Progestogen-only pill

Progestogen-only pills (POPs), colloquially known as "mini pills", are a type of oral contraceptive that contain synthetic progestogens (progestins). They are a form of hormonal contraception primarily used for the prevention of undesired pregnancy, although various medical uses beyond the prevention of pregnancy also exist.
Progestogen-only pills do not contain estrogens and are not the same as combined oral contraceptive pills (COPs), which consist of a combination of estrogens and progestin hormones, progestogen-only pills or progestin-only pills (POP) are contraceptive pills that contain only synthetic progestogens (progestins) and do not also contain estrogens.
Terminology
Although such pills are sometimes called "progesterone-only pills", they do not actually contain progesterone, but one of several chemically related compounds; and there are a number of progestogen-only contraceptive formulations do not also contain estrogens. They are colloquially known as mini pills.
Although such pills are sometimes called "progesterone-only pills", they do not actually contain progesterone, but one of several chemically related compounds; and there are a number of progestogen-only contraceptive formulations.
Medical uses
Progestogen-only pills are used by patients to avoid pregnancy. The theoretical efficacy of progestogen-only pills is reported to be similar to that of the combined oral contraceptive pill (COCP), and is generally reported as a failure rate of approximately 7% for typical use. However, many studies of contraceptive efficacy did not distinguish between combined oral contraceptive pills and progestogen-only pills, and/or were published before the widespread use of progestogen-only pills other than norethindrone. Patient groups who choose COCPs versus progestogen-only pills may also differ in important ways, as progesterone-only pills are often preferentially prescribed to subfertile groups such as recently postpartum women or older women. Reported efficacy varies between types of progestogen-only pills, but newer progestogen-only pills report higher efficacy rates: norgestrel has a reported failure rate of 2%, and drosperinone has a reported failure rate of 1.8%.
Some progestogen-only pills, such as norethindrone, were long thought to have a shorter duration of effect than COCPs, and many prescribers recommend that the pills be taken within 3 hours of the same time each day to be effective. However, more recent meta-analyses suggest that there is actually a significantly longer half-life for many progestogen-only pill formulations, and that more variation in dose timing can still effectively prevent pregnancy. Norgestrel and drosperinone in particular appear to have a longer window of efficacy. The effectiveness is, therefore, dependent upon compliance and on the type of progestogen-only pill used.
Progestogen-only pills are often prescribed for people who wish to use an oral form of birth control, but do not wish to use estrogen-containing methods due to medical contraindications, intolerable side effects, or personal preference. All estrogen-containing methods of contraception are not recommended for patients with a number of medical problems, including relatively common conditions such as hypertension, migraine headaches with aura, or a history of pulmonary embolism or deep vein thrombosis; however, progestogen-only pills are safe for use by all these groups. The progestogen-only pill is also recommended for people who have recently given birth and desire a pill for contraception, given the risk of blood clots for both postpartum patients and people using estrogen-containing methods of contraception.
Progestogen-only pills also have non-contraceptive benefits. Like combined pills, progesterone-only pills are thought to decrease the likelihood of pelvic inflammatory disease. Daily progesterone use decreases the risk of endometrial cancer, whereas it is unclear whether POPs provide protection against ovarian cancer to the extent that COCPs do.
Available forms
Commercially available progestogen-only pills include the following common or widely used formulations:
Desogestrel 75 µg (e.g., Cerazette)
Drospirenone 4 mg (e.g., Slynd)
Norethisterone 350 µg (e.g., Micronor, Nor-QD, Noriday)
Norgestrel 0.075 mg (e.g., Opill)
And the following rare or mostly discontinued formulations:
Etynodiol diacetate 500 µg (e.g., Femulen)
Levonorgestrel 30 µg (e.g., 28 mini, Microval, Norgeston)
Lynestrenol 500 µg (e.g., Exluton, Mini-kare)
Norethisterone 300 μg (e.g., Mini-Pe)
Norgestrel 75 µg (or levonorgestrel 37.5 µg) (e.g., Minicon, Neogest, Ovrette, Opill)
As well as the following completely discontinued formulations:
Chlormadinone acetate 0.5 mg
Quingestanol acetate 0.3 mg (e.g., Demovis, Pilomin)
In the United States, progestogen-only pills are available in 350-μg norethisterone, 4-mg drospirenone and norgestrel 0.075-mg formulations. Norgestrel is FDA-approved for over-the-counter availability, and norethindrone and drospirenone are available by prescription.
Side effects
Irregular menstrual bleeding and spotting is common with progestogen-only pills, especially in the first months after starting. This side effect may be bothersome but is not dangerous, and most users report improved bleeding patterns with longer usage.
