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combined oral contraceptive pill
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{{Short description|Birth control method which is taken orally}}{{Redirect|The pill|other uses|Pill (disambiguation)}}{{About|daily use of COC|occasional use|Emergency contraception}}{{Use dmy dates|date=February 2024}}{{cs1 config|name-list-style=vanc|display-authors=6}}- the content below is remote from Wikipedia
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Mechanism of action
Combined oral contraceptive pills were developed to prevent ovulation by suppressing the release of gonadotropins. Combined hormonal contraceptives, including COCPs, inhibit follicular development and prevent ovulation as a primary mechanism of action.BOOK, Hatcher RA, Trussell J, Nelson A, Cates W, Kowal D, Policar M, Contraceptive technology, 20th revised, 2011, Ardent Media, New York, 978-1-59708-004-0, 781956734, 249–341, Combined oral contraceptives (COCs), 0091-9721, pp. 257–258:{{blockquote|Mechanism of actionCOCs prevent fertilization and, therefore, qualify as contraceptives. There is no significant evidence that they work after fertilization. The progestins in all COCs provide most of the contraceptive effect by suppressing ovulation and thickening cervical mucus, although the estrogens also make a small contribution to ovulation suppression. Cycle control is enhanced by the estrogen.Because COCs so effectively suppress ovulation and block ascent of sperm into the upper genital tract, the potential impact on endometrial receptivity to implantation is almost academic. When the two primary mechanisms fail, the fact that pregnancy occurs despite the endometrial changes demonstrates that those endometrial changes do not significantly contribute to the pill’s mechanism of action.}}BOOK, Speroff L, Darney PD, A clinical guide for contraception, 5th, 2011, Lippincott Williams & Wilkins, Philadelphia, 978-1-60831-610-6, 19–152, Oral contraception, BOOK, Levin ER, Hammes SR, Goodman LS, Brunton LL, Chabner BA, Knollmann BC, Goodman & Gilman’s pharmacological basis of therapeutics, 12th, 2011, McGraw-Hill Medical, New York, 978-0-07-162442-8, 1163–1194, Estrogens and progestins, BOOK, Glasier A, Anna Glasier, Jameson JL, De Groot LJ, Endocrinology, 6th, 2010, Saunders Elsevier, Philadelphia, 978-1-4160-5583-9, 2417–2427, Contraception, Under normal circumstances, luteinizing hormone (LH) stimulates the theca cells of the ovarian follicle to produce androstenedione. The granulosa cells of the ovarian follicle then convert this androstenedione to estradiol. This conversion process is catalyzed by aromatase, an enzyme produced as a result of follicle-stimulating hormone (FSH) stimulation.{{Citation |last=Barbieri |first=Robert L. |title=The Endocrinology of the Menstrual Cycle |date=2014 |url=https://doi.org/10.1007/978-1-4939-0659-8_7 |work=Human Fertility: Methods and Protocols |series=Methods in Molecular Biology |volume=1154 |pages=145–169 |editor-last=Rosenwaks |editor-first=Zev |place=New York, NY |publisher=Springer |doi=10.1007/978-1-4939-0659-8_7 |pmid=24782009 |isbn=978-1-4939-0659-8 |access-date=15 September 2022 |editor2-last=Wassarman |editor2-first=Paul M. |archive-date=15 July 2023 |archive-url=https://web.archive.org/web/20230715025752link.springer.com/protocol/10.1007/978-1-4939-0659-8_7 |url-status=live }} In individuals using oral contraceptives, progestogen negative feedback decreases the pulse frequency of gonadotropin-releasing hormone (GnRH) release by the hypothalamus, which decreases the secretion of FSH and greatly decreases the secretion of LH by the anterior pituitary. Decreased levels of FSH inhibit follicular development, preventing an increase in estradiol levels. Progestogen negative feedback and the lack of estrogen positive feedback on LH secretion prevent a mid-cycle LH surge. Inhibition of follicular development and the absence of an LH surge prevent ovulation.Estrogen was originally included in oral contraceptives for better cycle control (to stabilize the endometrium and thereby reduce the incidence of breakthrough bleeding), but was also found to inhibit follicular development and help prevent ovulation. Estrogen negative feedback on the anterior pituitary greatly decreases the secretion of FSH, which inhibits follicular development and helps prevent ovulation.Another primary mechanism of action of all progestogen-containing contraceptives is inhibition of sperm penetration through the cervix into the upper genital tract (uterus and fallopian tubes) by decreasing the water content and increasing the viscosity of the cervical mucus.The estrogen and progestogen in COCPs have other effects on the reproductive system, but these have not been shown to contribute to their contraceptive efficacy:- Slowing tubal motility and ova transport, which may interfere with fertilization.
- Endometrial atrophy and alteration of metalloproteinase content, which may impede sperm motility and viability, or theoretically inhibit implantation.
- Endometrial edema, which may affect implantation.
Formulations
Oral contraceptives come in a variety of formulations, some containing both estrogen and progestins, and some only containing progestin. Doses of component hormones also vary among products, and some pills are monophasic (delivering the same dose of hormones each day) while others are multiphasic (doses vary each day). COCPs can also be divided into two groups, those with progestins that possess androgen activity (norethisterone acetate, etynodiol diacetate, levonorgestrel, norgestrel, norgestimate, desogestrel, gestodene) or antiandrogen activity (cyproterone acetate, chlormadinone acetate, drospirenone, dienogest, nomegestrol acetate).COCPs have been somewhat inconsistently grouped into “generations” in the medical literature based on when they were introduced.BOOK, Nelson AL, Cwiak C, 2011, Combined oral contraceptives, Hatcher RA, Trussell J, Nelson A, Cates W, Kowal D, Policar M, Contraceptive technology, 20th revised, New York, Ardent Media, 253–254, 978-1-59708-004-0, 0091-9721, 781956734, {{blockquote|Ten different progestins have been used in the COCs that have been sold in the United States. Several different classification systems for the progestins exist, but the one most commonly used system recapitulates the history of the pill in the United States by categorizing the progestins into the so-called “generations of progestins”. The first three generations of progestins are derived from 19-nortestosterone. The fourth generation is drospirenone. Newer progestins are hybrids.First-generation progestins. First-generation progestins include noretynodrel, norethisterone, norethisterone acetate, and etynodiol diacetate... These compounds have the lowest potency and relatively short half-lives. The short half-life did not matter in the early, high-dose pills but as doses of progestin were decreased in the more modern pills, problems with unscheduled spotting and bleeding became more common.Second-generation progestins. To solve the problem of unscheduled bleeding and spotting, the second generation progestins (norgestrol and levonorgestrel) were designed to be significantly more potent and to have longer half-lives than norethisterone-related progestins ... The second-generation progestins have been associated with more androgen-related side-effects such as adverse effect on lipids, oily skin, acne, and facial hair growth.Third-generation progestins. Third-generation progestins (desogestrel, norgestimate and elsewhere, gestodene) were introduced to maintain the potent progestational activity of second-generation progestins, but to reduce androgeneic side effects. Reduction in androgen impacts allows a fuller expression of the pill’s estrogen impacts. This has some clinical benefits... On the other hand, concern arose that the increased expression of estrogen might increase the risk of venous thromboembolism (VTE). This concern introduced a pill scare in Europe until international studies were completed and correctly interpreted.Fourth-generation progestins. Drospirenone is an analogue of spironolactone, a potassium-sparing diuretic used to treat hypertension. Drospirenone possesses anti-mineralocorticoid and anti-androgenic properties. These properties have led to new contraceptive applications, such as treatment of premenstrual dysphoric disorder and acne... In the wake of concerns around possible increased VTE risk with less androgenic third-generation formulations, those issues were anticipated with drospirenone. They were clearly answered by large international studies.Next-generation progestins. Progestins have been developed with properties that are shared with different generations of progestins. They have more profound, diverse, and discrete effects on the endometrium than prior progestins. This class would include dienogest (United States) and nomegestrol (Europe).}}BOOK, Speroff L, Darney PD, 2011, Oral contraception, A clinical guide for contraception, 5th, Philadelphia, Lippincott Williams & Wilkins, 40, 978-1-60831-610-6,- First generation COCPs are sometimes defined as those containing the progestins noretynodrel, norethisterone, norethisterone acetate, or etynodiol acetate; and sometimes defined as all COCPs containing ≥ 50 μg ethinylestradiol.
- Second generation COCPs are sometimes defined as those containing the progestins norgestrel or levonorgestrel; and sometimes defined as those containing the progestins norethisterone, norethisterone acetate, etynodiol acetate, norgestrel, levonorgestrel, or norgestimate and
- Third generation COCPs are sometimes defined as those containing the progestins desogestrel or gestodene; and sometimes defined as those containing desogestrel, gestodene, or norgestimate.
- Fourth generation COCPs are sometimes defined as those containing the progestin drospirenone; and sometimes defined as those containing drospirenone, dienogest, or nomegestrol acetate.
Medical use
(File:pillpacketopen.jpg|frame|Half-used blister pack of LevlenED)Contraceptive use
Combined oral contraceptive pills are a type of oral medication that were originally designed to be taken every day at the same time of day in order to prevent pregnancy.WEB,www.plannedparenthood.org/learn/birth-control/birth-control-pill/how-do-i-use-the-birth-control-pill, How to Use Birth Control Pills, Planned Parenthood, 29 November 2017, 6 December 2017,web.archive.org/web/20171206140038/https://www.plannedparenthood.org/learn/birth-control/birth-control-pill/how-do-i-use-the-birth-control-pill, live, BOOK, Callahan TL, Caughey AB, Blueprints obstetrics & gynecology, 2013, Lippincott Williams & Wilkins, 978-1-4511-1702-8, 6th, Baltimore, MD, 800907400, There are many different formulations or brands, but the average pack is designed to be taken over a 28-day period (also known as a cycle). For the first 21 days of the cycle, users take a daily pill that contains two hormones, estrogen and progestogen. During the last 7 days of the cycle, users take daily placebo (biologically inactive) pills and these days are considered hormone-free days. Although these are hormone-free days, users are still protected from pregnancy during this time.Some COCP packs only contain 21 pills and users are advised to take no pills for the last 7 days of the cycle. Other COCP formulations contain 91 pills, consisting of 84 days of active hormones followed by 7 days of placebo (Seasonale). COCP formulations can contain 24 days of active hormone pills followed by 4 days of placebo pills (e.g. Yaz 28 and Loestrin 24 Fe) as a means to decrease the severity of placebo effects. These COCPs containing active hormones and a placebo/hormone-free period are called cyclic COCPs. Once a pack of cyclical COCP treatment is completed, users start a new pack and new cycle.WEB,youngwomenshealth.org/birth-control-pills-all-guides/, Birth Control Pills All Guides, October 2014, 20 October 2018, 31 May 2023,web.archive.org/web/20230531032622/https://youngwomenshealth.org/birth-control-pills-all-guides/, live, Most monophasic COCPs can be used continuously such that patients can skip placebo days and continuously take hormone active pills from a COCP pack.JOURNAL, Teal S, Edelman A, Contraception Selection, Effectiveness, and Adverse Effects: A Review, JAMA, 326, 24, 2507–2518, December 2021, 34962522, 10.1001/jama.2021.21392, 245557522, free, doi, One of the most common reasons users do this is to avoid or diminish withdrawal bleeding. The majority of women on cyclic COCPs have regularly scheduled withdrawal bleeding, which is vaginal bleeding mimicking users’ menstrual cycles with the exception of lighter menstrual bleeding compared to bleeding patterns prior to COCP commencement. As such, a study reported that out of 1003 women taking COCPs approximately 90% reported regularly scheduled withdrawal bleeds over a 90-day standard reference period. Withdrawal bleeding usually occurs during the placebo, hormone-free days. Therefore, avoiding placebo days can diminish withdrawal bleeding among other placebo effects.Effectiveness
If used exactly as instructed, the estimated risk of getting pregnant is 0.3% which means that about 3 in 1000 women on COCPs will become pregnant within one year.BOOK, Selected practice recommendations for contraceptive use, World Health Organization, ((World Health Organization)), 978-92-4-156540-0, Third, Geneva, 150, 985676200, 2016, 10665/252267, free, World Health Organization, However, typical use of COCPs by users often consists of timing errors, forgotten pills, or unwanted side effects. With typical use, the estimated risk of getting pregnant is about 9% which means that about 9 in 100 women on COCPs will become pregnant in one year. The perfect use failure rate is based on a review of pregnancy rates in clinical trials, and the typical use failure rate is based on a weighted average of estimates from the 1995 and 2002 US National Surveys of Family Growth (NSFG), corrected for underreporting of abortions.JOURNAL, Trussell J, Understanding contraceptive failure, Best Practice & Research. Clinical Obstetrics & Gynaecology, 23, 2, 199–209, April 2009, 19223239, 3638203, 10.1016/j.bpobgyn.2008.11.008, Contraception and Sexual Health, JOURNAL, Trussell J, Contraceptive failure in the United States, Contraception, 83, 5, 397–404, May 2011, 21477680, 3638209, 10.1016/j.contraception.2011.01.021, Several factors account for typical use effectiveness being lower than perfect use effectiveness:- Mistakes on part of those providing instructions on how to use the method
- Mistakes on part of the user
- Conscious user non-compliance with instructions
- Missing more than one active pill in a packet,
- Delay in starting the next packet of active pills (i.e., extending the pill-free, inactive pill or placebo pill period beyond 7 days),
- Intestinal malabsorption of active pills due to vomiting or diarrhea,
- Drug-drug interactions among COCPs and other medications of the user that decrease contraceptive estrogen and/or progestogen levels.
