Case scenario

Amanda, 27, visits your pharmacy to buy condoms. She mentions to you that she is getting married in a couple of months and that, as luck would have it, her menstrual period is due the day before her wedding. She asks if there is anything she can do to delay her period until after her honeymoon – the week after the wedding.

Learning objectives

After successful completion of this CPD activity, pharmacists should be able to:

  • Describe the properties of various steroid compounds used in oral contraceptive pills available in Australia
  • Discuss the complimentary effects of estrogens and progestogens when used in combined oral contraceptive pills
  • Describe how pharmacists can help women using oral contraception.

Competency standards (2016) addressed: 1.1, 1.4, 1.5, 2.2, 3.1, 3.5

Already read the CPD in the journal? Scroll to the bottom to SUBMIT ANSWERS. 

Introduction

When oral contraceptive pills are taken correctly, they provide up to 99% protection from conception, though the typical effectiveness in real-life users is closer to 91%.1 Focus has shifted recently to the advantages of long-acting reversible contraceptives, such as intrauterine devices and contraceptive implants, because of their convenience and higher efficacy. A 2012 survey2 indicated that approximately 70% of more than 3,900 contraceptive consultations in Australian general practice settings were related to oral contraception, suggesting that oral contraception remains an important option for Australian women. Knowledge of the differences between various preparations of combined oral contraceptive pills (COCPs), and their non-contraceptive benefits, can help pharmacists guide women in their use. Progestogen-only pills (POPs) are also an important option for women who have medical contraindications to estrogen use. 

The choice of progestogen 

The existence of progestogen-only pills underlines the fact that it is the progestogen which confers the primary contraceptive effect. The term ‘progestogen’ refers to both natural progesterone, which is not used in oral contraception due to poor absorption, and the synthetically produced compounds developed to mimic its effects.3 At an adequate dose, progestogens supress the production of luteinising hormone (LH), preventing effective ovulation.3 Progestogens also have secondary effects, augmenting their effect on ovulation. They thicken cervical mucus, making sperm penetration more difficult, and make the uterine lining less favourable for pregnancy.3 Figure 1 shows the derivation of progestogens used in COCPs currently available in Australia. 

Progestogens derived from 17-acetoxyprogesterone more closely resemble natural progesterone. Both cyproterone acetate and nomegestrol acetate also have anti-androgenic properties, blocking the actions of naturally circulating androgens.5 Like their parent compound, most of the progestogens derived from 19-nortestosterone have androgenic qualities, though dienogest has been chemically manipulated to make it anti-androgenic. Theoretically the more androgenic progestogens may inhibit the expected positive effects of estrogen on acne and hirsutism. 

Drospirenone is a unique progestogen derived from the diuretic spironolactone; it retains both the anti-androgenic and anti-mineralocorticoid qualities of its parent compound.5 

The fall in progestogen, which occurs at the end of active pills in COCPs, initiates cyclical shedding of the uterine lining. All progestogens suppress the thickening of the uterine lining which would normally occur prior to ovulation. This is why scheduled bleeds on the COCP tend to be shorter, lighter and less painful than a normal menstrual period. This is beneficial for many women, particularly those with heavier menstrual bleeding. 

Conventional POPs have no scheduled breaks from active pill taking, and therefore any bleeding on these preparations is largely determined by the woman’s own endogenous estrogen levels. 

Figure 1 – Origin of progestogens

Reference: adapted from Sitruk-Ware4

The older progestogens 

Preparations containing the older progestogens – norethisterone and levonorgestrel – are generally considered first-line for women wishing to commence oral contraception.6 

COCPs containing norethisterone and levonorgestrel 

Norethisterone was first synthesised in the 1950s. Its relatively short half-life makes it less forgiving in terms of efficacy in the event of late or missed pills.7 

With lower-dose norethisterone pills (500 micrograms norethisterone/35 micrograms ethinylestradiol [EE]) breakthrough bleeding is common, particularly in the first few months of use. However, at the same estrogen dose, 1 mg norethisterone profoundly suppresses the endometrium, and scheduled withdrawal bleeding may be extremely light or even disappear over time. 

Though alarming for some women, a lack of withdrawal bleeding causes no medical problems and has no association with future fertility. Alternatively, this effect may make norethisterone COCPs a good choice for women who wish to run several packs together to reduce the number of scheduled withdrawal bleeds. There is no absolute time limit for extended COCP use, though irregular bleeding is more common the longer that it is continued.

