Progestogen-only pill

Progestogen-only pills or progestin-only pills (POP) are contraceptive pills that contain only synthetic progestogens (progestins) and do not also contain estrogens. They are colloquially known as mini pills.

Progestogen-only pill
Background
TypeHormonal
First use1968[1][2]
Failure rates (first year)
Perfect use0.3%[3]
Typical use9%[3]
Usage
Duration effect1 day
ReversibilityYes
User remindersTaken within same 3-hour window each day
Clinic review6 months
Advantages and disadvantages
STI protectionNo
WeightNo proven effect
Period disadvantagesLight spotting may be irregular
Period advantagesOften lighter and less painful
Medical notes
Unaffected by being on most (but not all) antibiotics. May be used, unlike COCPs, in patients with hypertension and history of migraines. Affected by some anti-epileptics.

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

Progesterone-only pills are used by patients to avoid pregnancy. The theoretical efficacy of progesterone-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.[4] However, many studies of contraceptive efficacy did not distinguish between combined oral contraceptive pills and progesterone-only pills, and/or were published before the widespread use of progesterone-only pills other than norethindrone. Patient groups who choose COCPs versus progesterone-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 progesterone-only pills, but newer progesterone-only pills report higher efficacy rates: norgestrel has a reported failure rate of 2%,[5] and drosperinone has a reported failure rate of 1.8%.[6]

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.[7] However, more recent meta-analyses suggest that there is actually a significantly longer half-life for many progesterone-only pill formulations, and that more variation in dose timing can still effectively prevent pregnancy.[8] 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 progesterone-only pill used.

Progesterone-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, progesterone-only pills are safe for use by all these groups.[9] The progestin-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.[10]

Progesterone-only pills also have non-contraceptive benefits. Like combined pills, progesterone-only pills are thought to decrease the likelihood of pelvic inflammatory disease.[11] Daily progesterone use decreases the risk of endometrial cancer,[12] whereas it is unclear whether POPs provide protection against ovarian cancer to the extent that COCPs do.

Available forms
Main article: Birth control pill formulations § Progestogen-only pills

Commercially available progestogen-only pills include the following common or widely used formulations:[13][14][15][16]

And the following rare or mostly discontinued formulations:[13][14][15][16]

As well as the following completely discontinued formulations:

In the United States, progestogen-only pills are available in 350-μg norethisterone, 4-mg drospirenone and norgestrel 0.075-mg formulations.[19] Norgestrel is FDA-approved for over-the-counter availability,[20] and norethindrone and drospirenone are available by prescription.

Side effects
  • Irregular menstrual bleeding and spotting is common with progesterone-only pills, especially in the first months after starting.[21][22] 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.[23] 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.[24] 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.[25][26]

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".[27]

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[28] have not spread to progestogen-only contraceptive use in premenopausal women.[29]

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.[30][31][32] 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.[31] 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.[31] 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.[30] 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.[33]

Mechanism of action

The mechanism of action of progestogen-only contraceptives depends on the progestogen activity and dose.[29]

  • 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.[34] 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.[1][2][16] However, it was withdrawn in 1970 due to safety concerns pertaining to long-term animal toxicity studies.[1][2][16] Subsequently, levonorgestrel 30 µg (brand name Microval) was marketed in Germany in 1971.[18][35] It was followed by a number of other POPs shortly thereafter in the early 1970s, including etynodiol diacetate, lynestrenol, norethisterone, norgestrel, and quingestanol acetate.[18][36] Desogestrel 75 µg (brand name Cerzette) was marketed in Europe in 2002 and was the most recent POP to be introduced.[37][36][38] It differs from earlier POPs in that it is able to inhibit ovulation in 97% of cycles.[36][38]

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.[39]