Role of placebo pills
The role of the placebo pills is two-fold: to allow the user to continue the routine of taking a pill every day and to simulate the average menstrual cycle. By continuing to take a pill every day, users remain in the daily habit even during the week without hormones. Failure to take pills during the placebo week does not impact the effectiveness of the pill, provided that daily ingestion of active pills is resumed at the end of the week.{{citation needed|date=July 2023}}The placebo, or hormone-free, week in the 28-day pill package simulates an average menstrual cycle, though the hormonal events during a pill cycle are significantly different from those of a normal ovulatory menstrual cycle. Because the pill suppresses ovulation (to be discussed more in the Mechanism of action section), birth control users do not have true menstrual periods. Instead, it is the lack of hormones for a week that causes a withdrawal bleed. The withdrawal bleeding that occurs during the break from active pills has been thought to be reassuring, a physical confirmation of not being pregnant.MAGAZINE, Gladwell M, 10 March 2000, John Rock’s Error,www.gladwell.com/2000/2000_03_10_a_rock.htm, The New Yorker,www.gladwell.com/2000/2000_03_10_a_rock.htm," title="web.archive.org/web/20130511133811www.gladwell.com/2000/2000_03_10_a_rock.htm,">web.archive.org/web/20130511133811www.gladwell.com/2000/2000_03_10_a_rock.htm, 11 May 2013, 4 February 2009, The withdrawal bleeding is also predictable. Unexpected breakthrough bleeding can be a possible side effect of longer term active regimens.WEB,www.mayoclinic.com/health/birth-control-pill/WO00098, Birth control pill FAQ: Benefits, risks and choices, Mayo Clinic staff, Mayo Clinic, 1 February 2013, 26 December 2012,www.mayoclinic.com/health/birth-control-pill/WO00098," title="web.archive.org/web/20121226060838www.mayoclinic.com/health/birth-control-pill/WO00098,">web.archive.org/web/20121226060838www.mayoclinic.com/health/birth-control-pill/WO00098, live, Since it is not uncommon for menstruating women to become anemic, some placebo pills may contain an iron supplement.WEB,www.patentstorm.us/patents/6451778/description.html, US Patent:Oral contraceptive:Patent 6451778 Issued on September 17, 2002 Estimated Expiration Date: July 2, 2017., PatentStorm LLC,www.patentstorm.us/patents/6451778/description.html," title="web.archive.org/web/20110613020809www.patentstorm.us/patents/6451778/description.html,">web.archive.org/web/20110613020809www.patentstorm.us/patents/6451778/description.html, 13 June 2011, dead, 19 November 2010, JOURNAL, Hercberg S, Preziosi P, Galan P, Iron deficiency in Europe, Public Health Nutrition, 4, 2B, 537–545, April 2001, 11683548, 10.1079/phn2001139, free, doi, This replenishes iron stores that may become depleted during menstruation. As well, birth control pills, such as COCPs, are sometimes fortified with folic acid as it is recommended to take folic acid supplementation in the months prior to pregnancy to decrease the likelihood of neural tube defect in infants.JOURNAL, Viswanathan M, Treiman KA, Kish-Doto J, Middleton JC, Coker-Schwimmer EJ, Nicholson WK, Folic Acid Supplementation for the Prevention of Neural Tube Defects: An Updated Evidence Report and Systematic Review for the US Preventive Services Task Force, JAMA, 317, 2, 190–203, January 2017, 28097361, 10.1001/jama.2016.19193, JOURNAL, Lassi ZS, Bhutta ZA, Clinical utility of folate-containing oral contraceptives, International Journal of Women’s Health, 4, 185–190, April 2012, 22570577, 3346209, 10.2147/IJWH.S18611, free, doi,No or less frequent placebos
If the pill formulation is monophasic, meaning each hormonal pill contains a fixed dose of hormones, it is possible to skip withdrawal bleeding and still remain protected against conception by skipping the placebo pills altogether and starting directly with the next packet. Attempting this with bi- or tri-phasic pill formulations carries an increased risk of breakthrough bleeding and may be undesirable. It will not, however, increase the risk of getting pregnant.Starting in 2003, women have also been able to use a three-month version of the pill.WEB,www.fda.gov/bbs/topics/ANSWERS/2003/ANS01251.html, FDA Approves Seasonal Oral Contraceptive, U.S. Food and Drug Administration (FDA), 25 September 2003,web.archive.org/web/20061007101134/https://www.fda.gov/bbs/topics/ANSWERS/2003/ANS01251.html, 7 October 2006, 9 November 2006, Similar to the effect of using a constant-dosage formulation and skipping the placebo weeks for three months, Seasonale gives the benefit of less frequent periods, at the potential drawback of breakthrough bleeding. Seasonique is another version in which the placebo week every three months is replaced with a week of low-dose estrogen.A version of the combined pill has also been packaged to eliminate placebo pills and withdrawal bleeds. Marketed as Anya or Lybrel, studies have shown that after seven months, 71% of users no longer had any breakthrough bleeding, the most common side effect of going longer periods of time without breaks from active pills.While more research needs to be done to assess the long term safety of using COCP’s continuously, studies have shown there may be no difference in short term adverse effects when comparing continuous use versus cyclic use of birth control pills.Non-contraceptive use
The hormones in the pill have also been used to treat other medical conditions, such as polycystic ovary syndrome (PCOS), endometriosis, adenomyosis, acne, hirsutism, amenorrhea, menstrual cramps, menstrual migraines, menorrhagia (excessive menstrual bleeding), menstruation-related or fibroid-related anemia and dysmenorrhea (painful menstruation).WEB,www.youngwomenshealth.org/med-uses-ocp.html, Medical Uses of the Birth Control Pill, CYWH Staff, 1 February 2013, 18 October 2011, 5 February 2013,www.youngwomenshealth.org/med-uses-ocp.html," title="web.archive.org/web/20130205071228www.youngwomenshealth.org/med-uses-ocp.html,">web.archive.org/web/20130205071228www.youngwomenshealth.org/med-uses-ocp.html, dead, Besides acne, no oral contraceptives have been approved by the US FDA for the previously mentioned uses despite extensive use for these conditions.WEB,www.fda.gov/Drugs/ResourcesForYou/Consumers/ucm450624.htm, Information for Consumers (Drugs) - Find Information about a Drug, U.S. Food and Drug Administration (FDA), 13 December 2017, 14 November 2017,web.archive.org/web/20171114004746/https://www.fda.gov/Drugs/ResourcesForYou/Consumers/ucm450624.htm, dead,PCOS
The cause of PCOS, or polycystic ovary syndrome, is multifactorial and not well-understood. Women with PCOS often have higher than normal levels of luteinizing hormone (LH) and androgens that impact the normal function of the ovaries.WEB, Patient education: Polycystic ovary syndrome (PCOS) (Beyond the Basics),www.uptodate.com/contents/polycystic-ovary-syndrome-pcos-beyond-the-basics, 15 September 2022, UpToDate, 15 September 2022,web.archive.org/web/20220915125817/https://www.uptodate.com/contents/polycystic-ovary-syndrome-pcos-beyond-the-basics, live, While multiple small follicles develop in the ovary, none are able to grow in size enough to become the dominant follicle and trigger ovulation.JOURNAL, Dumesic, Daniel A., Lobo, Rogerio A., August 2013, Cancer risk and PCOS, Steroids, 78, 8, 782–785, 10.1016/j.steroids.2013.04.004, 1878-5867, 23624028, 10185317, This leads to an imbalance of LH, follicle stimulating hormone, estrogen, and progesterone. Without ovulation, unopposed estrogen can lead to endometrial hyperplasia, or overgrowth of tissue in the uterus.WEB, Polycystic Ovary Syndrome (PCOS),www.acog.org/en/womens-health/faqs/polycystic-ovary-syndrome-pcos, 15 September 2022, American College of Obstetricians and Gynecologists, 15 September 2022,web.archive.org/web/20220915125811/https://www.acog.org/en/womens-health/faqs/polycystic-ovary-syndrome-pcos, live, This endometrial overgrowth is more likely to become cancerous than normal endometrial tissue.Barakat RR, Park RC, Grigsby PW, et al. Corpus: Epithelial Tumors. In: Principles and Practice of Gynecologic Oncology, 2nd, Hoskins WH, Perez CA, Young RC (Eds), Lippincott-Raven Publishers, Philadelphia 1997. p.859 Thus, although the data varies, it is generally agreed upon by most gynecological societies that due to the unopposed estrogen, women with PCOS are at higher risk for endometrial cancer.JOURNAL, Hardiman P, Pillay OC, Atiomo W, Polycystic ovary syndrome and endometrial carcinoma, Lancet, 361, 9371, 1810–2, May 2003, 12781553, 10.1016/s0140-6736(03)13409-5, 27453081, To reduce the risk of endometrial cancer, it is often recommended that women with PCOS who do not desire pregnancy take hormonal contraceptives to prevent the effects of unopposed estrogen. Both COCPs and progestin-only methods are recommended.{{citation needed|date=July 2023}} It is the progestin component of COCPs that protects the endometrium from hyperplasia, and thus reduces a woman with PCOS’s endometrial cancer risk.WEB, Can birth control pills cure PCOS,www.acog.org/en/womens-health/experts-and-stories/ask-acog/can-birth-control-pills-cure-pcos, 18 September 2022, American College of Obstetricians and Gynecologists, 20 September 2022,web.archive.org/web/20220920171751/https://www.acog.org/en/womens-health/experts-and-stories/ask-acog/can-birth-control-pills-cure-pcos, live, COCPs are preferred to progestin-only methods in women who also have uncontrolled acne, symptoms of hirsutism, and androgenic alopecia, because COCPs can help treat these symptoms.Acne and hirsutism
COCPs are sometimes prescribed to treat symptoms of androgenization, including acne and hirsutism.JOURNAL, Huber J, Walch K, January 2006, Treating acne with oral contraceptives: use of lower doses, Contraception, 73, 1, 23–9, 10.1016/j.contraception.2005.07.010, 16371290, The estrogen component of COCPs appears to suppress androgen production in the ovaries. Estrogen also leads to increased synthesis of sex hormone binding globulin, which causes a decrease in the levels of free testosterone.WEB, Hormonal Contraceptives and Acne: A Retrospective Analysis of 2147 Patients,jddonline.com/articles/hormonal-contraceptives-and-acne-a-retrospective-analysis-of-2147-patients-S1545961616P0670X/, 15 September 2022, JDDonline - Journal of Drugs in Dermatology, 19 May 2022,web.archive.org/web/20220519125904/https://jddonline.com/articles/hormonal-contraceptives-and-acne-a-retrospective-analysis-of-2147-patients-S1545961616P0670X/, live, Ultimately, the drop in the level of free androgens leads to a decrease in the production of sebum, which is a major contributor to development of acne.{{citation needed|date=July 2023}} Four different oral contraceptives have been FDA approved to treat moderate acne if the patient is at least 14 or 15 years old, has already begun menstruating, and needs contraception. These include Ortho Tri-Cyclen, Estrostep, Beyaz, and YAZ.WEB, Birth Control of Acne,www.webmd.com/skin-problems-and-treatments/acne/birth-control-for-acne-treatment, 1 February 2013, WebMD, LLC, Chang L, 26 January 2013,www.webmd.com/skin-problems-and-treatments/acne/birth-control-for-acne-treatment," title="web.archive.org/web/20130126051445www.webmd.com/skin-problems-and-treatments/acne/birth-control-for-acne-treatment,">web.archive.org/web/20130126051445www.webmd.com/skin-problems-and-treatments/acne/birth-control-for-acne-treatment, live, WEB, DailyMed - ORTHO TRI CYCLEN- norgestimate and ethinyl estradiol ORTHO CYCLEN- norgestimate and ethinyl estradiol,dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=384e7a40-dcbd-4908-bf5e-65abc9932973#section-1.1, 13 December 2017, dailymed.nlm.nih.gov, 14 December 2017,web.archive.org/web/20171214072204/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=384e7a40-dcbd-4908-bf5e-65abc9932973#section-1.1, live, WEB, Beyaz Package Insert,www.accessdata.fda.gov/drugsatfda_docs/label/2012/022532s004lbl.pdf, U.S. Food and Drug Administration (FDA), 6 August 2019, 15 April 2023,web.archive.org/web/20230415183259/https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/022532s004lbl.pdf, live, Hirsutism is the growth of coarse, dark hair where women typically grow only fine hair or no hair at all.WEB, Patient education: Hirsutism (excess hair growth in females) (Beyond the Basics),www.uptodate.com/contents/hirsutism-excess-hair-growth-in-women-beyond-the-basics, 18 September 2022, UpToDate, 20 September 2022,web.archive.org/web/20220920171546/https://www.uptodate.com/contents/hirsutism-excess-hair-growth-in-women-beyond-the-basics, live, This hair growth on the face, chest, and abdomen is also mediated by higher levels or action of androgens. Therefore, COCPs also work to treat these symptoms by lowering the levels of free circulating androgens.WEB, Hirsutism: What It Is, In Women, Causes, PCOS & Treatment,my.clevelandclinic.org/health/diseases/14523-hirsutism, 18 September 2022, Cleveland Clinic, 19 September 2022,web.archive.org/web/20220919044547/https://my.clevelandclinic.org/health/diseases/14523-hirsutism, live,Endometriosis