Preparations containing norethisterone tend to be estrogen dominant. In fact, a small fraction of norethisterone is converted metabolically to EE, which may enhance this estrogenic balance.8 Though a Cochrane review suggests most COCPs are likely to result in an overall improvement in skin problems,9 the estrogen dominance of preparations containing norethisterone may make them a useful first choice in patients with acne for whom a PBS-listed preparation is preferred.

Levonorgestrel was first synthesised in the early 1960s and is currently the progestogen against which others are measured. Levonorgestrel is a relatively potent progestogen, and estrogenic  adverse effects – such as breast tenderness and nausea – are uncommon in women using standard or low-dose levonorgestrel preparations. When combined with 30 micrograms EE, levonorgestrel provides excellent cycle control and predictable withdrawal bleeds. However, at the lower dose of 20 micrograms EE, irregular bleeding can be a problem, particularly initially.10,11 Levonorgestrel appears to counteract the effect of estrogen on sex hormone binding globulin (SHBG), potentially allowing for higher circulating free natural androgens.12 It may therefore be a useful choice in women who have experienced decreased libido on other preparations. Unfortunately, in some women, this more ‘androgenic’ balance can cause other adverse effects, such as mood changes, weight gain and acne.13

Both norethisterone and levonorgestrel can have adverse effects on lipid balance, increasing low-density lipoprotein and decreasing high-density lipoprotein.14 

Progestogen-only pills containing norethisterone or levonorgestrel

Conventional POPs containing either 350 micrograms norethisterone or 30 micrograms levonorgestrel have been marketed in Australia since the 1970s. At this dose of progestogen, 40–50% of women still ovulate, and the main contraceptive effect is achieved through effects on cervical mucus and the endometrium. Timing is critical for those using norethisterone or levonorgestrel POPs, since there is only a 3-hour window for retaining contraceptive cover in the case of a late pill.4 Variable effects on ovulation make unpredictable bleeding a problem, though if an unsatisfactory bleeding pattern occurs on one POP, it is worth trying the other progestogen.6 

There are few medical contraindications to the use of POPs, but the unpredictable bleeding pattern and strict time constraints mean that POPs are often perceived as second-line contraceptive pills, used mainly during lactation and when COCPs are unsuitable.5 

Both combined and progestogen-only pills containing norethisterone and levonorgestrel are listed on the PBS in Australia.

The newer progestogens

Available since the 1970s, the properties of the newer progestogens vary widely. Progestogens in this group include: desogestrel, gestodene, dienogest, drospirenone, cyproterone acetate and nomegestrol acetate. Developed to have less progestogenic/androgenic adverse effects, it is possible they may not counterbalance the effect of the estrogen component of a COCP as effectively as norethisterone or levonorgestrel. Newer progestogens may be associated with a higher risk of venous thromboembolism (VTE),15–18 though other large studies have found no significant increase in VTE risk.19–23 Newer progestogens appear to have less adverse effect on lipids than the older progestogens; it is unclear if this translates into clinical benefit.14 

Cyproterone acetate, drospirenone, dienogest and nomegestrol acetate have an affinity for both progesterone and androgen receptors, blocking the action of naturally circulating androgens. Theoretically, the use of an anti-androgenic progestogen in a COCP should enhance the effect of estrogen on acne management and hirsutism, though the evidence for this is limited.9 

However, if a patient has moderate acne, hirsutism or has failed to achieve sufficient improvement in their symptoms after 3 months of using an alternative COCP, a trial of an anti-androgenic progestogen is worthwhile.5 

Preparations containing cyproterone acetate are indicated primarily as anti-androgenic therapy, with their contraceptive effect seen as a secondary benefit.5 They are not regarded as an optimal long-term contraceptive option and require regular clinical review.

Women who experience significant fluid retention on other COCPs may find a preparation containing drospirenone (preferably at the lowest dose of estrogen) useful due to its inherent diuretic effect.5 Currently, none of the COCPs containing a newer progestogen is PBS-listed.

Like norethisterone, both dienogest and nomegestrol acetate have a profoundly suppressive effect on the endometrium, and many women experience extremely light or absent withdrawal bleeding while using COCPs containing these progestogens. They therefore should be considered for women experiencing poor cycle control on other COCPs or for those who wish to consider extended cycling. 

