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Home , Cyproterone acetate, Dienogest, Gestodene, List of antiandrogens, Nomegestrol acetate, Norelgestromin

Pharmacology Combined oral contraceptives

Dr Mary Stewart The pharmacology of combined oral contraceptive pills old and new. Medical Education Co-ordinator Family Planning NSW

Dr Betty Chaar Senior Lecturer, MPharm Co-ordinator, Faculty of Access to contraceptive choice is of oestrogen and and were associated with Pharmacy important for women, and their a relatively high risk of venous thromboembolic (VTE) and arterial University of Sydney partners, to control the number and a high likelihood of unwanted side-effects such as and spacing of their children. and tenderness. The risks have been reduced by Dr Deborah Bateson Contraceptives can be classified the development of COCs with lower doses of oestrogen and an Director of Clinical by their duration of action. Despite awareness of safe prescribing. Safe prescribing, taking a woman’s Services/Medical Director the increasing recognition that the risk factors in to account, remains paramount. Guidelines for Family Planning NSW long-acting reversible contraception the safe provision of contraception include the World Health (LARC) methods, namely implants, Organisation (WHO) Medical Eligibility Criteria (MEC)3 and UK- intrauterine methods and depot based MEC guidelines from the Faculty of Sexual and Reproductive injections, offer highly effective and cost-effective Health (FSRH).4,5 prevention across the reproductive lifespan, the combined (COC) remains the most commonly used method Developments in COC formulations by Australian women. Reasons for the relatively high use of the The earliest contraceptive pill was a progestogen-only formulation COC and low use of LARC, compared to similar developed at a dose that effectively inhibited although, in common countries appear to include lack of awareness and misconceptions with today’s progestogen-only contraceptives, it was associated by women and their healthcare providers, habitual prescribing with unpredictable ‘breakthrough’ resulting from an by GPs and an ability to stop and start the COC without medical unstable . Historically, the accidental contamination intervention.1 Additional non-contraceptive benefits of the COC, of some pill batches with oestrogen resulted in improved ‘cycle including control and an ability to manipulate bleeding control’ as well as enhanced contraceptive effectiveness – and as a patterns, can be attractive attributes for some women.2 result the ‘combined pill’ was born.2 The original COC contained norethynodrel, a derivative of 19-nor , and 150mcg of This article focuses on the pharmacology of the various combined , a of ethinyl oestradiol (EE).2 oral contraceptive (COC) pills available on the Australian market, with specific reference to their side-effect and risk profile. Newer were subsequently developed in an attempt to minimise androgenic and other troublesome side-effects The first COCs marketed in 1961 contained relatively high doses while the dose of EE was reduced to potentially lower the VTE risk and oestrogenic side-effects such as nausea and breast tenderness. All Microgynons/Levlen/Trifeme/Loette/ currently available COCs have an effect on Femmetab® metabolic parameters, including oestrogen- related increases in Sex Binding Globulin (SHBG), -Binding Brevinor/Norimin® Globulin (CBG) angiotensinogen and apolipoprotein A1 and a change in various / and fibrinolysis factors, which Marvelon/Minulet® are modulated by the combination and Ethinyl oestradiol dose of oestrogen and progestogen in 6 ® a given pill type. It is important to note, Diana/Estelle/Brenda/Juliet however, that the effects of hormonal combinations on metabolic markers for vascular disease do not always directly Yasmin/Yaz® translate into disease outcomes and controversy continues about the modulating effect of progestogen type on VTE risk. Valette® The dose effect of EE on VTE risk is clearer however with today’s low dose COCs, containing 35mcg of EE or less, posing a Oestradiol valerate ® Qlaira low VTE risk when appropriately prescribed. Since 2010 COCs containing either 17 β Oestradiol Nomegestrel acetate (NOMAc) oestradial or its prodrug oestradiol valerate in place of EE have been available. These Zoely® oestrogens are structurally identical to the 17 β oestradiol (E2) produced by the . Figure 1. COCP types in (not all generics are included). In the laboratory setting COCs with 17 β