For pelvic pain associated with endometriosis, COCPs are considered a first-line medical treatment, along with NSAIDs, GnRH agonists, and aromatase inhibitors.WEB,www.acog.org/Patients/FAQs/Endometriosis#treated, ACOG Endometriosis FAQ, 3 March 2019, 1 February 2020,web.archive.org/web/20200201032951/https://www.acog.org/Patients/FAQs/Endometriosis#treated, live, COCPs work to suppress the growth of the extra-uterine endometrial tissue. This works to lessen its inflammatory effects. COCPs, along with the other medical treatments listed above, do not eliminate the extra-uterine tissue growth, they just reduce the symptoms. Surgery is the only definitive treatment. Studies looking at rates of pelvic pain recurrence after surgery have shown that continuous use of COCPs is more effective at reducing the recurrence of pain than cyclic use.JOURNAL, Zorbas KA, Economopoulos KP, Vlahos NF, Continuous versus cyclic oral contraceptives for the treatment of endometriosis: a systematic review, Archives of Gynecology and Obstetrics, 292, 1, 37–43, July 2015, 25644508, 10.1007/s00404-015-3641-1, 23340983,Adenomyosis
Similar to endometriosis, adenomyosis is often treated with COCPs to suppress the growth the endometrial tissue that has grown into the myometrium. Unlike endometriosis however, levonorgestrel containing IUDs are more effective at reducing pelvic pain in adenomyosis than COCPs.Menorrhagia
In the average menstrual cycle, a woman typically loses 35 to 40 milliliters of blood.WEB, Heavy Menstrual Bleeding,www.acog.org/en/womens-health/faqs/heavy-menstrual-bleeding, 18 September 2022, American College of Obstetricians and Gynecologists, 20 September 2022,web.archive.org/web/20220920170333/https://www.acog.org/en/womens-health/faqs/heavy-menstrual-bleeding, live, However, up to 20% of women experience much heavier bleeding, or menorrhagia.JOURNAL, Apgar, Barbara S., Kaufman, Amanda H., George-Nwogu, Uche, Kittendorf, Anne, 15 June 2007, Treatment of Menorrhagia,www.aafp.org/pubs/afp/issues/2007/0615/p1813.html, American Family Physician, 75, 12, 1813–1819, 17619523, 15 September 2022, 6 October 2022,web.archive.org/web/20221006155406/https://www.aafp.org/pubs/afp/issues/2007/0615/p1813.html, live, This excess blood loss can lead to anemia, with symptoms of fatigue and weakness, as well as disruption in their normal life activities.WEB, Patient education: Heavy or prolonged menstrual bleeding (menorrhagia) (Beyond the Basics),www.uptodate.com/contents/heavy-or-prolonged-menstrual-bleeding-menorrhagia-beyond-the-basics/print, 15 September 2022, UpToDate, 15 September 2022,web.archive.org/web/20220915132011/https://www.uptodate.com/contents/heavy-or-prolonged-menstrual-bleeding-menorrhagia-beyond-the-basics/print, live, COCPs contain progestin, which causes the lining of the uterus to be thinner, resulting in lighter bleeding episodes for those with heavy menstrual bleeding.WEB, Noncontraceptive Benefits of Birth Control Pills,www.reproductivefacts.org/news-and-publications/patient-fact-sheets-and-booklets/documents/fact-sheets-and-info-booklets/noncontraceptive-benefits-of-birth-control-pills/, 15 September 2022, American Society for Reproductive Medicine (ASRM), 13 September 2022,web.archive.org/web/20220913013344/https://www.reproductivefacts.org/news-and-publications/patient-fact-sheets-and-booklets/documents/fact-sheets-and-info-booklets/noncontraceptive-benefits-of-birth-control-pills/, dead,Amenorrhea
Although the pill is sometimes prescribed to induce menstruation on a regular schedule for women bothered by irregular menstrual cycles, it actually suppresses the normal menstrual cycle and then mimics a regular 28-day monthly cycle.Women who are experiencing menstrual dysfunction due to female athlete triad are sometimes prescribed oral contraceptives as pills that can create menstrual bleeding cycles.{{Citation|title=Five Things Physicians and Patients Should Question|date=24 April 2014|url=http://www.choosingwisely.org/doctor-patient-lists/american-medical-society-for-sports-medicine/|author1=American Medical Society for Sports Medicine|author1-link=American Medical Society for Sports Medicine|work=Choosing Wisely: an initiative of the ABIM Foundation|publisher=American Medical Society for Sports Medicine|access-date=29 July 2014|archive-date=29 July 2014|archive-url=https://web.archive.org/web/20140729224526www.choosingwisely.org/doctor-patient-lists/american-medical-society-for-sports-medicine/|url-status=live}} However, the condition’s underlying cause is energy deficiency and should be treated by correcting the imbalance between calories eaten and calories burned by exercise. Oral contraceptives should not be used as an initial treatment for female athlete triad.Contraindications
While combined oral contraceptives are generally considered to be a relatively safe medication, they are contraindicated for those with certain medical conditions. The World Health Organization and the US Centers for Disease Control and Prevention publish guidance, called medical eligibility criteria, on the safety of birth control in the context of medical conditions.Hypercoagulability
Estrogen in high doses can increase risk of blood clots. All COCP users have a small increase in the risk of venous thromboembolism compared with non-users; this risk is greatest within the first year of COCP use.JOURNAL, Black A, Guilbert E, Costescu D, Dunn S, Fisher W, Kives S, Mirosh M, Norman WV, Pymar H, Reid R, Roy G, Varto H, Waddington A, Wagner MS, Whelan AM, No. 329-Canadian Contraception Consensus Part 4 of 4 Chapter 9: Combined Hormonal Contraception, Journal of Obstetrics and Gynaecology Canada, 39, 4, 229–268.e5, April 2017, 28413042, 10.1016/j.jogc.2016.10.005, Individuals with any pre-existing medical condition that also increases their risk for blood clots have a more significant increase in risk of thrombotic events with COCP use. These conditions include but are not limited to high blood pressure, pre-existing cardiovascular disease (such as valvular heart disease or ischemic heart diseaseBOOK, Cooper DB, Patel P, Mahdy H, Oral Contraceptive Pills, 2019,www.ncbi.nlm.nih.gov/books/NBK430882/, StatPearls, StatPearls Publishing, 28613632, 5 August 2019, 3 May 2019,web.archive.org/web/20190503071035/https://www.ncbi.nlm.nih.gov/books/NBK430882/, live, ), history of thromboembolism or pulmonary embolism, cerebrovascular accident, and a familial tendency to form blood clots (such as familial factor V Leiden).WEB,www.webmd.com/sex/birth-control/birth-control-pills?page=5#1, Can Any Woman Take Birth Control Pills?, WebMD, 8 May 2016, 3 May 2016,www.webmd.com/sex/birth-control/birth-control-pills?page=5#1," title="web.archive.org/web/20160503120843www.webmd.com/sex/birth-control/birth-control-pills?page=5#1,">web.archive.org/web/20160503120843www.webmd.com/sex/birth-control/birth-control-pills?page=5#1, live, There are conditions that, when associated with COCP use, increase risk of adverse effects other than thrombosis. For example, women with a history of migraine with aura have an increased risk of stroke when using COCPs, and women who smoke over age 35 and use COCPs are at higher risk of myocardial infarction.Pregnancy and postpartum
Women who are known to be pregnant should not take COCPs. Those in the postpartum period who are breastfeeding are also advised not to start COCPs until 4 weeks after birth due to increased risk of blood clots. While studies have demonstrated conflicting results about the effects of COCPs on lactation duration and milk volume, there exist concerns about the transient risk of COCPs on breast milk production when breastfeeding is being established early postpartum.JOURNAL, Lopez LM, Grey TW, Stuebe AM, Chen M, Truitt ST, Gallo MF, Combined hormonal versus nonhormonal versus progestin-only contraception in lactation, The Cochrane Database of Systematic Reviews, 3, CD003988, March 2015, 2015, 25793657, 10.1002/14651858.CD003988.pub2, Cochrane Fertility Regulation Group, 10644229, Due to the stated risks and additional concerns on lactation, women who are breastfeeding are not advised to start COCPs until at least six weeks postpartum, while women who are not breastfeeding and have no other risks factors for blood clots may start COCPs after 21 days postpartum.WEB, 9 April 2020, Classifications for Combined Hormonal Contraceptives,www.cdc.gov/reproductivehealth/contraception/mmwr/mec/appendixd.html, 7 December 2020, U.S. Centers for Disease Control and Prevention (CDC), 27 November 2020,web.archive.org/web/20201127184611/https://www.cdc.gov/reproductivehealth/contraception/mmwr/mec/appendixd.html, live, BOOK,www.who.int/publications/i/item/9789241549158, Medical eligibility criteria for contraceptive use, World Health Organization, 2015, 978-92-4-154915-8, Fifth, Geneva, Switzerland, 932048744, 10665/181468, free, ((World Health Organization)), World Health Organization, 11 February 2024, 11 February 2024,web.archive.org/web/20240211070350/https://www.who.int/publications/i/item/9789241549158, live,Breast cancer
The World Health Organization (WHO) does not recommend the use of COCPs in women with breast cancer.JOURNAL, Curtis KM, Tepper NK, Jatlaoui TC, Berry-Bibee E, Horton LG, Zapata LB, Simmons KB, Pagano HP, Jamieson DJ, Whiteman MK, July 2016, U.S. Medical Eligibility Criteria for Contraceptive Use, 2016,www.cdc.gov/mmwr/volumes/65/rr/pdfs/rr6503.pdf, MMWR. Recommendations and Reports, 65, 3, 1–103, 10.15585/mmwr.rr6503a1, 27467196, 1057-5987, free, doi, 11 February 2024, 16 October 2020,web.archive.org/web/20201016231003/https://www.cdc.gov/mmwr/volumes/65/rr/pdfs/rr6503.pdf, live, JOURNAL, Tepper NK, Curtis KM, Cox S, Whiteman MK, Update to U.S. Medical Eligibility Criteria for Contraceptive Use, 2016: Updated Recommendations for the Use of Contraception Among Women at High Risk for HIV Infection, MMWR. Morbidity and Mortality Weekly Report, 69, 14, 405–410, April 2020, 32271729, 7147901, 10.15585/mmwr.mm6914a3,www.cdc.gov/mmwr/volumes/69/wr/pdfs/mm6914a3-H.pdf, free, doi, 11 February 2024, 9 June 2023,web.archive.org/web/20230609055201/https://www.cdc.gov/mmwr/volumes/69/wr/pdfs/mm6914a3-H.pdf, live, Since COCPs contain both estrogen and progestin, they are not recommended to be used in those with hormonally-sensitive cancers, including some types of breast cancer.WEB, Is There a Link Between Birth Control Pills and Higher Breast Cancer Risk?,www.breastcancer.org/research-news/study-questions-birth-control-and-risk, 18 September 2022, www.breastcancer.org, 20 September 2022,web.archive.org/web/20220920171723/https://www.breastcancer.org/research-news/study-questions-birth-control-and-risk, live, {{Unreliable medical source|date=February 2024}}WEB, Pernambuco-Holsten, Christina, Birth Control and Cancer Risk: 6 Things You Should Know,www.mskcc.org/news/birth-control-and-cancer-risk, 18 September 2022, Memorial Sloan Kettering Cancer Center, 25 September 2018, 20 September 2022,web.archive.org/web/20220920173430/https://www.mskcc.org/news/birth-control-and-cancer-risk, live, Non-hormonal contraceptive methods, such as the Copper IUD or condoms,WEB, What are the best birth control options that aren’t hormonal?,www.plannedparenthood.org/learn/ask-experts/what-are-the-best-birth-control-options-that-arent-hormonal, 18 September 2022, Planned Parenthood, 20 September 2022,web.archive.org/web/20220920171208/https://www.plannedparenthood.org/learn/ask-experts/what-are-the-best-birth-control-options-that-arent-hormonal, live, should be the first-line contraceptive choice for these patients instead of COCPs.WEB, Do Hormonal Contraceptives Increase Breast Cancer Risk?,www.breastcancer.org/research-news/do-hormonal-contraceptives-increase-risk, 18 September 2022, www.breastcancer.org, 20 September 2022,web.archive.org/web/20220920172638/https://www.breastcancer.org/research-news/do-hormonal-contraceptives-increase-risk, live, {{Unreliable medical source|date=February 2024}}Other