The progestogen in COCPs primarily influences glucose metabolism and insulin resistance.24 This impact on insulin resistance varies with both the dose and type of progestogen, with levonorgestrel, desogestrel, gestodene and dienogest causing the greatest effect, and cyproterone acetate and nomegestrol acetate the least.25 COCPs containing nomegestrol acetate may be a good choice for women with risk factors for insulin resistance.26

Newer progestogen-only pills

A POP containing 75 micrograms desogestrel is available in some countries, though currently not in Australia. Like conventional POPs, it contains 28 active tablets, which are taken continuously.27 However, unlike conventional POPs, there is a 12-hour leeway for late pills.27 The bleeding pattern remains unpredictable, though there is a trend to less bleeding over time.

A 4 mg drospirenone POP became available in Australia in August 2021. This POP has a 24-hour leeway for late pills before contraceptive cover is lost.28 Unlike other POPs, this preparation has 24 active pills and 4 green placebo pills.28 This is designed to facilitate regular scheduled bleeding, though bleeding has been found to decrease over time. After 12 months of use, up to 68% of women have no bleeding.29–31 In clinical trials, about 3–5% of women discontinued use of the drospirenone POP due to unacceptable bleeding.29–31

Both of these newer POPs reliably suppress ovulation, which makes them as effective as a COCP in typical use. 

Table 1 – Some medicines that may reduce the efficacy of oral contraceptives

MEDICINE CLASS MEDICINES
Antiepileptic medicines
  • carbamazepine
  • lamotrigine
  • oxcarbazepine
  • phenobarbital
  • phenytoin
  • primidone
  • rufinamide
  • topiramate
Antibacterials
  • rifabutin
  • rifampicin
HIV-protease inhibitors
  • HIV-protease inhibitors with or without low-dose ritonavir 
  • atazanavir
  • ritonavir and combination regimens with ritonavir
Non-nucleoside reverse transcriptase inhibitors
  • efavirenz
  • nevirapine
Herbal medicines
  • St John’s wort (Hypericum)
Other
  • aprepitant
  • bosentan
  • griseofulvin
  • lumacaftor
  • modafinil

Reference: AMH5, FSRH38 Note: This list is not exhaustive. Pharmacists should consult a reliable reference source for a complete list of potential interactions before supply of a medicine.

Why add estrogen to the mix?

Estrogens enhance the contraceptive effect of progestogens by suppressing follicle stimulating hormone (FSH), which prevents the development of a mature ovum. Estrogens also have intrinsic beneficial effects on acne and hirsutism, though improvements in these symptoms may take several months to occur. The main reason estrogen was added to the COCP was to stabilise the endometrium to avoid the irregular bleeding pattern seen in POPs. Unfortunately, estrogen is responsible for serious adverse effects, such as blood clots and stroke. Other adverse effects due to estrogen use include breast tenderness, nausea and fluid retention.5

Choice of estrogen

EE was one of the first synthetic estrogens developed in the 1960s and is still found in the majority of COCPs used in Australia today. It is more resistant to liver metabolism than natural estradiol, giving it a long half-life of around 24 hours.15 

EE also promotes the production of SHBG in the liver. SHBG binds circulating androgens, making them less available to act on androgen receptors. This enhances EE’s intrinsic positive effects on acne and hirsutism. 

Modern COCPs have only a fraction of the estrogen dose of the pills used in the 1960s. This has reduced the risk of serious adverse effects (e.g. VTE) without significantly impacting contraceptive efficacy.32–34 The dose of estrogen in the COCP makes the pill high or low dose. ‘High dose’ COCPs have an EE dose of 50 micrograms or more and are rarely used today.5 Standard-dose COCPs have an EE dose of 30–35 micrograms, and ‘low dose’ COCPs have an EE dose of ≤20 micrograms.5 Preparations containing 50 micrograms of mestranol are equivalent to about 35 micrograms of EE.5

More recently estradiol and estradiol valerate have been used as the estrogen component in some COCPs. Once metabolised, these estrogens are identical to the 17β-oestradiol produced naturally by women. Both estradiol preparations deliver an estrogen dose equivalent to around 20 micrograms of EE – making them ‘low dose’ preparations. 