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oestradiol/oestradiol valerate perform favourably compared with combination is quadriphasic with an increasing oestrogen and EE pills in relation to their effect on coagulation factors and decreasing progestogen dose through the pill pack. While all resistance. However we will need to wait some years until the COCs reduce menstrual blood loss and can be useful for the completion of post-marketing surveillance studies on these newer management of (HMB), both the pill formulations to see if these effects translate into improved 17β-oestrodiol and oestradiol valerate pills are associated with a health outcomes.2 high chance of an absent withdrawal bleed in the pill-free break. Qlaira has an additional indication for the management of HMB In relation to the COC progestogen component, earlier laboratory in women requiring contraception. and registry studies suggested that pills with levonorgestrel (LNG) are associated with a lower VTE risk than those containing newer In addition to their effect on blood loss, 17β-oestrodiol and its pro- progestogens. However, later large, well-designed cohort studies oestrodiol valerate, are associated with less pronounced effects have not confirmed a difference in risk between progestogen on haemostatic and lipid variables.6 Whereas EE increases VLDL types7 and a recent controlled, prospective, observational, active levels, 17β-oestradiol increases the HDL level without increasing the surveillance study of more than 85 000 women that compared a VLDL level.6 While the effects on laboratory-based vascular disease COC containing 30mcg EE and drospirenone in an extended 24- markers are favourable for these newer COCs, evidence for their day regimen to other commonly used COCs in a routine clinical effect on VTE and arterial vascular disease is pending. setting, supports a lack of difference in the risk of serious adverse cardiovascular events between available COC types.8 While all The progestogen component of the COC large database studies can be criticised for bias7, it is reasonable While itself cannot be used in the COC due to to conclude that a woman’s own underlying risk factors for VTE or its rapid , the synthetic progestogens in COCs arterial vascular disease have a much more significant impact on are structurally related either to progesterone ( and her risk than any differences between product constituents.6 19-norpregnanes) or to testosterone (T) ( and ), see Table 1. Several newer progestogens have been developed to The oestrogen component of the COC bind more selectively to the while minimising Figure 1 shows the constituents of most of the different COCs androgenic, oestrogenic and/or receptor interactions available in Australia. The majority contain the potent synthetic and their related potential side-effects.6 The earliest progestogens, EE which, as a result of its 17α ethinyl group, has a levonorgestrel (LNG) and norethisterone (NET) are derived from pronounced effect on hepatic metabolism. Today’s low-dose COCs testosterone. while the later progestogens have been derived from contain 35mcg or less of EE. It is unknown whether the lowest dose progesterone or its related , (see pill formulations available in Australia (with 20mcg EE) offer a safety Figure 2). benefit over those with 35 or 30mcg EE and any potential safety advantage must be offset by an increased chance of unpredictable Progestogens and vascular risk breakthrough bleeding.5 Progestogen-only contraceptives including the progestogen-only pills, the and LNG-releasing IUD, do not Administering EE via a non-oral route, as a or patch appear to increase the risk of VTE. Despite a growing body of (not currently available in Australia), does not appear to mitigate evidence pointing to a minimal role of progestogen type in the its hepatic impact6 with one study suggesting an increased risk of COC on VTE risk compared to oestrogen, this topic remains VTE for non-oral delivery methods.9 Earlier attempts to substitute controversial.7 Recurrent media scares about the pill and VTE EE with oestradiol, in an effort to potentially reduce cardiovascular risk create confusion and for women so it is essential for risk, had been thwarted owing to unfavourable bleeding patterns, doctors to provide clear balanced evidence-based information but this has been successfully overcome by novel combinations when prescribing contraception. The risk of VTE for women using with either desogestrel (Qlaira) or nomogestrol acetate (Zoely) any of the low-dose COCs (pills containing 35mcg or less of thanks to their strong anti-proliferative endometrial effect.10 The EE) appears to be approximately two-to-six fold2 compared to 17β-oestrodiol/nomogestrel acetate pill is monophasic (in other non-users which is substantially lower than the risk associated with words all pills contain the same hormonal dose) with a four-day pregnancy or the postnatal period. hormone-free break while the oestradiol valerate/desogestrel

Table 1. Pharmacologic classification of progestogens used in contraceptives (available contraceptives and contraceptive agents in development).6 Related to progesterone Related to testosterone Pure progestational (19nor-pregnanes) Partly estrogenic and androgenic (estranes) • Nestorone • Norethisterone • ac • Antiandrogenic Partly androgenic (gonanes) • Cyproterone Ac • Levonorgestrel • Nomegestrol Ac • Gestodene • Ac • Desogestrel► , • ► Partly Glucocorticoid Anti-androgenic (non-ethyl ) • Ac • Dienogest Related to Spironolactone Antialdosterone and antiandrogenic • Drospirenone

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Figure 2. The development of progestogens.