Women with known or suspected endometrial cancer or unexplained uterine bleeding should also not take COCPs to avoid health risks. COCPs are also contraindicated for people with advanced diabetes, liver tumors, hepatic adenoma or severe cirrhosis of the liver. COCPs are metabolized in the liver and thus liver disease can lead to reduced elimination of the medication. Additionally, severe hypercholesterolemia and hypertriglyceridemia are also contraindications, but the evidence showing that COCP’s lead to worse outcomes in this population is weak. Obesity is not considered to be a contraindication to taking COCPs.Side effects
It is generally accepted that the health risks of oral contraceptives are lower than those from pregnancy and birth,BOOK, Crooks RL, Baur K, Our Sexuality, 2005, Thomson Wadsworth, Belmont, CA, 978-0-534-65176-3, {{page needed|date=August 2012}} and “the health benefits of any method of contraception are far greater than any risks from the method”.BOOK, WHO, 2005,www.who.int/publications/i/item/9241593229, Decision-Making Tool for Family Planning Clients and Providers, Appendix 10: Myths about contraception, 14 September 2022, 7 January 2007,www.who.int/reproductive-health/family_planning/counselling.htm," title="web.archive.org/web/20070107004503www.who.int/reproductive-health/family_planning/counselling.htm,">web.archive.org/web/20070107004503www.who.int/reproductive-health/family_planning/counselling.htm, live, Some organizations have argued that comparing a contraceptive method to no method (pregnancy) is not relevant—instead, the comparison of safety should be among available methods of contraception.WEB, Holck S, Contraceptive Safety, Special Challenges in Third World Women’s Health, 1989 Annual Meeting of the American Public Health Association,www.users.interport.net/i/w/iwhc/sc_cs.html, 7 October 2006, 8 November 2017,www.users.interport.net/i/w/iwhc/sc_cs.html," title="web.archive.org/web/20171108202427www.users.interport.net/i/w/iwhc/sc_cs.html,">web.archive.org/web/20171108202427www.users.interport.net/i/w/iwhc/sc_cs.html, live,Common
Different sources note different incidence of side effects. The most common side effect is breakthrough bleeding. A 1992 French review article said that as many as 50% of new first-time users discontinue the birth control pill before the end of the first year because of the annoyance of side effects such as breakthrough bleeding and amenorrhea.JOURNAL, Serfaty D, Medical aspects of oral contraceptive discontinuation, Advances in Contraception, 8, Suppl 1, 21–33, October 1992, 1442247, 10.1007/bf01849448, 11876371, A 2001 study by the Kinsey Institute exploring predictors of discontinuation of oral contraceptives found that 47% of 79 people discontinued the pill.JOURNAL, Sanders SA, Graham CA, Bass JL, Bancroft J, A prospective study of the effects of oral contraceptives on sexuality and well-being and their relationship to discontinuation, Contraception, 64, 1, 51–8, July 2001, 11535214, 10.1016/S0010-7824(01)00218-9, One 1994 study found that women using birth control pills blinked 32% more often than those not using the contraception.JOURNAL, Yolton DP, Yolton RL, López R, Bogner B, Stevens R, Rao D, The effects of gender and birth control pill use on spontaneous blink rates, Journal of the American Optometric Association, 65, 11, 763–70, November 1994, 7822673, On the other hand, the pills can sometimes improve conditions such as dysmenorrhea, premenstrual syndrome, and acne,JOURNAL, Huber JC, Bentz EK, Ott J, Tempfer CB, Non-contraceptive benefits of oral contraceptives, Expert Opinion on Pharmacotherapy, 9, 13, 2317–2325, September 2008, 18710356, 10.1517/14656566.9.13.2317, 73326364, reduce symptoms of endometriosis and polycystic ovary syndrome, and decrease the risk of anemia.BOOK, Nelson RJ, An introduction to behavioral endocrinology, 3rd, 2005, Sinauer Associates, Sunderland, Mass, 978-0-87893-617-5, {{page needed|date=August 2012}} Use of oral contraceptives also reduces lifetime risk of ovarian and endometrial cancer.JOURNAL, Vo C, Carney ME, Ovarian cancer hormonal and environmental risk effect, Obstetrics and Gynecology Clinics of North America, 34, 4, 687–700, viii, December 2007, 18061864, 10.1016/j.ogc.2007.09.008, JOURNAL, Bandera CA, Advances in the understanding of risk factors for ovarian cancer, The Journal of Reproductive Medicine, 50, 6, 399–406, June 2005, 16050564, JOURNAL, Pragout D, Laurence V, Baffet H, Raccah-Tebeka B, Rousset-Jablonski C, Contraception et cancer. RPC Contraception CNGOF, Contraception and cancer: CNGOF Contraception Guidelines, Gynécologie Obstétrique Fertilité & Sénologie, 46, 12, 834–844, December 2018, 30385358, 10.1016/j.gofs.2018.10.010, 196536513, Women have experienced amenorrhea, easy administration, and improvement in sexual function in some patients.JOURNAL, Wanyonyi, Sikolia Z., Stones, William R., Sequeira, Evan, 2011, Health-related quality of life changes among users of depot medroxyprogesterone acetate for contraception, Contraception, 84, 5, e17–e22, 10.1016/j.contraception.2011.05.022, 22018133, Nausea, vomiting, headache, bloating, breast tenderness, swelling of the ankles/feet (fluid retention), or weight change may occur. Vaginal bleeding between periods (spotting) or missed/irregular periods may occur, especially during the first few months of use.WEB,www.webmd.com/drugs/2/drug-17518-115/apri-oral/progestin-estrogen-contraceptive---oral/details, Apri oral : Uses, Side Effects, Interactions, Pictures, Warnings & Dosing, 2 December 2016, 13 December 2016,www.webmd.com/drugs/2/drug-17518-115/apri-oral/progestin-estrogen-contraceptive---oral/details," title="web.archive.org/web/20161213184059www.webmd.com/drugs/2/drug-17518-115/apri-oral/progestin-estrogen-contraceptive---oral/details,">web.archive.org/web/20161213184059www.webmd.com/drugs/2/drug-17518-115/apri-oral/progestin-estrogen-contraceptive---oral/details, live,Heart and blood vessels
Combined oral contraceptives increase the risk of venous thromboembolism (including deep vein thrombosis (DVT) and pulmonary embolism (PE)).JOURNAL, Blanco-Molina A, Monreal M, Venous thromboembolism in women taking hormonal contraceptives, Expert Review of Cardiovascular Therapy, 8, 2, 211–5, February 2010, 20136607, 10.1586/erc.09.175, 41309800, While lower doses of estrogen in COC pills may have a lower risk of stroke and myocardial infarction compared to higher estrogen dose pills (50 μg/day), users of low estrogen dose COC pills still have an increased risk compared to non-users.JOURNAL, Roach RE, Helmerhorst FM, Lijfering WM, Stijnen T, Algra A, Dekkers OM, Combined oral contraceptives: the risk of myocardial infarction and ischemic stroke, The Cochrane Database of Systematic Reviews, 8, 8, CD011054, August 2015, 26310586, 6494192, 10.1002/14651858.CD011054.pub2, These risks are greatest in women with additional risk factors, such as smoking (which increases risk substantially) and long-continued use of the pill, especially in women over 35 years of age.BOOK, Rang HP, Dale MM, Ritter JM, Flower RJ, Henderson G, Rang and Dale’s pharmacology, 7th, 2012, Elsevier/Churchill Livingstone, Edinburgh, 978-0-7020-3471-8, 426, The reproductive system, The overall absolute risk of venous thrombosis per 100,000 woman-years in current use of combined oral contraceptives is approximately 60, compared with 30 in non-users. The risk of thromboembolism varies with different types of birth control pills; compared with combined oral contraceptives containing levonorgestrel (LNG), and with the same dose of estrogen and duration of use, the rate ratio of deep venous thrombosis for combined oral contraceptives with norethisterone is 0.98, with norgestimate 1.19, with desogestrel (DSG) 1.82, with gestodene 1.86, with drospirenone (DRSP) 1.64, and with cyproterone acetate 1.88. In comparison, venous thromboembolism occurs in 100–200 per 100.000 pregnant women every year.JOURNAL, Venous thromboembolism in women: a specific reproductive health risk, Human Reproduction Update, 19, 5, 471–82, 2013, 23825156, 10.1093/humupd/dmt028, ESHRE Capri Workshop Group, free, doi, One study showed more than a 600% increased risk of blood clots for women taking COCPs with drospirenone compared with non-users, compared with 360% higher for women taking birth control pills containing levonorgestrel.JOURNAL, Lidegaard Ø, Milsom I, Geirsson RT, Skjeldestad FE, July 2012, Hormonal contraception and venous thromboembolism, Acta Obstetricia et Gynecologica Scandinavica, 91, 7, 769–78, 10.1111/j.1600-0412.2012.01444.x, 22568831, 2691199, free, doi, The US Food and Drug Administration (FDA) initiated studies evaluating the health of more than 800,000 women taking COCPs and found that the risk of VTE was 93% higher for women who had been taking drospirenone COCPs for 3 months or less and 290% higher for women taking drospirenone COCPs for 7–12 months, compared with women taking other types of oral contraceptives.JOURNAL, Dunn N, The risk of deep venous thrombosis with oral contraceptives containing drospirenone, BMJ, 342, d2519, April 2011, 21511807, 10.1136/bmj.d2519, 42721801, Based on these studies, in 2012, the FDA updated the label for drospirenone COCPs to include a warning that contraceptives with drospirenone may have a higher risk of dangerous blood clots.WEB, Highlights of Prescribing Information for Yasmin,www.accessdata.fda.gov/drugsatfda_docs/label/2012/021098s022lbl.pdf, U.S. Food and Drug Administration (FDA), 11 November 2012, 25 April 2012,www.accessdata.fda.gov/drugsatfda_docs/label/2012/021098s022lbl.pdf," title="web.archive.org/web/20120425002550www.accessdata.fda.gov/drugsatfda_docs/label/2012/021098s022lbl.pdf,">web.archive.org/web/20120425002550www.accessdata.fda.gov/drugsatfda_docs/label/2012/021098s022lbl.pdf, live, A 2015 systematic review and meta-analysis found that combined birth control pills were associated with 7.6-fold higher risk of cerebral venous sinus thrombosis, a rare form of stroke in which blood clotting occurs in the cerebral venous sinuses.JOURNAL, Amoozegar F, Ronksley PE, Sauve R, Menon BK, Hormonal contraceptives and cerebral venous thrombosis risk: a systematic review and meta-analysis, Front Neurol, 6, 7, 2015, 25699010, 4313700, 10.3389/fneur.2015.00007, free, doi, {{Risk of venous thromboembolism with hormone therapy and birth control pills (QResearch/CPRD)}}Cancer
Decreased risk of ovarian, endometrial, and colorectal cancers
Usage of combined oral concetraption decreased the risk of ovarian cancer, endometrial cancer, and colorectal cancer.BOOK, Bast RC, Brewer M, Zou C, Hernandez MA, Daley M, Ozols R, Lu K, Lu Z, Badgwell D, Mills GB, Skates S, Zhang Z, Chan D, Lokshin A, Yu Y, Prevention and Early Detection of Ovarian Cancer: Mission Impossible?, Cancer Prevention, 174, 91–100, 2007, 17302189, 10.1007/978-3-540-37696-5_9, 978-3-540-37695-8, Recent Results in Cancer Research, Two large cohort studies published in 2010 both found a significant reduction in adjusted relative risk of ovarian and endometrial cancer mortality in ever-users of OCs compared with never-users.JOURNAL, Hannaford PC, Iversen L, Macfarlane TV, Elliott AM, Angus V, Lee AJ, Mortality among contraceptive pill users: cohort evidence from Royal College of General Practitioners’ Oral Contraception Study, BMJ, 340, c927, March 2010, 20223876, 2837145, 10.1136/bmj.c927, JOURNAL, Vessey M, Yeates D, Flynn S, Factors affecting mortality in a large cohort study with special reference to oral contraceptive use, Contraception, 82, 3, 221–9, September 2010, 20705149, 10.1016/j.contraception.2010.04.006, The use of oral contraceptives (birth control pills) for five years or more decreases the risk of ovarian cancer in later life by 50%.JOURNAL, Nappi, Rossella E., Pellegrinelli, Alice, Campolo, Federica, Lanzo, Gabriele, Santamaria, Valentina, Suragna, Alessandro, Spinillo, Arsenio, Benedetto, Chiara, 2 January 2015, Effects of combined hormonal contraception on health and wellbeing: Women’s knowledge in northern Italy, The European Journal of Contraception & Reproductive Health Care, 20, 1, 36–46, 10.3109/13625187.2014.961598, 1362-5187, 25317952, 26048792, Combined oral contraceptive use reduces the risk of ovarian cancer by 40% and the risk of endometrial cancer by 50% compared with never users. The risk reduction increases with duration of use, with an 80% reduction in risk for both ovarian and endometrial cancer with use for more than 10 years. The risk reduction for both ovarian and endometrial cancer persists for at least 20 years.Increased risk of breast, cervical, and liver cancers