To enable effective cycle control using these relatively weak estrogens, it is critical that they are paired with a very suppressive progestogen. Light or absent withdrawal bleeding is not uncommon on both estradiol and estradiol valerate preparations. Estradiol also has less effect on SHBG levels than EE. Though evidence is limited, less suppression of androgen levels could potentially have less impact on libido. However, it may also mean less beneficial effects on acne and hirsutism than is seen in pills containing EE. Estradiol has been shown to support bone density more effectively than EE.35 This may make it a better option in very young or underweight women, and perhaps in the years leading up to menopause.

The US has recently approved a new COCP that uses estetrol as its estrogen component. First discovered in 1965, estetrol is only produced in nature by the foetal liver during pregnancy. It works selectively on different estrogen receptors, and animal studies indicate a less proliferative effect on normal breast epithelial cells.36 However, it is unclear if this translates into a lower breast cancer risk than seen with conventional COCPs. Estetrol does not appear to increase SHBG, making it less likely to affect circulating androgen levels. It also appears to have less impact on coagulation factors and haemostasis than either EE or estradiol. It is unclear when preparations containing estetrol will be marketed in Australia. 

Table 2 – Options that may help manage some adverse effects associated with COCP use

SITUATION SUGGESTED MANAGEMENT
Nausea (exclude pregnancy)
  • take COCP at night after main meal
  • reduce the estrogen dose
  • change to a vaginal ring with steady-state delivery
  • consider switch to progestogen-only contraceptive method
Breast tenderness
  • reduce estrogen and/or progestogen dose
  • change to a more potent progestogen such as levonorgestrel or to drospirenone which has a mild diuretic effect
  • change to a vaginal ring with steady-state delivery 
  • consider switch to progestogen-only contraceptive method
Bloating and fluid retention
  • reduce estrogen dose 
  • change to preparation containing drospirenone
  • change to a vaginal ring with steady-state delivery
  • consider switch to progestogen-only contraceptive method
Persistent breakthrough bleeding beyond first  3 months of use or occurring later as a new symptom
  • exclude other causes (e.g. chlamydia infection)
  • check adherence and for drug interactions, specifically with medicines that can interfere with absorption
  • change to a different progestogen (preferably more endometrially suppressive such as norethisterone/ nomegestrol acetate/dienogest)
  • consider vaginal ring with steady-state delivery system
  • consider increase in estrogen dose from low to standard dose; as a last resort, consider increase from standard to high dose. Use of >50 microgram EE is not recommended due to increased risk of VTE
Missed (or very light) periods which are of concern to patient
  • exclude possible pregnancy
  • change to alternative progestogen (e.g. levonorgestrel)
  • change from an estradiol COCP to EE COCP
  • consider increase in estrogen dose from low to standard dose; as a last resort, consider increase from standard to high dose. Use of >50 microgram EE is not recommended due to increased risk of VTE
Headache/migraine during pill-free week (if migraine with aura occurs, cease COCP)
  • consider COCP with shorter (2–4 day) pill-free interval
  • consider extended regimen use of the COCP
  • consider progestogen-only contraceptive method
Persisting acne/hirsutism beyond 6 months of use
  • change to a progestogen with an anti-androgenic effect
  • change formulation; consider use of a less potent progestogen (e.g. norethisterone)
  • consider increase in estrogen dose from low to standard dose; as a last resort, consider increase from standard to high dose. Use of >50 microgram EE is not recommended due to increased risk of VTE 
Decreased libido
  • change progestogen; try levonorgestrel or estradiol pill
  • change to a levonorgestrel POP or non-hormonal method 

Note: Recommendations in this table are based on relatively low-level evidence. Reference: AMH,5 Therapeutic Guidelines,6 Barr N,39 Edlow A,40 Van den Heuvel,41 Stachenfeld NS,42 Oddsson K,43 Edelman AB,44 Lawrie TA,45 Mansour D,46 Ahrendt HJ,47 

Knowledge to practice

Any discussion of oral contraception with patients should occur within a broader discussion of the range of contraceptive options available in Australia. In the absence of any contraindications to the COCP, it is recommended that a woman start with a standard-dose estrogen preparation containing either levonorgestrel or norethisterone.5 All women commencing the COCP should be warned of symptoms that might suggest VTE or stroke, since the incidence of these is highest in the first 3–4 months or when restarting after a break.37

Most pill failures result from human error, therefore the discussion should include methods to reduce the risk of late or missed pills, and women should be informed of the use of emergency contraception as a backup. 