Despite the lack of strong evidence for a clinically relevant some anti-androgenic properties.15 In a randomised, open label, difference between progestogens, it is postulated that the more comparative trial evaluating effects on haemostasis, lipids, and androgenic progestogens, such as LNG and NET, are able to carbohydrate metabolism, NOMAc 2.5 mg/17β (E2) counteract the potent EE-induced stimulation of liver proteins and 1.5 mg showed less impact overall on as well as coagulation factors, while non or anti-androgenic progestogens other parameters than a COC containing LNG 150 mcg/EE 30 such as drospirenone have a limited mitigating effect on EE’s mcg per daily pill.16 action.6 The COCs which contain the anti- have also been associated with an increased risk of VTE Cyproterone acetate, an anti-androgen with weak progestogenic compared to LNG COCs11, although this information is based on activity, in combination with EE provides highly effective treatment relatively small case-control studies. for as well as providing effective contraception. COCs with anti-androgenic progestogens (drospirenone The most androgenic progestogens may be associated with or dienogest) or less androgenic progestogens (gestodene, impaired glucose tolerance and increased insulin resistance, desogestrel or NOMAc) also have a theoretical advantage for both risk factors for and Type II women who request treatment for androgenic symptoms. However, mellitus.6 Again, evidence for clinically relevant differences it is important to be aware that the oestrogenic component of all between progestogen types is lacking and the use of COCs in COCs is likely to improve acne via increased SHBG levels and a women with polycystic ovarian syndrome (PCOS) has not, for reduction of free testosterone, even at a low dose and even when example, been found to be associated with clinically significant combined with an androgenic progestogen. A Cochrane review adverse metabolic consequences.12 concluded that few important differences were found between COC types in their effectiveness for treating acne.5 In contrast to VTE risk, the delivery of oestrogen and progestogen vaginally via the EE/etonogestrel vaginal ring does not appear to In practice, the evidence for the benefit of one COC type affect insulin sensitivity.6 Progestogen-only pills, the contraceptive over another is often limited in relation to the management of implant and LNG-releasing IUD have a minimal effect on lipids.6 troublesome side-effects or for additional non-contraceptive benefits on acne and menstrual bleeding and it may be a matter of trial In practice, we can conclude that women with pre-existing risk and error in finding the most appropriate formulation to suit an factors for venous or arterial disease, which make the COC an individual woman. unsafe option, still have progestogen-only or non-hormonal highly effective methods to choose from (see Table 2). Conversely, Conclusion women with no contraindications to the use of oestrogen can While increasing awareness and uptake of LARC methods are likely potentially use any of the available COCs with choice being to impact on the proportion of women using the COC in the future, determined by side-effects, additional non-contraceptive benefits, many women will continue to choose an oral method of cost and personal preference. control. There have been significant changes to COC formulations over the past 50 years, including the development of progestogens Side-effects and non-contraceptive benefits with anti-androgenic activity and positive benefits on HMB, and the Drosperinone, dienogest and are newer replacement of EE with oestradiol. However, future developments progestogens designed to bind more specifically to the in are more likely to be related to progesterone receptor and to minimise side-effects related to alternative delivery systems, especially those which can be either androgenic, oestrogenic or interactions self-administered or minimise the woman’s need to interact with the experienced with the earlier progestogens.6 Drosperinone, a health system. derivative of spironolactone, counteracts the effect of EE-induced increases in angiotensin and production, which In the meantime, it remains imperative that COCs are prescribed 13 lead to water and salt retention. It also has anti-androgenic safely according to the WHO/FSRH Medical Eligibility Criteria. properties. Dienogest is a non-ethyl estrane progestogen Since differences between COC types as a result of their which has no androgenic action but rather an anti-androgenic progestogen and oestrogenic constituents appear to have little 14 effect. Nomegestrol acetate (NOMAc) is a derivative of impact on relative safety, COC choice for eligible women will 19-norprogesterone, with a strong anti-proliferative effect on therefore be based on individual preference in relation to potential the endometrium, producing good cycle control combined with side-effect profile, additional non-contraceptive benefits as well as

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Table 2 MEC* categories with risk factors for VTE (not including the first six weeks post-partum).5 Condition CHCs POPs ENG Cu-IUD LNG-EC implants, DMPA, LNG- IUD Past history of VTE 4 2 1 1 Current VTE, on anticoagulant 4 2 1 2 Family history of VTE First degree relative aged <45 3 1 1 1 First degree relative aged ≥45 years 2 1 1 1 Known thrombogenic mutation 4 2 1 1 BMI 30-34kg/m2 2 1 1 1 BMI ≥35kg/m2 3 1 1 1 Surgery with prolonged immobilisation 4 2 1 1 Surgery without prolonged immobilisation 2 1 1 1 Immobilisation unrelated to surgery 3 1 1 1 Thrombophlebitis 2 1 1 1