A report by a 2005 International Agency for Research on Cancer (IARC) working group found that COCs increase the risk of cancers of the breast, cervix and liver.JOURNAL, IARC Monographs on the Evaluation of Carcinogenic Risks to Humans, 91, 2007, Combined Estrogen-Progestogen Contraceptives,monographs.iarc.fr/ENG/Monographs/vol91/mono91-6.pdf, IARC working group, 14 September 2010, 3 August 2016,monographs.iarc.fr/ENG/Monographs/vol91/mono91-6.pdf," title="web.archive.org/web/20160803085912monographs.iarc.fr/ENG/Monographs/vol91/mono91-6.pdf,">web.archive.org/web/20160803085912monographs.iarc.fr/ENG/Monographs/vol91/mono91-6.pdf, live, A systematic review in 2010 did not support an increased overall cancer risk in users of combined oral contraceptive pills, but did find a slight increase in breast cancer risk among current users, which disappears 5–10 years after use has stopped; the study also found an increased risk of cervical and liver cancers.JOURNAL, Cibula D, Gompel A, Mueck AO, La Vecchia C, Hannaford PC, Skouby SO, Zikan M, Dusek L, Hormonal contraception and risk of cancer, Human Reproduction Update, 16, 6, 631–50, 2010, 20543200, 10.1093/humupd/dmq022, free, doi, A 2013 meta-analysis concluded that every use of birth control pills is associated with a modest increase in the risk of breast cancer (relative risk 1.08) and a reduced risk of colorectal cancer (relative risk 0.86) and endometrial cancer (relative risk 0.57). Cervical cancer risk in those infected with HPV is increased.JOURNAL, Gierisch JM, Coeytaux RR, Urrutia RP, Havrilesky LJ, Moorman PG, Lowery WJ, Dinan M, McBroom AJ, Hasselblad V, Sanders GD, Myers ER, Oral contraceptive use and risk of breast, cervical, colorectal, and endometrial cancers: a systematic review, Cancer Epidemiology, Biomarkers & Prevention, 22, 11, 1931–43, November 2013, 24014598, 10.1158/1055-9965.EPI-13-0298, free, doi, A similar small increase in breast cancer risk was observed in other meta analyses.JOURNAL, Anothaisintawee T, Wiratkapun C, Lerdsitthichai P, Kasamesup V, Wongwaisayawan S, Srinakarin J, Hirunpat S, Woodtichartpreecha P, Boonlikit S, Teerawattananon Y, Thakkinstian A, Risk factors of breast cancer: a systematic review and meta-analysis, Asia-Pacific Journal of Public Health, 25, 5, 368–87, September 2013, 23709491, 10.1177/1010539513488795, 206616972, JOURNAL, Zhu H, Lei X, Feng J, Wang Y, Oral contraceptive use and risk of breast cancer: a meta-analysis of prospective cohort studies, The European Journal of Contraception & Reproductive Health Care, 17, 6, 402–14, December 2012, 23061743, 10.3109/13625187.2012.715357, 33708638, A study of 1.8 million Danish women of reproductive age followed for 11 years found that the risk of breast cancer was 20% higher among those who currently or recently used hormonal contraceptives than among women who had never used hormonal contraceptives.JOURNAL, Mørch, LS, Skovlund, CW, Hannaford, PC, Iversen, L, Fielding, S, Lidegaard, Ø, Contemporary Hormonal Contraception and the Risk of Breast Cancer., The New England Journal of Medicine, 7 December 2017, 377, 23, 2228–2239, 10.1056/NEJMoa1700732, 29211679, 2164/15157, 4498610, free, This risk increased with duration of use, with a 38% increase in risk after more than 10 years of use.Weight
A 2016 systematic review found low quality evidence that studies of combination hormonal contraceptives showed no large difference in weight when compared with placebo or no intervention groups.JOURNAL, Lopez, Laureen M., Ramesh, Shanthi, Chen, Mario, Edelman, Alison, Otterness, Conrad, Trussell, James, Helmerhorst, Frans M., 28 August 2016, Progestin-only contraceptives: effects on weight, The Cochrane Database of Systematic Reviews, 2016, 8, CD008815, 10.1002/14651858.CD008815.pub4, 1469-493X, 5034734, 27567593, The evidence was not strong enough to be certain that contraceptive methods do not cause some weight change, but no major effect was found. This review also found “that women did not stop using the pill or patch because of weight change”.Sexual function and risk aversion
Sexual desire
{{See also|Gene-centered view of evolution|Automatic and controlled processes|Sexual arousal}}Some researchers question a causal link between COCP use and decreased libido;BOOK, Weir GC, DeGroot LJ, Grossman A, Marshall JF, Melmed S, Potts JT, Endocrinology, 5th, 2006, Elsevier Saunders, St. Louis, Mo, 978-0-7216-0376-6, 2999,archive.org/details/endocrinology0003unse/page/2999, {{page needed|date=August 2012}} a 2007 study of 1700 women found COCP users experienced no change in sexual satisfaction.JOURNAL, Westhoff CL, Heartwell S, Edwards S, Zieman M, Stuart G, Cwiak C, Davis A, Robilotto T, Cushman L, Kalmuss D, Oral contraceptive discontinuation: do side effects matter?, American Journal of Obstetrics and Gynecology, 196, 4, 412.e1–6; discussion 412.e6–7, April 2007, 17403440, 1903378, 10.1016/j.ajog.2006.12.015, A 2005 laboratory study of genital arousal tested fourteen women before and after they began taking COCPs. The study found that women experienced a significantly wider range of arousal responses after beginning pill use; decreases and increases in measures of arousal were equally common.JOURNAL, Seal BN, Brotto LA, Gorzalka BB, Oral contraceptive use and female genital arousal: methodological considerations, Journal of Sex Research, 42, 3, 249–58, August 2005, 19817038, 10.1080/00224490509552279, 10402534, JOURNAL, Higgins JA, Davis AR, Contraceptive sex acceptability: a commentary, synopsis and agenda for future research, Contraception, 90, 1, 4–10, July 2014, 24792147, 4247241, 10.1016/j.contraception.2014.02.029, In 2012, The Journal of Sexual Medicine published a review of research studying the effects of hormonal contraceptives on female sexual function that concluded that the sexual side effects of hormonal contraceptives are not well-studied and especially in regards to impacts on libido, with research establishing only mixed effects where only small percentages of women report experiencing an increase or decrease and majorities report being unaffected.JOURNAL, Burrows LJ, Basha M, Goldstein AT, 2012, The Effects of Hormonal Contraceptives on Female Sexuality: A Review, The Journal of Sexual Medicine, Elsevier, 9, 9, 2213–2223, 10.1111/j.1743-6109.2012.02848.x, 22788250, In 2013, The European Journal of Contraception & Reproductive Health Care published a review of 36 studies including 8,422 female subjects in total taking COCPs that found that 5,358 subjects (or 63.6 percent) reported no change in libido, 1,826 subjects (or 21.7 percent) reported an increase, and 1,238 subjects (or 14.7 percent) reported a decrease.JOURNAL, Pastor Z, Holla K, Chmel R, The influence of combined oral contraceptives on female sexual desire: a systematic review, The European Journal of Contraception & Reproductive Health Care, Taylor & Francis, 18, 1, 27–43, 2013, 23320933, 10.3109/13625187.2012.728643, 34748865, In 2019, Neuroscience & Biobehavioral Reviews published a meta-analysis of 22 published and 4 unpublished studies (with 7,529 female subjects in total) that evaluated whether women expose themselves to greater health risks at different points in the menstrual cycle including by sexual activity with partners and found that subjects in the last third of the follicular phase and at ovulation (when levels of endogenous estradiol and luteinizing hormones are heightened) experienced increased sexual activity with partners as compared with the luteal phase and during menstruation.JOURNAL, Boudesseul J, Gildersleeve KA, Haselton MG, Bègue L, Martie Haselton, 2019, Do women expose themselves to more health-related risks in certain phases of the menstrual cycle? A meta-analytic review, Neuroscience & Biobehavioral Reviews, 107, 505–524, 31513819, 10.1016/j.neubiorev.2019.08.016,psyarxiv.com/k8s5y/, 27 April 2023, 6 May 2023,web.archive.org/web/20230506202444/https://psyarxiv.com/k8s5y/, live, A 2006 study of 124 premenopausal women measured sex hormone-binding globulin (SHBG), including before and after discontinuation of the oral contraceptive pill. Women continuing use of oral contraceptives had SHBG levels four times higher than those who never used it, and levels remained elevated even in the group that had discontinued its use.JOURNAL, Panzer C, Wise S, Fantini G, Kang D, Munarriz R, Guay A, Goldstein I, Impact of oral contraceptives on sex hormone-binding globulin and androgen levels: a retrospective study in women with sexual dysfunction, The Journal of Sexual Medicine, 3, 1, 104–13, January 2006, 16409223, 10.1111/j.1743-6109.2005.00198.x,
Description of the study results in Medical News Today: WEB, Birth Control Pill Could Cause Long-Term Problems With Testosterone, New Research Indicates,www.medicalnewstoday.com/articles/35663.php, 4 January 2006, 9 April 2011, 24 April 2011,www.medicalnewstoday.com/articles/35663.php," title="web.archive.org/web/20110424204010www.medicalnewstoday.com/articles/35663.php,">web.archive.org/web/20110424204010www.medicalnewstoday.com/articles/35663.php, dead, JOURNAL, Panzer C, Wise S, Fantini G, Kang D, Munarriz R, Guay A, Goldstein I, Impact of oral contraceptives on sex hormone-binding globulin and androgen levels: a retrospective study in women with sexual dysfunction, The Journal of Sexual Medicine, 3, 1, 104–13, January 2006, 16409223, 10.1111/j.1743-6109.2005.00198.x, Theoretically, an increase in SHBG may be a physiologic response to increased hormone levels, but may decrease the free levels of other hormones, such as androgens, because of the unspecificity of its sex hormone binding. In 2020, The Lancet Diabetes & Endocrinology published a cross-sectional study of 588 premenopausal female subjects aged 18 to 39 years from the Australian states of Queensland, New South Wales, and Victoria with regular menstrual cycles whose SHBG levels were measured by immunoassay that found that after controlling for age, body mass index, cycle stage, smoking, parity, partner status, and psychoactive medication, SHBG was inversely correlated with sexual desire.JOURNAL, Zheng J, Islam RM, Skiba MA, Bell RJ, Davis SR, 2020, Associations between androgens and sexual function in premenopausal women: a cross-sectional study, The Lancet Diabetes & Endocrinology, Elsevier, 8, 8, 693–702, 10.1016/S2213-8587(20)30239-4, 32707117, 225473332,
Sexual attractiveness and function
{{See also|Sexual attraction|Concealed ovulation|3=Estrous cycle|6=Menstruation (mammal)}}COCPs may increase natural vaginal lubrication, while some women experience decreased lubrication.BOOK, Hatcher RD, Nelson AL, Contraceptive technology, 18th, 2004, Ardent Media, Inc, New York, 978-0-9664902-5-1, 403, 432, 434, Combined Hormonal Contraceptive Methods, Hatcher RD, BOOK, Speroff L, A clinical guide for contraception, 4th, 2005, Lippincott Williams & Wilkins, Hagerstown, MD, 978-0-7817-6488-9, 72, In 2004, the (Proceedings of the Royal Society B: Biological Sciences) published a study where pairs of digital photographs of the faces of 48 women at Newcastle University and Charles University between the ages 19 and 33 who were not taking hormonal contraceptives during the study were photographed in the late follicular and early mid-luteal phases of their menstrual cycles and the photographs were then rated by 261 blinded subjects (130 male and 131 female) at their respective universities who compared the facial attractiveness of each photographed woman in their photograph pairs, and found that the subjects perceived the late follicular phase images of the photographed women as being more attractive than the luteal phase images by more than expected by random chance.JOURNAL, Roberts SC, Havlicek J, Flegr J, Hruskova M, Little AC, Jones BC, Perrett DI, Petrie M, Jaroslav Flegr, Benedict Jones, David Perrett, 2004, Female facial attractiveness increases during the fertile phase of the menstrual cycle, Proceedings of the Royal Society B: Biological Sciences, Royal Society, 271, Supplemental 5, S270–S272, 10.1098/rsbl.2004.0174, 15503991, 1810066, 4142824, In 2007, Evolution and Human Behavior published a study where 18 professional lap dancers recorded their menstrual cycles, work shifts, and tip earnings at gentlemen’s clubs for 60 days that found by a mixed model analysis of 296 work shifts (or approximately 5,300 lap dances) that the 11 dancers with normal menstrual cycles earned US$335 per 5-hour shift during the late follicular phase and at ovulation, US$260 per shift during the luteal phase, and US$185 per shift during menstruation, while the 7 dancers using hormonal contraceptives showed no earnings peak during the late follicular phase and at ovulation.JOURNAL, Ovulatory cycle effects on tip earnings by lap dancers: economic evidence for human estrus?, Miller GF, Tybur JM, Jordan BD, Geoffrey Miller (psychologist), Joshua Tybur, 2007, Evolution and Human Behavior, 10.1016/j.evolhumbehav.2007.06.002, 28, 6, 375–381, 10.1.1.154.8176,www.unm.edu/~gfmiller/cycle_effects_on_tips.pdf, 16 May 2023, 13 June 2023,www.unm.edu/~gfmiller/cycle_effects_on_tips.pdf," title="web.archive.org/web/20230613025953www.unm.edu/~gfmiller/cycle_effects_on_tips.pdf,">web.archive.org/web/20230613025953www.unm.edu/~gfmiller/cycle_effects_on_tips.pdf, live, In 2008, Evolution and Human Behavior published a study where the voices of 51 female students at the State University of New York at Albany were recorded with the women counting from 1 to 10 at four different points in their menstrual cycles were rated by blinded subjects who listened to the recordings to be more attractive at the points of the menstrual cycle with higher probabilities of conception, while the ratings of the voices of the women who were taking hormonal contraceptives showed no variation over the menstrual cycle in attractiveness.JOURNAL, Pipitone RN, Gallup GG, Gordon G. Gallup, 2008, Women’s voice attractiveness varies across the menstrual cycle, Evolution and Human Behavior, Elsevier, 29, 4, 268–274, 10.1016/j.evolhumbehav.2008.02.001,Risk-taking behaviour