All women should be reminded that oral contraception is a medicine and it is important they report its use during any medical interactions. They should also be informed that some medicines (see Table 1) may make oral contraceptives less effective.

The adverse effect profile of any COCP is determined by the balance between the dose and the qualities of the estrogen and progestogen used. Since the choice of estrogens is limited, it is mainly the progestogens which endow any COCP with its unique properties. Table 2 provides suggestions for managing some common issues women may encounter when taking the COCP (note that the recommendations in this table are based on relatively low-level evidence).

Further information

An evidence-based summary of the medical eligibility criteria for the use of both combined and progestogen-only pills (UK resource) can be found at http://ukmec.pagelizard.com/2016.

Australian-based information on contraception for women and health providers can be found through the state family planning organisations:

Case scenario continued

You suggest to Amanda that it may be possible to use a combined oral contraceptive pill (COCP) for an extended regimen. You discuss the available options as well as some of the benefits and potential adverse effects when taking a COCP. You encourage her to speak to her GP. Amanda makes an appointment with her GP, who determines this approach is suitable and prescribes a standard-dose monophasic COCP. When you dispense the prescription, you ask Amanda to join you in the consult room to discuss the medicine. You provide Amanda with advice on the correct use of the COCP (e.g. starting with active tablets), time to contraceptive effect, potential adverse effects (e.g. spotting, breast tenderness) and discuss, in detail, how to use the COCP for an extended regimen.

Conclusion 

Knowledge of the properties of the hormones used in oral contraceptive preparations and the ways these interact with each other should make it possible to find the right preparation for most women. Pharmacists can help women to achieve this by providing advice on appropriate contraceptive options, recognising potential drug interactions, and providing education on the appropriate action to take when pills are missed or late. Women should be encouraged to engage with the health professionals involved in their care to maximise potential positive effects and minimise troublesome adverse effects. Women should be reminded to report any adverse effects and concerns.  

Key points

  • The progestogen in a COCP is responsible for the main contraceptive effect.
  • The estrogen component of the COCP is associated with serious vascular complications, such as VTE and stroke, but is also responsible for non-contraceptive benefits such as cycle control.
  • Different combinations of estrogens and progestogens provide options for women with different requirements. 

This article is accredited for group 2 CPD credits. Click submit answers to complete the quiz and automatically record CPD against your record.

SUBMIT ANSWERS

If you do get an enrolment error, please click here

Dr TERRI FORAN MBBS (Syd), MClinEd (UNSW), FAChSHM is a sexual health physician with a special interest in contraception, menopause issues and the management of sexually transmitted infections. She holds the position of Conjoint Senior Lecturer in the School of Women’s and Children’s Health at UNSW Sydney, where she lectures both undergraduate and postgraduate students.

Conflict of interest 

Dr Foran has entered into financial relationships (educational development, conference presentation, advisory board membership and/or consultancy) with Bayer, Merck Sharpe and Dohme, Pfizer, Besins and Mayne Pharma, which manufacture contraceptive products. This paper was prepared independently of any pharma input or editorial influence, and Dr Foran reports no other conflicts of interest in this work.