See also

References
  1. Annetine Gelijns (1991). Innovation in Clinical Practice: The Dynamics of Medical Technology Development. National Academies. pp. 172–. NAP:13513. Development of the minipill, which contains only a progestin, was another result of concerns over the thromboembolic side effects of combination oral contraceptives.36 This development was also driven by the expectation that lower steroid doses would diminish effects on the metabolic and reproductive systems, lessen complaints about nausea and headache, and improve compliance (because it offered a regimen of continuous pill taking rather than the cyclic regimen of earlier pill formulations).37 Syntex was the first to introduce a 0.5 milligram chlor- madinone acetate minipill in 1968 in France, although this pill was withdrawn from the market in 1970 when long-term animal toxicity tests for the FDA revealed the occurrence of breast nodules in beagles.38 Nevertheless, other manufacturers began to pursue minipill development using their own progestogens, and since 1970 a variety of compounds have been introduced.
  2. Bennett, John P. (1974). "The Second Generation of Hormonal Contraceptives". Chemical Contraception. pp. 39–62. doi:10.1007/978-1-349-02287-8_4. ISBN 978-1-349-02289-2. Chlormadinone acetate was the first minipill contraceptive to be marketed, in Mexico during July 1968. This compound was removed from clinical use in February 1970 because it produced nodules in the breast tissues of beagle dogs [...]
  3. Trussell, James (2011). "Contraceptive efficacy". In Hatcher, Robert A.; Trussell, James; Nelson, Anita L.; Cates, Willard Jr.; Kowal, Deborah; Policar, Michael S. (eds.). Contraceptive technology (20th revised ed.). New York: Ardent Media. pp. 779–863. ISBN 978-1-59708-004-0. ISSN 0091-9721. OCLC 781956734. Table 26–1 = Table 3–2 Percentage of women experiencing an unintended pregnancy during the first year of typical use and the first year of perfect use of contraception, and the percentage continuing use at the end of the first year. United States.
  4. Trussell, James (May 2011). "Contraceptive failure in the United States". Contraception. 83 (5): 397–404. doi:10.1016/j.contraception.2011.01.021. ISSN 1879-0518. PMC 3638209. PMID 21477680.
  5. Food and Drug Administration (FDA). "Opill Tablets" (PDF).
  6. Food and Drug Administration (FDA). "SLYND (drosperione), tablets for oral use" (PDF).
  7. Bowman, J. A. (1968-12-01). "The effect of norethindrone-mestranol on cervical mucus". American Journal of Obstetrics and Gynecology. 102 (7): 1039–1040. doi:10.1016/0002-9378(68)90467-5. ISSN 0002-9378. PMID 5724391.
  8. Wollum, Alexandra; Zuniga, Carmela; Blanchard, Kelly; Teal, Stephanie (June 2023). "A commentary on progestin-only pills and the "three-hour window" guidelines: Timing of ingestion and mechanisms of action". Contraception. 122: 109978. doi:10.1016/j.contraception.2023.109978. ISSN 1879-0518. PMID 36801392.
  9. "US Medical Eligibility Criteria for Contraceptive Use, 2016 (US MEC) | CDC". www.cdc.gov. 2023-03-27. Retrieved 2023-07-13.
  10. "US Medical Eligibility Criteria for Contraceptive Use, 2016 (US MEC) | CDC". www.cdc.gov. 2023-03-27. Retrieved 2023-07-13.
  11. "IUD users may have higher risk of contracting PID, studies find; pill may have protective effect". Family Planning Perspectives. 12 (4): 206–208. 1980. doi:10.2307/2134786. ISSN 0014-7354. JSTOR 2134786. PMID 7439343.
  12. Weiderpass, E.; Adami, H. O.; Baron, J. A.; Magnusson, C.; Bergström, R.; Lindgren, A.; Correia, N.; Persson, I. (1999-07-07). "Risk of endometrial cancer following estrogen replacement with and without progestins". Journal of the National Cancer Institute. 91 (13): 1131–1137. doi:10.1093/jnci/91.13.1131. ISSN 0027-8874. PMID 10393721.