{{See also|Behavioral modernity|Evolutionary mismatch|Human factors and ergonomics|l3=Human factors}}In 1998, Evolution and Human Behavior published a study of 300 female undergraduate students at the State University of New York at Albany between the ages of 18 and 54 (with a mean age of 21.9 years) that surveyed the subjects engagement in 18 different behaviors over the 24 hours prior to filling out the study’s questionnaire that varied in their risk of potential rape or sexual assault and the first day of their last menstruations, and found that subjects at ovulation showed statistically significant decreased engagement in behaviors that risked rape and sexual assault while subjects taking birth control pills showed no variation over their menstrual cycles in the same behaviors (suggesting a psychologically adaptive function of the hormonal fluctuations during the menstrual cycle in causing avoidance of behaviors that risk rape and sexual assault).JOURNAL, Chavanne TJ, Gallup GG, 1998, Variation in Risk Taking Behavior Among Female College Students as a Function of the Menstrual Cycle, Evolution and Human Behavior, Elsevier, 19, 1, 27–32, 10.1016/S1090-5138(98)00016-6, BOOK, Buss DM, David Buss, The Evolution of Desire: Strategies of Human Mating, The Evolution of Desire, 2016, 1994, Basic Books, New York, 3rd, 260–262, 978-0-465-09776-0, In 2003, Evolution and Human Behavior published a conceptual replication study of the 1998 survey that confirmed its findings.JOURNAL, Bröder A, Hohmann N, 2003, Variations in risk taking behavior over the menstrual cycle: An improved replication, Evolution and Human Behavior, Elsevier, 24, 6, 391–398, 10.1016/S1090-5138(03)00055-2, In 2006, a study presented at the annual conference of the Cognitive Science Society surveyed 176 female undergraduate students at Michigan State University (with a mean age of 19.9 years) in a decision-making experiment where the subjects chose between an option with a guaranteed outcome or an option involving risk and indicated the first day of their last menstruations, and found that the subjects risk aversion preferences varied over the menstrual cycle (with none of the subjects at ovulation preferring the risky option) and only subjects not taking hormonal contraceptives showed the menstrual cycle effect on risk aversion.JOURNAL, Burns BD, 2006, Cognitive Neuroendocrinology: Risk Preference Changes Across the Menstrual Cycle, Proceedings of the Annual Meeting of the Cognitive Science Society, 28, 125–130, 1069-7977,escholarship.org/uc/item/37k5j9w2, 27 April 2023, 27 April 2023,web.archive.org/web/20230427055609/https://escholarship.org/uc/item/37k5j9w2, live, In the 2019 Neuroscience & Biobehavioral Reviews meta-analysis, the research reviewed also evaluated whether the 7,529 female subjects across the 26 studies showed greater risk recognition and avoidance of potentially threatening people and dangerous situations at different phases of the menstrual cycle and found that the subjects displayed better risk accuracy recognition during the late follicular phase and at ovulation as compared to the luteal phase.Depression
Low levels of serotonin, a neurotransmitter in the brain, have been linked to depression. High levels of estrogen, as in first-generation COCPs, and progestin, as in some progestin-only contraceptives, have been shown to lower the brain serotonin levels by increasing the concentration of a brain enzyme that reduces serotonin. A growing body of research evidence has suggested that hormonal contraception may have an adverse effect on women’s psychological health.JOURNAL, Kulkarni J, Depression as a side effect of the contraceptive pill, Expert Opinion on Drug Safety, 6, 4, 371–4, July 2007, 17688380, 10.1517/14740338.6.4.371, 8836005, JOURNAL, Skovlund CW, Mørch LS, Kessing LV, Lidegaard Ø, Association of Hormonal Contraception With Depression, JAMA Psychiatry, 73, 11, 1154–1162, November 2016, 27680324, 10.1001/jamapsychiatry.2016.2387, free, doi, JOURNAL, Zettermark S, Perez Vicente R, Merlo J, 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, 22 March 2018, 29566064, 5864056, 10.1371/journal.pone.0194773, 2018PLoSO..1394773Z, free, doi, In 2016, a large Danish study of one million women (followed-up from January 2000 to December 2013) showed that use of COCPs, especially among adolescents, was associated with a statistically significantly increased risk of subsequent depression, although the sizes of the effects are small (for example, 2.1% of the women who took any form of oral birth control were prescribed anti-depressants for the first time, compared to 1.7% of women in the control group). Similarly, in 2018, the findings from a large nationwide Swedish cohort study investigating the effect of hormonal contraception on mental health amongst women (n=815,662, aged 12–30) were published, highlighting an association between hormonal contraception and subsequent use of psychotropic drugs for women of reproductive age. This association was particularly large for young adolescents (aged 12–19). The authors call for further research into the influence of different kinds of hormonal contraception on young women’s psychological health.Progestin-only contraceptives are known to worsen the condition of women who are already depressed.WEB, Burnett-Watson K, Is The Pill Playing Havoc With Your Mental Health?, October 2005,www.aphroditewomenshealth.com/news/hormones_depression.shtml, 20 March 2007, dead,www.aphroditewomenshealth.com/news/hormones_depression.shtml," title="web.archive.org/web/20070320002408www.aphroditewomenshealth.com/news/hormones_depression.shtml,">web.archive.org/web/20070320002408www.aphroditewomenshealth.com/news/hormones_depression.shtml, 20 March 2007, , which cites:
JOURNAL, Kulkarni J, Liew J, Garland KA, Depression associated with combined oral contraceptives--a pilot study, Australian Family Physician, 34, 11, 990, November 2005, 16299641, JOURNAL, Young EA, Kornstein SG, Harvey AT, Wisniewski SR, Barkin J, Fava M, Trivedi MH, Rush AJ, Influences of hormone-based contraception on depressive symptoms in premenopausal women with major depression, Psychoneuroendocrinology, 32, 7, 843–53, August 2007, 17629629, 2100423, 10.1016/j.psyneuen.2007.05.013, However, current medical reference textbooks on contraception and major organizations such as the American ACOG,JOURNAL, 10.1097/00006250-200606000-00055, 16738183, ACOG Practice Bulletin No. 73: Use of Hormonal Contraception in Women with Coexisting Medical Conditions, 2006, Obstetrics & Gynecology, 107, 6, 1453–72, ACOG Committee on Practice Bulletins-Gynecology, the WHO, and the United Kingdom’s RCOGWEB, FFPRHC, 2006, The UK Medical Eligibility Criteria for Contraceptive Use (2005/2006),www.ffprhc.org.uk/admin/uploads/UKMEC200506.pdf, 31 March 2007,www.ffprhc.org.uk/admin/uploads/UKMEC200506.pdf," title="web.archive.org/web/20070619230102www.ffprhc.org.uk/admin/uploads/UKMEC200506.pdf,">web.archive.org/web/20070619230102www.ffprhc.org.uk/admin/uploads/UKMEC200506.pdf, 19 June 2007, Royal College of Obstetricians and Gynaecologists, agree that current evidence indicates low-dose combined oral contraceptives are unlikely to increase the risk of depression, and unlikely to worsen the condition in women that are depressed.
Hypertension
Bradykinin lowers blood pressure by causing blood vessel dilation. Certain enzymes are capable of breaking down bradykinin (Angiotensin Converting Enzyme, Aminopeptidase P). Progesterone can increase the levels of Aminopeptidase P (AP-P), thereby increasing the breakdown of bradykinin, which increases the risk of developing hypertension.JOURNAL, Cilia La Corte AL, Carter AM, Turner AJ, Grant PJ, Hooper NM, The bradykinin-degrading aminopeptidase P is increased in women taking the oral contraceptive pill, Journal of the Renin-Angiotensin-Aldosterone System, 9, 4, 221–5, December 2008, 19126663, 10.1177/1470320308096405, 206729914, free, doi,Other effects
Other side effects associated with low-dose COCPs are leukorrhea (increased vaginal secretions), reductions in menstrual flow, mastalgia (breast tenderness), and decrease in acne. Side effects associated with older high-dose COCPs include nausea, vomiting, increases in blood pressure, and melasma (facial skin discoloration); these effects are not strongly associated with low-dose formulations.{{Medical citation needed|date=December 2020}}Excess estrogen, such as from birth control pills, appears to increase cholesterol levels in bile and decrease gallbladder movement, which can lead to gallstones.WEB,digestive.niddk.nih.gov/ddiseases/pubs/gallstones/, Gallstones, NDDIC, July 2007, 13 August 2010,digestive.niddk.nih.gov/ddiseases/pubs/gallstones/," title="web.archive.org/web/20100811052827digestive.niddk.nih.gov/ddiseases/pubs/gallstones/,">web.archive.org/web/20100811052827digestive.niddk.nih.gov/ddiseases/pubs/gallstones/, 11 August 2010, dead, Progestins found in certain formulations of oral contraceptive pills can limit the effectiveness of weight training to increase muscle mass.NEWS,www.sciencenews.org/blog/science-the-public/birth-control-pills-can-limit-muscle-training-gains, Birth control pills can limit muscle-training gains, Raloff J, 23 April 2009, Science News, 22 October 2018, 11 June 2012,www.sciencenews.org/view/generic/id/43210/title/Science_+_the_Public__Birth_control_pills_can_limit_muscle-training_gains," title="web.archive.org/web/20120611084209www.sciencenews.org/view/generic/id/43210/title/Science_+_the_Public__Birth_control_pills_can_limit_muscle-training_gains,">web.archive.org/web/20120611084209www.sciencenews.org/view/generic/id/43210/title/Science_+_the_Public__Birth_control_pills_can_limit_muscle-training_gains, live, This effect is caused by the ability of some progestins to inhibit androgen receptors. One study claims that the pill may affect what male body odors a woman prefers, which may in turn influence her selection of partner.NEWS,www.abc.net.au/news/stories/2008/08/14/2335871.htm?section=world, Love woes can be blamed on contraceptive pill: research – ABC News (Australian Broadcasting Corporation), ABC News, Abc.net.au, 14 August 2008, 20 March 2010, 22 July 2010,www.abc.net.au/news/stories/2008/08/14/2335871.htm?section=world," title="web.archive.org/web/20100722002011www.abc.net.au/news/stories/2008/08/14/2335871.htm?section=world,">web.archive.org/web/20100722002011www.abc.net.au/news/stories/2008/08/14/2335871.htm?section=world, live, JOURNAL, Kollndorfer K, Ohrenberger I, Schöpf V, Contraceptive Use Affects Overall Olfactory Performance: Investigation of Estradiol Dosage and Duration of Intake, PLOS ONE, 11, 12, e0167520, 2016, 28002464, 5176159, 10.1371/journal.pone.0167520, 2016PLoSO..1167520K, free, doi, JOURNAL, Roberts SC, Gosling LM, Carter V, Petrie M, MHC-correlated odour preferences in humans and the use of oral contraceptives, Proceedings. Biological Sciences, 275, 1652, 2715–22, December 2008, 18700206, 2605820, 10.1098/rspb.2008.0825, Use of combined oral contraceptives is associated with a reduced risk of endometriosis, giving a relative risk of endometriosis of 0.63 during active use, yet with limited quality of evidence according to a systematic review.JOURNAL, Vercellini P, Eskenazi B, Consonni D, Somigliana E, Parazzini F, Abbiati A, Fedele L, Oral contraceptives and risk of endometriosis: a systematic review and meta-analysis, Human Reproduction Update, 17, 2, 159–70, 2010, 20833638, 10.1093/humupd/dmq042, free, doi, Combined oral contraception decreases total testosterone levels by approximately 0.5 nmol/L, free testosterone by approximately 60%, and increases the amount of sex hormone binding globulin (SHBG) by approximately 100 nmol/L. Contraceptives containing second generation progestins and/or estrogen doses of around 20 –25 mg EE were found to have less impact on SHBG concentrations.JOURNAL, Zimmerman Y, Eijkemans MJ, Coelingh Bennink HJ, Blankenstein MA, Fauser BC, The effect of combined oral contraception on testosterone levels in healthy women: a systematic review and meta-analysis, Human Reproduction Update, 20, 1, 76–105, 2013, 24082040, 3845679, 10.1093/humupd/dmt038, Combined oral contraception may also reduce bone density.JOURNAL, Scholes D, Rebecca Hubbard, Hubbard RA, Ichikawa LE, LaCroix AZ, Spangler L, Beasley JM, Reed S, Ott SM, Oral contraceptive use and bone density change in adolescent and young adult women: a prospective study of age, hormone dose, and discontinuation, The Journal of Clinical Endocrinology and Metabolism, 96, 9, E1380–7, September 2011, 21752879, 3167673, 10.1210/jc.2010-3027,Drug interactions