References

  1. Trussell J. Contraceptive failure in the United States. Contraception 2011;83(5):397-404.
  2. Mazza D, Harrison C, Taft A, et al. Current contraceptive management in Australian general practice: an analysis of BEACH data. Med J Aust 2012;197(2):110-4.
  3. Barbara S, Apgar M, et al. Using progestins in clinical practice. Am Fam Physician 2000;62(8):1839–46.
  4. Sitruk-Ware R. Pharamacological profile of progestins. Maturitas 2008;61(1–2):151–7.
  5. Rossi S, ed. Australian Medicines Handbook. Adelaide: Australian Medicines Handbook 2021.
  6. Sexual and Reproductive Health expert group. Sexual and Reproductive Health in eTG Complete. Melbourne; Therapeutic Guidelines; 2020.
  7. Fotherby K. Pharmacokinetics and metabolism of progestins in humans. In: Goldzicher JE, ed. Pharmacology of the contraceptive steroids. New York, NY: Raven Press; 1994:99–126.
  8. Kuhnz W, Heuner A, Hümpel M, et al. In vivo conversion of norethisterone and norethisterone acetate to ethinyl estradiol in postmenopausal women. Contraception 1997;56(6):379–85.
  9. Arowojolu AO, Gallo MF, Lopez LM, et al. Combined oral contraceptive pills for treatment of acne. Cochrane Database Syst Rev 2012;(7):CD004425.
  10. Archer DF, Maheux R, DelConte A, et al. A new low-dose monophasic combination oral contraceptive (Alesse) with levonorgestrel 100 micrograms and ethinyl estradiol 20 micrograms. North American Levonorgestrel Study Group (NALSG). Contraception 1997;55(3):139–44.
  11. Bannemerschult R, Hanker JP, Wünsch C, et al. A multicenter, uncontrolled clinical investigation of the contraceptive efficacy, cycle control, and safety of a new low dose oral contraceptive containing 20 micrograms ethinyl estradiol and 100 micrograms levonorgestrel over six treatment cycles. Contraception 1997;56(5):285–90.
  12. 12.Crona N, Silfverstolpe G, Samsioe G. Changes in serum apo-lipoprotein AI and sex-hormone-binding globulin levels after treatment with two different progestins administered alone and in combination with ethinyl estradiol. Contraception 1984;29(3):261–70.
  13. Salvaggio HL, Zaenglein AL. Examining the use of oral contraceptives in the management of acne. Int J Women’s Health 2010;2:69–76.
  14. Speroff L, DeCherney A. Evaluation of a new generation of oral contraceptives. The Advisory Board for the New Progestins. Obstet Gynecol 1993;81(6):1034–47.
  15. Lobo RA, Stanczyk FZ. New knowledge in the physiology of hormonal contraceptives. Am J Obstet Gynecol 1994;170(5 Pt 2):1499–507.
  16. van Hylckama Vlieg A, Helmerhorst FM, Vandenbroucke JP, et al. The venous thrombotic risk of oral contraceptives, effects of oestrogen dose and progestogen type: results of the MEGA-case control study. BMJ 2009;339:b2921.
  17. Jick SS, Hernandez RK. Risk of non-fatal venous thromboembolism in women using oral contraceptives containing drospirenone compared with women using oral contraceptives containing levonorgestrel: case-control study using United States claims data. BMJ 201;342:d2151.
  18. Vinogradova Y, Coupland C, Hippisley-Cox J. Use of combined oral contraceptives and risk of venous thromboembolism: nested case-control studies using the QResearch and CPRD databases. BMJ 2015;350:h2135.
  19. Dinger JC, Heinemann LAJ, Kühl-Habich D. The safety of a drospirenone-containing oral contraceptive: final results from the European Active Surveillance Study on oral contraceptives based on 142,475 women-years of observation. Contraception 2007;75(5): 344–54.
  20. 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.
  21. Heinemann LA, Dinger JC, Assmann A, et al. Use of oral contraceptives containing gestodene and risk of venous thromboembolism: outlook 10 years after the third-generation “pill scare”. Contraception 2010;81(5):401–7.
  22. Seeger JD, Loughlin J, Eng PM, et al. Risk of thromboembolism in women taking ethinylestradiol/drospirenone and other oral contraceptives. Obstet Gynecol 2007;110(3):587–93.
  23. Dinger J, Assmann A, Möhner S, et al. Risk of venous thromboembolism and the use of dienogest- and drospirenone-containing oral contraceptives: results from a German case-control study. J Fam Plann Reprod Health Care. 2010;36(3):123–9.
  24. Wynn V. In Bardin CW, Milgrom E, Mauvis-Jarvis P (eds): Progesterone and Progestins, pp 395–410. New York, Raven Press, 1983.
