Shorter-Acting Progestin-Only Contraception



Shorter-Acting Progestin-Only Contraception


Elizabeth Micks, MD, MPH

Sarah Prager, MD, MAS



Contraceptives containing only progestins are available in intrauterine devices (IUDs), subdermal implants, injectable contraceptives, and shorter-acting progestin-only pills (POPs), patches, and vaginal rings. This chapter will address the shorter-acting progestin-only methods.


The Progestin-Only Pill

The POP contains a small dose of a progestational agent and must be taken daily, in a continuous fashion.1,2 The first oral contraceptives were initially designed to be POPs; only through an accident did the combined estrogen-progestin pill evolve. The first POPs were marketed after combined pills with the intention to reduce the side effects and thromboembolic risks associated with estrogen-containing pills.3 Continuous dosing was expected to improve compliance. The first POP, containing chlormadinone acetate 0.5 mg, was approved in France in 1968. Several other POPs became available in the United States and Europe in the early 1970s, including norgestrel, norethindrone (also known as norethisterone), and levonorgestrel (the levo enantiomer of norgestrel).4

The only POP currently available in the United States is norethindrone 0.35 mg, used by approximately 0.4% of contracepting women.5 The brand-name products initially marketed were Micronor and Nor-QD; today, numerous therapeutic equivalent products are also available including Camila and Jolivette. Other formulations commercially available around the globe include pills containing 0.03 mg levonorgestrel, 0.5 mg ethynodiol diacetate, and 0.075 mg desogestrel (Table 9.1).6 Of these, only the levonorgestrel, norethindrone, and desogestrel pills are in common use. Levonorgestrel and norethindrone POPs have been available for decades, and desogestrel POPs have been available since 2003.

Two more POPs are currently under development. A norgestrel 0.075 mg pill, which was previously marketed as Ovrette, is being developed with the intention of over-the-counter sales in the United States (Clinicaltrials.gov NCT03585712). A novel 24/4 cyclic regimen POP containing drospirenone 4.0 mg daily for 24 days followed by a 4-day hormone-free interval has been studied over the last decade.7,8 The product was approved in the United States in June 2019 (brand-name Slynd) with plans for marketing in late 2019.









Table 9.1 Progestin-Only Pills





















































Drug


Dose


Brand-Name Products


Therapeutic Equivalent Products


U.S. Availability


Norethindrone (norethisterone)


0.35 mg


Micronor, Nor-QD


Camila, Jolivette, Heather, Errin, Nora-Be, Noriday


Yes


Norgestrel


0.075 mg


Ovrette


Cryselle, Minicon, Neogest


No*


Levonorgestrel


0.03 mg


Norgeston, Microlut, Microval



No


Lynestrenol


0.5 mg


Exluton


Minikare


No


Ethynodiol diacetate


0.5 mg


Femulen



No


Desogestrel


0.075 mg


Cerazette



No


Drospirenone


4 mg


Slynd



Yes


* Approved but not currently available.




Mechanism of Action

POPs historically have about 25% of the amount of circulating progestin as combined oral contraceptives (COCs); hence, they are commonly referred to as the “minipill.”6 For POPs containing levonorgestrel, norgestrel, and norethindrone, this low dose of progestin results in predominantly cervical and endometrial effects, though the precise mechanism of action is based on very limited clinical evidence.9 POPs appear to cause the cervical mucus to become thick and impermeable, likely the major contraceptive effect.2 These progestins have less of an effect on ovulatory function, as the gonadotropins are not consistently suppressed. Hence, approximately 40% of patients using these POPs ovulate normally.10,11,12 Tubal physiology may also be affected, but this is speculative.

However, POPs containing desogestrel and drospirenone provide more inhibition of ovulation. The desogestrel POP suppresses ovulation comparable to that of COCs.13,14 The drospirenone POP also suppresses ovulation; this suppression is maintained over a 4-day hormone-free interval and is comparable to desogestrel POPs dosed daily.7,8,15

Because of the low dose, and lack of ovulation inhibition, norethindrone norgestrel, levonorgestrel, ethynodiol diacetate, and lynestrenol POPs must be taken every day at about the same time of day. Based on limited data, the changes in cervical mucus associated with the POP appear to develop quickly and diminish quickly.9 Thickened cervical mucus reportedly occurs within 2 to 4 hours of dosing, with impermeability to sperm declining 22 hours after administration, and by 24 hours, some sperm penetration occurs.16 While the available data support the need for consistent “on-time” dosing of POPs, and use of a backup method in the event of a late pill, the quality of this evidence is weak.9 The requirement for maintaining this rigorous schedule may present a barrier to some potential users. In contrast, users of desogestrel POPs can miss a pill by up to 12 hours, and drospirenone POP users can delay taking a pill for 24 hours without impacting the contraceptive efficacy.8,17


Efficacy

Perfect-use failure rates have been documented to be as low as 1.1 per 100 women in the first year of use.18,19 The actual use failure rate for all contraceptive pills (COCs and POPs) reported from the National Survey of Family Growth 2006 to 2010 is 7.2 per 100 women in the first year of use.20 In this cohort, failure rates differ by age (10.4 per 100 women aged 25 to 29 vs. 4.1 per 100 women aged 30 to 44) and by race/ethnicity (13.1 per 100 black women and 6.1 per 100 white women). A systematic review of POPs for contraception did not find statistically significant differences in efficacy between POP types, though the analyses favored desogestrel over levonorgestrel and norethindrone over desogestrel.6 Higher rates of discontinuation were seen with desogestrel due to bleeding irregularities, which likely limited its overall efficacy. There are no published efficacy data comparing
drospirenone POPs with any other formulations. When women are able to adhere to recommended timing of POP administration, the failure rate may be comparable to the rate (<1 per 100 woman-years) with COCs.18 However, use of population data to compare effectiveness of POPs and COCs is limited by selection bias, as users of POPs may have lower fertility risk for a variety of reasons (e.g., age, breastfeeding).


Who Might Use Progestin-Only Pills

POPs can be an effective, well-tolerated contraceptive method for many women. This method is frequently used by individuals who prefer an oral contraceptive and have an intolerance to, a personal preference to avoid, or a medical contraindication to estrogen-containing contraceptives. According to the U.S. Medical Eligibility Criteria (MEC) for Contraceptive Use, POPs are category 1 (no restrictions) or category 2 (advantages generally outweigh theoretical or proven risks) for women over the age of 35 who smoke or for those who have migraines with aura, history of venous or arterial thrombosis, hypertension, diabetes with vascular disease, or cardiovascular disease.21 In general, women with liver tumors, cirrhosis, or breast cancer should not use the POP or other methods of hormonal contraception. Individuals with certain forms of bariatric surgery (malabsorptive procedures) that impair drug absorption should not use oral contraceptives.

All potential POP users must be counseled regarding the need for consistent timing to maximize efficacy, using a patient-centered approach. Theoretically, POPs may be associated with decreased efficacy in certain populations, such as adolescents and obese women. Use of POPs in adolescent women is poorly studied and less common, so precise estimates of failure rates are not available. However, clinicians may avoid the use of POPs in adolescents due to concerns about their compliance with the dosing regimen. Studies of obese women using COCs demonstrate they may require a longer period of time to reach full contraceptive efficacy, though the data do not suggest higher doses of hormones are necessary.22 Based on very limited epidemiologic data, obese women who use POPs are not at higher risk of pregnancy than nonobese women.23

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Mar 1, 2020 | Posted by in OBSTETRICS | Comments Off on Shorter-Acting Progestin-Only Contraception
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