*MEC 1: a condition for which there is no restriction for the use of the contraceptive method MEC 2: a condition where the advantages of using the method generally outweigh the theoretical or proven risks MEC 3: a condition where the theoretical or proven risks usually outweigh the advantages of using the method MEC 4: a condition which represents an unacceptable health risk if the contraceptive method is used

cost. While the earlier LNG and NET COCs are subsidised by the Apr; 89(4): 253-63. doi: 10.1016/j.contraception.2014.01.023. PBS in Australia, subsidy of the newer formulations would require Epub 2014 Feb 4. a body of evidence demonstrating clinical and/or economic 9 Lidegaard O, Nielson L, Skovlund CW, Lokkegaard E. Venous superiority over the older established pill types. We await with in users of non-oral hormonal contraception: follow-up study, 2001- 10. BMJ 2012;344:e2990. interest the outcomes of post-marketing surveillance studies of the 10 Fruzzetti F, Trémollieres F, Bitzer J. An overview of the development of newer COC formulations. combined oral contraceptives containing estradiol: focus on /dienogest. Gynecol Endocrinol 2012;28:400-8. Doi: Acknowledgement 10.3109/09513590.2012.662547. The authors wish to thank Amanda Young, Family Planning NSW acting 11 Vasilakis-Scaramozza C, Jick H. Risk of venous thromboembolism librarian, for assistance with referencing. with cyproterone or levonorgestrel contraceptives. Lancet. 2001;358(9291):1427-9. References 12 Halperin IJ, Kumar SS, Stroup DF, Laredo SE. The association 1 Kirsten I Black, Deborah Bateson and Caroline Harvey. Australian between the combined oral contraceptive pill and insulin resistance, women need increased access to long-acting reversible contraception. dysglycemia and dyslipidemia in women with poly-cystic ovary Med J Aust 2013; 199 (5): 317-318. syndrome: a systematic review and meta-analysis of observational 2 Paula Briggs, Gabor Kovacs, John Guillebaud (editors) Contraception: studies. Hum Reprod. 2011;26:191-201. a casebook from menarche to . Cambridge: Cambridge 13 Oelkers W, Foidart JM, Dombrovicz N, et al. Effects of a new oral University Press, 2013. contraceptive containing an antimineralocorticoid progestogen, 3 World Health Organization. Medical eligibility criteria for drospirenone, on the renin-aldosterone system, body weight, blood contraceptive use. 4th ed. [Internet] Geneva: WHO; 2009 pressure, glucose tolerance, and lipid metabolism. J Clin Endocrinol [cited 2014 April 17]. Available from: http://whqlibdoc.who.int/ Metab. 1995;80:1816-21. publications/2010/9789241563888_eng.pdf . 14 Sasagawa S, Shimizu Y, Kami H, Takeuchi T, Mita S, Imada K, 4 Faculty of Family Planning and Reproductive Healthcare. UK medical et.al. Dienogest is a selective progesterone receptor in eligibility criteria for contraceptive use. [Internet] London: FSRH; transactivation analysis with potent oral endometrial activity due to its 2009 [cited 2014 April 17]. Available from: www.fsrh.org/pdfs/ efficient pharmacokinetic profile. . 2008;73:222-31. UKMEC2009.pdf . 15 Ruana X, Seegerb H, Mueck AO. The pharmacology of nomegestrol 5 Bateson D, Harvey C, McNamee K. Contraception: an Australian acetate. Maturitas. 2012;71:345-53. clinical practice handbook. 3rd ed. Brisbane 2012. 16 Ågren UM, Anttila M, Mäenpää-Liukko K, Rantala ML, Rautiainen H, 6 Sitruk-Ware R, Nath A. Metabolic effects of contraceptive steroids. Rev Sommer WF, Mommers E. Effects of a monophasic combined oral Endocr Metab Disord. 2011; 12:63–75. Doi: 10.1007/s11154-011- contraceptive containing nomegestrol acetate and 17β-oestradiol 9182-4. compared with one containing levonorgestrel and 7 Bitzer J. Position statement. Statement on combined hormonal on haemostasis, lipids and carbohydrate metabolism. Eur J contraceptives containing third- or fourth-generation progestogens or Contracept Reprod Health Care. 2011 Dec;16(6):444-57. Doi: cyproterone acetate, and the associated risk of thromboembolism. Eur 10.3109/13625187.2011.604450. J Contracept Reprod Health Care. 2013; 18:143-147. 8 Dinger J, Bardenheuer K, Heinemann K. Cardiovascular and general Permission granted for use by Family Planning NSW for educational safety of a 24-day regimen of drospirenone-containing combined oral purposes. © RANZCOG 2014 contraceptives: final results from the International Active Surveillance Study of Women Taking Oral Contraceptives. Contraception 2014

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