May cause mastalgia (breast tenderness, pain)
Available data on the average impact of POPs on mood are limited and conflicting, and do not show a clear link between POP usage and mental health changes. However, some patients may experience mood swings, including feelings of anxiety and depression.
Follicular ovarian cysts are more common in POP users than in those not using hormones. The follicular changes tend to regress over time, and no intervention other than reassurance is required in asymptomatic individuals.
Breast cancer risk
Epidemiological evidence on POPs and breast cancer risk is based on much smaller populations of users and so is less conclusive than that for COCPs.
In the largest (1996) reanalysis of previous studies of hormonal contraceptives and breast cancer risk, less than 1% were POP users. Current or recent POP users had a slightly increased relative risk (RR 1.17) of breast cancer diagnosis that just missed being statistically significant. The relative risk was similar to that found for current or recent COCP users (RR 1.16), and, as with COCPs, the increased relative risk decreased over time after stopping, vanished after 10 years, and was consistent with being due to earlier diagnosis or promoting the growth of a preexisting cancer.
The most recent (1999) IARC evaluation of progestogen-only hormonal contraceptives reviewed the 1996 reanalysis as well as 4 case-control studies of POP users included in the reanalysis. They concluded that: "Overall, there was no evidence of an increased risk of breast cancer".
Recent anxieties about the contribution of progestogens to the increased risk of breast cancer associated with HRT in postmenopausal women such as found in the WHI trials have not spread to progestogen-only contraceptive use in premenopausal women.
Depression
There is a growing body of research investigating the links between hormonal contraception, such as the progestogen-only pill, and potential adverse effects on women’s psychological health. The findings from a large Danish study of one million women (followed-up from January 2000 to December 2013) were published in 2016, and reported that the use of hormonal contraception, particularly amongst adolescents, was associated with a statistically significant increased risk of subsequent depression. The authors found that women on the progestogen-only pill in particular, were 34% more likely to subsequently take anti-depressants or be given a diagnosis of depression, in comparison with those not on hormonal contraception. In 2018, a similarly large nationwide cohort study in Sweden amongst women aged 12–30 (n=815,662) found an association, particularly amongst young adolescents (aged 12–19), between hormonal contraception and subsequent use of psychotropic drugs. Such studies highlight the need for further research into the influence of hormonal contraception, including the progestogen-only pill on women’s psychological health.
Weight gain
There is some evidence that progestin-only contraceptives may lead to slight weight gain (on average less than 2 kg in the first year) compared to women not using any hormonal contraception.
Mechanism of action
The mechanism of action of progestogen-only contraceptives depends on the progestogen activity and dose.
Very-low-dose progestogen-only contraceptives, such as traditional progestogen-only pills (and subdermal implants Norplant and Jadelle and intrauterine systems Progestasert and Mirena), inconsistently inhibit ovulation in ~50% of cycles and rely mainly on their progestogenic effect of thickening the cervical mucus, thereby reducing sperm viability and penetration.
Intermediate-dose progestogen-only contraceptives, such as the progestogen-only pill Cerazette (or the subdermal implant Nexplanon), allow some follicular development (part of the steps of ovulation) but much more consistently inhibit ovulation in 97–99% of cycles. The same cervical mucus changes occur as with very-low-dose progestogens.
High-dose progestogen-only contraceptives, such as the injectables Depo-Provera and Noristerat, completely inhibit follicular development and ovulation. The same cervical mucus changes occur as with very-low-dose and intermediate-dose progestogens.
In anovulatory cycles using progestogen-only contraceptives, the endometrium is thin and atrophic. If the endometrium were also thin and atrophic during an ovulatory cycle, this could, in theory, interfere with implantation of a blastocyst (embryo).
History
The first POP to be introduced contained 0.5 mg chlormadinone acetate and was marketed in Mexico and France in 1968. However, it was withdrawn in 1970 due to safety concerns pertaining to long-term animal toxicity studies. Subsequently, levonorgestrel 30 µg (brand name Microval) was marketed in Germany in 1971. It was followed by a number of other POPs shortly thereafter in the early 1970s, including etynodiol diacetate, lynestrenol, norethisterone, norgestrel, and quingestanol acetate. Desogestrel 75 µg (brand name Cerzette) was marketed in Europe in 2002 and was the most recent POP to be introduced. It differs from earlier POPs in that it is able to inhibit ovulation in 97% of cycles.
In July 2023, the USA Food and Drug Administration (FDA) approved the first over-the-counter (OTC) POP birth control pill to be sold without a prescription in the United States. The pill, marketed under the brand name Opill, is once daily 0.075 mg oral norgestrel.
See also
Progestogen-only injectable contraceptive
Oral contraceptive formulations
References
Hormonal contraception
Progestogens