  13. Grimes DA, Lopez LM, O'Brien PA, Raymond EG (2013). "Progestin-only pills for contraception". Cochrane Database Syst Rev (11): CD007541. doi:10.1002/14651858.CD007541.pub3. PMID 24226383.
  14. Hussain SF (2004). "Progestogen-only pills and high blood pressure: is there an association? A literature review". Contraception. 69 (2): 89–97. doi:10.1016/j.contraception.2003.09.002. PMID 14759612.
  15. Sylvia K. Rosevear (15 April 2008). Handbook of Gynaecology Management. John Wiley & Sons. pp. 2–. ISBN 978-1-4051-4742-2.
  16. M.R. Henzl (1978). "Natural and Synthetic Female Sex Hormones". In S.S.C. Yen; R.B. Jaffe (eds.). Reproductive Endocrinology: Physiology, Pathophysiology, and Clinical Management. W.B. Saunders Co. pp. 421–468. ISBN 978-0721696256.
  17. https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/211367s000lbl.pdf
  18. Population Reports: Oral contraceptives. Department of Medical and Public Affairs, George Washington Univ. Medical Center. 1975. p. A-64. Distribution and Use of the Minipill. [...] Progestogen & Dose in mg: d-Norgestrel 0.03. Manufacturer: Schering AG. Brand Names: Microlut, Nordrogest. Where & When First Marketed: Federal Republic of Germany 1971.
  19. "Drugs@FDA: FDA Approved Drug Products". United States Food and Drug Administration. Retrieved 6 January 2018.
  20. Commissioner, Office of the (2023-07-13). "FDA Approves First Nonprescription Daily Oral Contraceptive". FDA. Retrieved 2023-07-14.
  21. Belsey, E. M. (August 1988). "Vaginal bleeding patterns among women using one natural and eight hormonal methods of contraception". Contraception. 38 (2): 181–206. doi:10.1016/0010-7824(88)90038-8. ISSN 0010-7824. PMID 2971505.
  22. Steiner, Mitchell (September 1998). "Campbell's Urology, 7th ed.WalshP.C.: Philadelphia: Lippincott Williams & Wilkins. Philadelphia: W. B. Saunders Co.1998. 210 pages.RetikA.B.: Philadelphia: Lippincott Williams & Wilkins. Philadelphia: W. B. Saunders Co.1998. 210 pages.VaughanE.D.: Philadelphia: Lippincott Williams & Wilkins. Philadelphia: W. B. Saunders Co.1998. 3,426 pages.WeinA.J.: Philadelphia: Lippincott Williams & Wilkins. Philadelphia: Isis Medical Media Ltd.1998. 3,426 pages". Journal of Urology. 160 (3 Part 1): 967–968. doi:10.1016/s0022-5347(01)62878-7. ISSN 0022-5347.
  23. Worly, Brett L.; Gur, Tamar L.; Schaffir, Jonathan (June 2018). "The relationship between progestin hormonal contraception and depression: a systematic review". Contraception. 97 (6): 478–489. doi:10.1016/j.contraception.2018.01.010. ISSN 1879-0518. PMID 29496297.
  24. Tayob, Y.; Adams, J.; Jacobs, H. S.; Guillebaud, J. (October 1985). "Ultrasound demonstration of increased frequency of functional ovarian cysts in women using progestogen-only oral contraception". British Journal of Obstetrics and Gynaecology. 92 (10): 1003–1009. doi:10.1111/j.1471-0528.1985.tb02994.x. ISSN 0306-5456. PMID 3902074.
  25. Collaborative Group on Hormonal Factors in Breast Cancer (1996). "Breast cancer and hormonal contraceptives: collaborative reanalysis of individual data on 53,297 women with breast cancer and 100,239 women without breast cancer from 54 epidemiological studies". Lancet. 347 (9017): 1713–27. doi:10.1016/S0140-6736(96)90806-5. PMID 8656904. S2CID 36136756.
  26. Collaborative Group on Hormonal Factors in Breast Cancer (1996). "Breast cancer and hormonal contraceptives: further results". Contraception. 54 (3 Suppl): 1S–106S. doi:10.1016/s0010-7824(15)30002-0. PMID 8899264.
