshina M.B., Abdullaeva R.G., Lebedeva M.G. Hormonal contraception – treatment and prevention of reproductive disorders in adolescent girls. [Gormonal'naya kontracepciya – lechenie i profilaktika reproduktivnyh narushenij u devushek-podrostkov]. Doktor.Ru. 2008;(6):54–8. (In Russ.)