Some drugs reduce the effect of the pill and can cause breakthrough bleeding, or increased chance of pregnancy. These include drugs such as rifampicin, barbiturates, phenytoin and carbamazepine. In addition cautions are given about broad spectrum antibiotics, such as ampicillin and doxycycline, which may cause problems “by impairing the bacterial flora responsible for recycling ethinylestradiol from the large bowel” (BNF 2003).The effects of broad-spectrum antibiotics on Combined contraceptive pills is not found on systematic interaction metanalysis (Archer, 2002), although “individual patients do show large decreases in the plasma concentrations of ethinylestradiol when they take certain other antibiotics” (Dickinson, 2001). “experts on this topic still recommend informing oral contraceptive users of the potential for a rare interaction” (DeRossi, 2002) and this remains current (2006) UK Family Planning Association advice {{Webarchive|url=https://web.archive.org/web/20070208155326www.fpa.org.uk/information/leaflets/documents_and_pdfs/detail.cfm?contentID=130#17 |date=8 February 2007 }}.JOURNAL, Archer JS, Archer DF, Oral contraceptive efficacy and antibiotic interaction: a myth debunked, Journal of the American Academy of Dermatology, 46, 6, 917–23, June 2002, 12063491, 10.1067/mjd.2002.120448, JOURNAL, Dickinson BD, Altman RD, Nielsen NH, Sterling ML, Drug interactions between oral contraceptives and antibiotics, Obstetrics and Gynecology, 98, 5 Pt 1, 853–60, November 2001, 11704183, 10.1016/S0029-7844(01)01532-0, 41354899, JOURNAL, DeRossi SS, Hersh EV, Antibiotics and oral contraceptives, Dental Clinics of North America, 46, 4, 653–64, October 2002, 12436822, 10.1016/S0011-8532(02)00017-4, 10.1.1.620.9933, The traditional medicinal herb St John’s Wort has also been implicated due to its upregulation of the P450 system in the liver which could increase the metabolism of ethinyl estradiol and progestin components of some combined oral contraception.JOURNAL, Berry-Bibee EN, Kim MJ, Tepper NK, Riley HE, Curtis KM, Co-administration of St. John’s wort and hormonal contraceptives: a systematic review, Contraception, 94, 6, 668–677, December 2016, 27444983, 10.1016/j.contraception.2016.07.010, Introduction of first-generation birth control pills“>History{| class“wikitable sortable floatright mw-collapsible” style@margin-left: auto; margin-right: auto; border: none;” Introduction of first-generation birth control pills
Progesterone to prevent ovulation
Progesterone, given by injections, was first shown to inhibit ovulation in animals in 1937 by Makepeace and colleagues.In 1951, reproductive physiologist Gregory Pincus, a leader in hormone research and co-founder of the Worcester Foundation for Experimental Biology (WFEB) in Shrewsbury, Massachusetts, first met American birth control movement founder Margaret Sanger at a Manhattan dinner hosted by Abraham Stone, medical director and vice president of Planned Parenthood (PPFA), who helped Pincus obtain a small grant from PPFA to begin hormonal contraceptive research.WEB,www.chicagotribune.com/lifestyles/books/ct-prj-birth-of-the-pill-jonathan-eig-20141016-story.html#page=1, Jonathan Eig on ‘The Birth of the Pill’, Nance K, Chicago Tribune, 16 October 2014, 19 October 2014, 19 April 2019,web.archive.org/web/20190419195123/https://www.chicagotribune.com/lifestyles/books/ct-prj-birth-of-the-pill-jonathan-eig-20141016-story.html#page=1, live, WEB,books.wwnorton.com/books/The-Birth-of-the-Pill/, The Birth of the Pill, W. W. Norton & Company, 19 October 2014, 11 October 2014,books.wwnorton.com/books/The-Birth-of-the-Pill/," title="web.archive.org/web/20141011202602books.wwnorton.com/books/The-Birth-of-the-Pill/,">web.archive.org/web/20141011202602books.wwnorton.com/books/The-Birth-of-the-Pill/, live, NEWS,www.washingtonpost.com/opinions/book-review-the-birth-of-the-pill-and-the-reinvention-of-sex-by-jonathan-eig/2014/10/17/914acb3c-48c0-11e4-b72e-d60a9229cc10_story.html, Book review: ‘The Birth of the Pill,’ and the reinvention of sex, by Jonathan Eig, Manning K, 17 October 2014, The Washington Post, 25 August 2017, 9 December 2022,web.archive.org/web/20221209061302/https://www.washingtonpost.com/opinions/book-review-the-birth-of-the-pill-and-the-reinvention-of-sex-by-jonathan-eig/2014/10/17/914acb3c-48c0-11e4-b72e-d60a9229cc10_story.html, live, Research started in April 1951, with reproductive physiologist Min Chueh Chang repeating and extending the 1937 experiments of Makepeace et al. that was published in 1953 and showed that injections of progesterone suppressed ovulation in rabbits. In October 1951, G. D. Searle & Company refused Pincus’ request to fund his hormonal contraceptive research, but retained him as a consultant and continued to provide chemical compounds to evaluate.BOOK, Reed J, 1978, From Private Vice to Public Virtue: The Birth Control Movement and American Society Since 1830, New York, Basic Books, 978-0-465-02582-4, BOOK, Speroff L, 2009, A Good Man: Gregory Goodwin Pincus: The Man, His Story, The Birth Control Pill, Portland, Oregon, Arnica, 978-0-9801942-9-6, In March 1952, Sanger wrote a brief note mentioning Pincus’ research to her longtime friend and supporter, suffragist and philanthropist Katharine Dexter McCormick, who visited the WFEB and its co-founder and old friend Hudson Hoagland in June 1952 to learn about contraceptive research there. Frustrated when research stalled from PPFA’s lack of interest and meager funding, McCormick arranged a meeting at the WFEB in June 1953, with Sanger and Hoagland, where she first met Pincus who committed to dramatically expand and accelerate research with McCormick providing fifty times PPFA’s previous funding.BOOK, Fields A, 2003, Katharine Dexter McCormick: Pioneer for Women’s Rights, Westport, Conn., Prager, 978-0-275-98004-7, Pincus and McCormick enlisted Harvard clinical professor of gynecology John Rock, chief of gynecology at the Free Hospital for Women and an expert in the treatment of infertility, to lead clinical research with women. At a scientific conference in 1952, Pincus and Rock, who had known each other for many years, discovered they were using similar approaches to achieve opposite goals. In 1952, Rock induced a three-month anovulatory “pseudopregnancy” state in eighty of his infertility patients with continuous gradually increasing oral doses of an estrogen (5 to 30 mg/day diethylstilbestrol) and progesterone (50 to 300 mg/day), and within the following four months 15% of the women became pregnant.BOOK, McLaughlin L, 1982, The Pill, John Rock, and the Church: The Biography of a Revolution, Boston, Little, Brown, 978-0-316-56095-5,archive.org/details/pilljohnrock00mcla, JOURNAL, Rock J, Garcia CR, Pincus G, Synthetic progestins in the normal human menstrual cycle, Recent Progress in Hormone Research, 13, 323–39; discussion 339–46, 1957, 13477811, In 1953, at Pincus’ suggestion, Rock induced a three-month anovulatory “pseudopregnancy” state in twenty-seven of his infertility patients with an oral 300 mg/day progesterone-only regimen for 20 days from cycle days 5–24 followed by pill-free days to produce withdrawal bleeding.JOURNAL, Pincus G, The hormonal control of ovulation and early development, Postgraduate Medicine, 24, 6, 654–60, December 1958, 13614060, 10.1080/00325481.1958.11692305, This produced the same 15% pregnancy rate during the following four months without the amenorrhea of the previous continuous estrogen and progesterone regimen. But 20% of the women experienced breakthrough bleeding and in the first cycle ovulation was suppressed in only 85% of the women, indicating that even higher and more expensive oral doses of progesterone would be needed to initially consistently suppress ovulation. Similarly, Ishikawa and colleagues found that ovulation inhibition occurred in only a “proportion” of cases with 300 mg/day oral progesterone.BOOK, Pincus G, Progestational Agents and the Control of Fertility, 17, 1959, 307–324, 0083-6729, 10.1016/S0083-6729(08)60274-5, Ishikawa et al. (1957) employing the same regime of progesterone administration also observed suppression of ovulation in a proportion of the cases taken to laparotomy. Although sexual intercourse was practised freely by the subjects of our experiments and those of Ishikawa el al., no pregnancies occurred. Since ovulation presumably took place in a proportion of cycles, the lack of any pregnancies may be due to chance, but Ishikawa et al. (1957) have presented data indicating that in women receiving oral progesterone the cervical mucus becomes impenetrable to sperm., Vitamins & Hormones, Academic Press, 978-0-12-709817-3, Despite the incomplete inhibition of ovulation by oral progesterone, no pregnancies occurred in the two studies, although this could have simply been due to chance.JOURNAL, Diczfalusy E, Probable mode of action of oral contraceptives, BMJ, 2, 5475, 1394–9, December 1965, 5848673, 1847181, 10.1136/bmj.2.5475.1394, At the Fifth International Conference on Planned Parenthood in Tokyo, Pincus (1955) reported an ovulation inhibition by progesterone or norethynodrel1 taken orally by women. This report indicated the beginning of a new era in the history of contraception. ... That the cervical mucus might be one of the principal sites of action was suggested by the first studies of Pincus (1956, 1959) and of Ishikawa et al. (1957). These investigators found that no pregnancies occurred in women treated orally with large doses of progesterone, though ovulation was inhibited only in some 70% of the cases studied. ... The mechanism of protection in this method—and probably in that of Pincus (1956) and of Ishikawa et al. (1957)—must involve an effect on the cervical mucus and/or endometrium and Fallopian tubes., However, Ishikawa et al. reported that the cervical mucus in women taking oral progesterone became impenetrable to sperm, and this may have accounted for the absence of pregnancies.Progesterone was abandoned as an oral ovulation inhibitor following these clinical studies due to the high and expensive doses required, incomplete inhibition of ovulation, and the frequent incidence of breakthrough bleeding.BOOK, Pincus G, Bialy G, Drugs Used in Control of Reproduction, 3, 285–313, 1964, 14232795, 10.1016/S1054-3589(08)61115-1, The original observation of Makepeace et al. (1937) that progesterone inhibited ovulation in the rabbit was substantiated by Pincus and Chang (1953). In women, 300 mg of progesterone per day taken orally resulted in ovulation inhibition in 80% of cases (Pincus, 1956). The high dosage and frequent incidence of breakthrough bleeding limited the practical application of the method. Subsequently, the utilization of potent 19-norsteroids, which could be given orally, opened the field to practical oral contraception., Advances in Pharmacology, Academic Press, 978-0-12-032903-8, BOOK, RamÃrez de Arellano AB, Seipp C, Colonialism, Catholicism, and Contraception: A History of Birth Control in Puerto Rico,books.google.com/books?id=0fs4DwAAQBAJ&pg=PT107, 10 October 2017, University of North Carolina Press, 978-1-4696-4001-3, 107–, Still, neither of the two researchers was completely satisfied with the results. Progesterone tended to cause “premature menses”, or breakthrough bleeding, in approximately 20 percent of the cycles, an occurrence that disturbed the patients and worried Rock.17 In addition, Pincus was concerned about the failure to inhibit ovulation in all the cases. Only large doses of orally administered progesterone could insure the suppression of ovulation, and these doses were expensive. The mass use of this regimen as a birth control method was thus seriously imperiled., 2 May 2019, 15 July 2023,web.archive.org/web/20230715025752/https://books.google.com/books?id=0fs4DwAAQBAJ&pg=PT107, live, Instead, researchers would turn to much more potent synthetic progestogens for use in oral contraception in the future.Progestins to prevent ovulation