  25. Wynn V, Godsland I. Effects of oral contraceptives on carbohydrate metabolism. J Reprod Med 1986;31(9 Suppl):892–7.
  26. Agren UM, Anttila M, Mäenpää-Liukko K, et al. Effects of a monophasic combined oral contraceptive containing nomegestrol acetate and 17β-oestradiol compared with one containing levonorgestrel and ethinylestradiol on haemostasis, lipids and carbohydrate metabolism. Eur J Contracept Reprod Health Care 2011;16(6):444–57.
  27. Organon (New Zealand) Limited. New Zealand Data Sheet – Cerazette 75 microgram film-coated tablet. 2021.
  28. Besins Healthcare Australia. Australian Product Information – Slinda (drospirenone) tablets. 2021.
  29. Archer DF, Ahrendt HJ, Drouin D. Drospirenone-only oral contraceptive: results from a multicenter noncomparative trial of efficacy, safety and tolerability. Contraception 2015;92(5):439–44.
  30. Kimble T, Burke AE, Barnhart KT, et al. A 1-year prospective, open-label, single-arm, multicenter, phase 3 trial of the contraceptive efficacy and safety of the oral progestin-only pill drospirenone 4 mg using a 24/4-day regimen. Contraception 2020;2:100020.
  31. Palacios S, Regidor PA, Colli E, et al. Oestrogen-free oral contraception with a 4 mg drospirenone-only pill: new data and a review of the literature. Eur J Contracept Reprod Health Care 2020;25(3):221–7.
  32. Lidegaard Ø, Løkkegaard E, Svendsen AL, et al. Hormonal contraception and risk of venous thromboembolism: national follow-up study. BMJ 2009;339:b2890.
  33. Fitzgerald C, Feichtinger W, Spona J, et al. A comparison of the effects of two monophasic low dose oral contraceptives on the inhibition of ovulation. Adv Contracept 1994;10(1):5–18.
  34. Crosignani PG, Testa G, Vegetti W, et al. Ovarian activity during regular oral contraceptive use. Contraception 1996;54(5):271–3.
  35. Crofton PM, Evans N, Bath LE, et al. Physiological versus standard sex steroid replacement in young women with premature ovarian failure: effects on bone mass acquisition and turnover. Clin Endocrinol (Oxf) 2010;73(6):707–14.
  36. Gérard C, Blacher S, Communal L, et al. Estetrol is a weak estrogen antagonising estradiol-dependent mammary gland proliferation. J Endocrinol 2015;224(1):85–95.
  37. Venous thromboembolic disease and combined oral contraceptives: results of international multicentre case-control study. World Health Organization Collaborative Study of Cardiovascular Disease and Steroid Hormone Contraception. Lancet1995;346(8990):1575–82.
  38. The Faculty of Sexual & Reproductive Healthcare. Clinical guidance: drug interactions with hormonal contraception. 2019.
  39. Barr N, Geffen D. Managing adverse effects of hormonal contraceptives. Am Fam Physician 2010;82(12):1499–1506.
  40. Edlow A, Bartz D. Hormonal contraceptive options for women with headache: a review of the evidence. Rev Obstet Gynecol 2010 Spring;3(2): 55–65.
  41. Van den Heuvel MW, van Bragt AJ, Alnabawy AK, et al. Comparison of ethinylestradiol pharmacokinetics in three hormonal contraceptive formulations: the vaginal ring, the transdermal patch and an oral contraceptive. Contraception 2005 Sep;72(3):168–74.
  42. Stachenfeld NS. Sex hormone effects on body fluid regulation. Exerc Sport Sci Rev 2008;36(3):152–159.
  43. Oddsson K, Leifels-Fischer B, Wiel-Masson D, et al. Superior cycle control with a contraceptive vaginal ring compared with an oral contraceptive containing 30 microg ethinylestradiol and 150 microg levonorgestrel: a randomized trial. Hum Reprod 2005 Feb;20(2):557–62.
  44. Edelman AB, Koontz SL, Nichols MD, et al. Continuous oral contraceptives: are bleeding patterns dependent on the hormones given? Obstet Gynecol 2006 Mar;107(3):657–65.
  45. Lawrie TA, Helmerhorst FM, Maitra NK, et al. Types of progestogens in combined oral contraception: effectiveness and side-effects. Cochrane Database of Systemic Reviews. 2011 Issue 5.
  46. Mansour D, Verhoeven C, Sommer W, et al. Efficacy and tolerability of a monophasic combined oral contraceptive containing nomegestrol acetate and 17beta-oestradiol in a 24/4 regimen, in comparison to an oral contraceptive containing ethinylestradiol and drospirenone in a 21/7 regimen. Eur J Contracept Reprod Health Care 2011;16: 430–443
  47. Ahrendt HJ, Makalová 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;80(5):436–444.

RELATED ARTICLESMORE FROM AUTHOR