  27. IARC Working Group on the Evaluation of Carcinogenic Risks to Humans (1999). "Hormonal contraceptives, progestogens only". Hormonal contraception and post-menopausal hormonal therapy; IARC monographs on the evaluation of carcinogenic risks to humans, Volume 72. Lyon: IARC Press. pp. 339–397. ISBN 92-832-1272-X.
  28. Chlebowski R, Hendrix S, Langer R, Stefanick M, Gass M, Lane D, Rodabough R, Gilligan M, Cyr M, Thomson C, Khandekar J, Petrovitch H, McTiernan A (2003). "Influence of estrogen plus progestin on breast cancer and mammography in healthy postmenopausal women: the Women's Health Initiative Randomized Trial". JAMA. 289 (24): 3243–53. doi:10.1001/jama.289.24.3243. PMID 12824205.
  29. Glasier, Anna (March 20, 2015). "Chapter 134. Contraception". In Jameson, J. Larry; De Groot, Leslie J.; de Krester, David; Giudice, Linda C.; Grossman, Ashley; Melmed, Shlomo; Potts, John T., Jr.; Weir, Gordon C. (eds.). Endocrinology: Adult and Pediatric (7th ed.). Philadelphia: Saunders Elsevier. p. 2306. ISBN 978-0-323-18907-1.{{cite book}}: CS1 maint: multiple names: editors list (link)
  30. Zettermark, Sofia; Vicente, Raquel Perez; Merlo, Juan (2018-03-22). "Hormonal contraception increases the risk of psychotropic drug use in adolescent girls but not in adults: A pharmacoepidemiological study on 800 000 Swedish women". PLOS ONE. 13 (3): e0194773. Bibcode:2018PLoSO..1394773Z. doi:10.1371/journal.pone.0194773. ISSN 1932-6203. PMC 5864056. PMID 29566064.
  31. Skovlund, Charlotte Wessel; Mørch, Lina Steinrud; Kessing, Lars Vedel; Lidegaard, Øjvind (2016-11-01). "Association of Hormonal Contraception With Depression". JAMA Psychiatry. 73 (11): 1154–1162. doi:10.1001/jamapsychiatry.2016.2387. ISSN 2168-6238. PMID 27680324.
  32. Kulkarni, Jayashri (July 2007). "Depression as a side effect of the contraceptive pill". Expert Opinion on Drug Safety. 6 (4): 371–374. doi:10.1517/14740338.6.4.371. ISSN 1744-764X. PMID 17688380. S2CID 8836005.
  33. Lopez, LM; Ramesh, S; Chen, M; Edelman, A; Otterness, C; Trussell, J; Helmerhorst, FM (28 August 2016). "Progestin-only contraceptives: effects on weight". The Cochrane Database of Systematic Reviews. 2016 (8): CD008815. doi:10.1002/14651858.CD008815.pub4. PMC 5034734. PMID 27567593.
  34. Pattman, Richard; Sankar, K. Nathan; Elewad, Babiker; Handy, Pauline; Price, David Ashley, eds. (November 19, 2010). "Chapter 33. Contraception including contraception in HIV infection and infection reduction". Oxford Handbook of Genitourinary Medicine, HIV, and Sexual Health (2nd ed.). Oxford: Oxford University Press. p. 360. ISBN 978-0-19-957166-6. Ovulation may be suppressed in 15–40% of cycles by POPs containg levonorgestrel, norethisterone, or etynodiol diacetate, but in 97–99% by those containing desogestrel.
  35. Greenberg (19 February 2016). Exploring the Dimensions of Human Sexuality. Jones & Bartlett Learning. pp. 481–. ISBN 978-1-284-11474-4. The progestin-only pill was introduced in 1972.
  36. Amy Whitaker; Melissa Gilliam (27 June 2014). Contraception for Adolescent and Young Adult Women. Springer. pp. 26, 97. ISBN 978-1-4614-6579-9.
  37. Kathy French (9 November 2009). Sexual Health. John Wiley & Sons. pp. 92–93. ISBN 978-1-4443-2257-6.
  38. J. Larry Jameson; Leslie J. De Groot (18 May 2010). Endocrinology - E-Book: Adult and Pediatric. Elsevier Health Sciences. pp. 2424–. ISBN 978-1-4557-1126-0. In 2002, a POP containing desogestrel 75 ug/day, a dose sufficient to inhibit ovulation in almost every cycle, was introduced in Europe.51
  39. Commissioner, Office of the (2023-07-13). "FDA Approves First Nonprescription Daily Oral Contraceptive". FDA. Retrieved 2023-07-13.
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