In October 1951, Chemist Luis Miramontes, working under the supervision of Carl Djerassi, and the direction of George Rosenkranz at Syntex in Mexico City, synthesized the first oral contraceptive, which was based on highly active progestin norethisterone. Frank B. Colton at Searle in Skokie, Illinois synthesized the orally highly active progestins noretynodrel (an isomer of norethisterone) in 1952 and norethandrolone in 1953.Pincus asked his contacts at pharmaceutical companies to send him chemical compounds with progestogenic activity. Chang screened nearly 200 chemical compounds in animals and found the three most promising were Syntex’s norethisterone and Searle’s noretynodrel and norethandrolone.JOURNAL, Chang MC, Development of the oral contraceptives, American Journal of Obstetrics and Gynecology, 132, 2, 217–9, September 1978, 356615, 10.1016/0002-9378(78)90928-6, In December 1954, Rock began the first studies of the ovulation-suppressing potential of 5–50 mg doses of the three oral progestins for three months (for 21 days per cycle—days 5–25 followed by pill-free days to produce withdrawal bleeding) in fifty of his patients with infertility in Brookline, Massachusetts. Norethisterone or noretynodrel 5 mg doses and all doses of norethandrolone suppressed ovulation but caused breakthrough bleeding, but 10 mg and higher doses of norethisterone or noretynodrel suppressed ovulation without breakthrough bleeding and led to a 14% pregnancy rate in the following five months. Pincus and Rock selected Searle’s noretynodrel for the first contraceptive trials in women, citing its total lack of androgenicity versus Syntex’s norethisterone very slight androgenicity in animal tests.JOURNAL, Garcia CR, Pincus G, Rock J, Effects of certain 19-nor steroids on the normal human menstrual cycle, Science, 124, 3227, 891–3, November 1956, 13380401, 10.1126/science.124.3227.891, 1956Sci...124..891R, BOOK, Rock J, GarcÃa CR, 1957, Observed effects of 19-nor steroids on ovulation and menstruation, Proceedings of a Symposium on 19-Nor Progestational Steroids, Chicago, Searle Research Laboratories, 14–31, 935295,Combined oral contraceptive
Noretynodrel (and norethisterone) were subsequently discovered to be contaminated with a small percentage of the estrogen mestranol (an intermediate in their synthesis), with the noretynodrel in Rock’s 1954–5 study containing 4–7% mestranol. When further purifying noretynodrel to contain less than 1% mestranol led to breakthrough bleeding, it was decided to intentionally incorporate 2.2% mestranol, a percentage that was not associated with breakthrough bleeding, in the first contraceptive trials in women in 1954. The noretynodrel and mestranol combination was given the proprietary name Enovid.JOURNAL, Pincus G, Rock J, Garcia CR, Ricewray E, Paniagua M, Rodriguez I, Fertility control with oral medication, American Journal of Obstetrics and Gynecology, 75, 6, 1333–46, June 1958, 13545267, 10.1016/0002-9378(58)90722-1, The first contraceptive trial of Enovid led by Celso-Ramón GarcÃa and Edris Rice-Wray began in April 1956 in RÃo Piedras, Puerto Rico.JOURNAL, GarcÃa CR, Development of the pill, Annals of the New York Academy of Sciences, 1038, 223–6, December 2004, 1, 15838117, 10.1196/annals.1315.031, 2004NYASA1038..223G, 25550745, JOURNAL, Strauss JF, Mastroianni L, In memoriam: Celso-Ramon Garcia, M.D. (1922-2004), reproductive medicine visionary, Journal of Experimental & Clinical Assisted Reproduction, 2, 1, 2, January 2005, 15673473, 548289, 10.1186/1743-1050-2-2, free, doi, JOURNAL, Junod SW, Marks L, Women’s trials: the approval of the first oral contraceptive pill in the United States and Great Britain, Journal of the History of Medicine and Allied Sciences, 57, 2, 117–60, April 2002, 11995593, 10.1093/jhmas/57.2.117, 36533080, free, doi, A second contraceptive trial of Enovid (and norethisterone) led by Edward T. Tyler began in June 1956 in Los Angeles.JOURNAL, Tyler ET, Olson HJ, Fertility promoting and inhibiting effects of new steroid hormonal substances, Journal of the American Medical Association, 169, 16, 1843–54, April 1959, 13640942, 10.1001/jama.1959.03000330015003, In January 1957, Searle held a symposium reviewing gynecologic and contraceptive research on Enovid through 1956 and concluded Enovid’s estrogen content could be reduced by 33% to lower the incidence of estrogenic gastrointestinal side effects without significantly increasing the incidence of breakthrough bleeding.BOOK, Winter IC, 1957, Summary, Proceedings of a Symposium on 19-Nor Progestational Steroids, Chicago, Searle Research Laboratories, 120–122, 935295, While these large-scale trials contributed to the initial understanding of the pill formulation’s clinical effects, the ethical implications of the trials generated significant controversy. Of note is the apparent lack of both autonomy and informed consent among participants in the Puerto Rican cohort prior to the trials. Many of these participants hailed from impoverished, working-class backgrounds.Public availability
United States
(File:Patient Package Insert for Oral Contraceptives (FDA 079) (8249451687).jpg|thumb|right|Oral contraceptives, 1970s)In June 1957, the Food and Drug Administration (FDA) approved Enovid 10 mg (9.85 mg noretynodrel and 150 μg mestranol) for menstrual disorders, based on data from its use by more than 600 women. Numerous additional contraceptive trials showed Enovid at 10, 5, and 2.5 mg doses to be highly effective. In July 1959, Searle filed a supplemental application to add contraception as an approved indication for 10, 5, and 2.5 mg doses of Enovid. The FDA refused to consider the application until Searle agreed to withdraw the lower dosage forms from the application. In May 1960, the FDA announced it would approve Enovid 10 mg for contraceptive use, and did so in June 1960. At that point, Enovid 10 mg had been in general use for three years and, by conservative estimate, at least half a million women had used it.BOOK, Marks L, 2001, Sexual Chemistry: A History of the Contraceptive Pill, New Haven, Yale University Press, 978-0-300-08943-1,archive.org/details/sexualchemistryh00mark, JOURNAL, Winter IC, Industrial pressure and the population problem--the FDA and the pill, JAMA, 212, 6, 1067–8, May 1970, 5467404, 10.1001/jama.212.6.1067, Although FDA-approved for contraceptive use, Searle never marketed Enovid 10 mg as a contraceptive. Eight months later, in February 1961, the FDA approved Enovid 5 mg for contraceptive use. In July 1961, Searle finally began marketing Enovid 5 mg (5 mg noretynodrel and 75 μg mestranol) to physicians as a contraceptive.BOOK, Watkins ES, 1998, On the Pill: A Social History of Oral Contraceptives, 1950–1970, Baltimore, Johns Hopkins University Press, 978-0-8018-5876-5, Although the FDA approved the first oral contraceptive in 1960, contraceptives were not available to married women in all states until Griswold v. Connecticut in 1965, and were not available to unmarried women in all states until Eisenstadt v. Baird in 1972.The first published case report of a blood clot and pulmonary embolism in a woman using Enavid (Enovid 10 mg in the US) at a dose of 20 mg/day did not appear until November 1961, four years after its approval, by which time it had been used by over one million women.JOURNAL, Winter IC, Metabolism, 14, Supplement, SUPPL:422–8, March 1965, 14261427, 10.1016/0026-0495(65)90029-6, The incidence of thromboembolism in Enovid users, JOURNAL, Jordan WM, Anand JK, 18 November 1961, Pulmonary embolism, Lancet, 278, 7212, 1146–1147, 10.1016/S0140-6736(61)91061-3, It would take almost a decade of epidemiological studies to conclusively establish an increased risk of venous thrombosis in oral contraceptive users and an increased risk of stroke and myocardial infarction in oral contraceptive users who smoke or have high blood pressure or other cardiovascular or cerebrovascular risk factors. These risks of oral contraceptives were dramatized in the 1969 book The Doctors’ Case Against the Pill by feminist journalist Barbara Seaman who helped arrange the 1970 Nelson Pill Hearings called by Senator Gaylord Nelson.BOOK, Seaman B, 1969, The Doctors’ Case Against the Pill, New York, P. H. Wyden, 978-0-385-14575-6, The hearings were conducted by senators who were all men and the witnesses in the first round of hearings were all men, leading Alice Wolfson and other feminists to protest the hearings and generate media attention. Their work led to mandating the inclusion of patient package inserts with oral contraceptives to explain their possible side effects and risks to help facilitate informed consent.JOURNAL, ((US Food and Drug Administration)), Food and Drug Administration, 11 June 1970, Statement of policy concerning oral contraceptive labeling directed to users, Federal Register, 35, 113, 9001–9003, JOURNAL, ((US Food and Drug Administration)), Food and Drug Administration, 31 January 1978, Oral contraceptives; requirement for labeling directed to the patient, Federal Register, 43, 21, 4313–4334, JOURNAL, ((US Food and Drug Administration)), Food and Drug Administration, 25 May 1989, Oral contraceptives; patient package insert requirement, Federal Register, 54, 100, 22585–22588, Today’s standard dose oral contraceptives contain an estrogen dose that is one third lower than the first marketed oral contraceptive and contain lower doses of different, more potent progestins in a variety of formulations.Beginning in 2015, certain states passed legislation allowing pharmacists to prescribe oral contraceptives. Such legislation was considered to address physician shortages and decrease barriers to birth control for women.JOURNAL,www.pharmacytimes.com/publications/issue/2018/november2018/prescriptive-authority-for-pharmacists-oral-contraceptives, Prescriptive Authority for Pharmacists: Oral Contraceptives, Pharmacy Times, November 2018 Cough, Cold, & Flu, 19 November 2018, 84, 11, 2 August 2019, 2 August 2019,web.archive.org/web/20190802214230/https://www.pharmacytimes.com/publications/issue/2018/november2018/prescriptive-authority-for-pharmacists-oral-contraceptives, dead, Pharmacists in Oregon, California, Colorado, Hawaii, Maryland, and New Mexico have authority to prescribe birth control after receiving specialized training and certification from their respective state Board of Pharmacy.WEB,naspa.us/resource/contraceptives/, Pharmacist Prescribing for Hormonal Contraceptive Medications, NASPA, 2 August 2019, 2 August 2019,web.archive.org/web/20190802214231/https://naspa.us/resource/contraceptives/, live, WEB,naspa.us/2017/05/pharmacists-authorized-prescribe-birth-control-states/, Pharmacists Authorized to Prescribe Birth Control in More States, 4 May 2017, NASPA, 2 August 2019, 2 August 2019,web.archive.org/web/20190802214231/https://naspa.us/2017/05/pharmacists-authorized-prescribe-birth-control-states/, live, {{Asof|2024|01}}, pharmacists in 29 states can prescribe oral contraceptives.NEWS, Doctor: Why I’m cheering about pharmacists in my state prescribing birth control pills, CNN, 30 January 2024,www.cnn.com/2024/01/30/opinions/pharmacist-birth-control-ranney/index.html, 11 February 2024, 8 February 2024,web.archive.org/web/20240208020319/https://www.cnn.com/2024/01/30/opinions/pharmacist-birth-control-ranney/index.html, live,Australia
The first oral contraceptive introduced outside the United States was Schering’s Anovlar (norethisterone acetate 4 mg + ethinylestradiol 50 μg) in January 1961, in Australia.WEB,www.scheringstiftung.de/scripts/index/web/en/content/index/174, History of Schering AG, 6 December 2007, bot: unknown,www.scheringstiftung.de/scripts/index/web/en/content/index/174," title="web.archive.org/web/20080415221032www.scheringstiftung.de/scripts/index/web/en/content/index/174,">web.archive.org/web/20080415221032www.scheringstiftung.de/scripts/index/web/en/content/index/174, 15 April 2008,Germany
The first oral contraceptive introduced in Europe was Schering’s Anovlar in June 1961, in West Germany. The lower hormonal dose, still in use, was studied by the Belgian Gynaecologist Ferdinand Peeters.WEB, Van den Broeck K, Gynaecoloog Ferdinand Peeters: De vergeten stiefvader van de pil, Gynecologist Ferdinand Peeters: The forgotten stepfather of the pil, Knack (magazine), Knack, Extra #4, 5 March 2010, 6–13, Dutch,www.slideshare.net/MarcPeeters6/de-pil-ferdinand-peeters-de-vergeten-stiefvader-van-de-pil, 14 September 2022, 14 September 2022,web.archive.org/web/20220914171941/https://www.slideshare.net/MarcPeeters6/de-pil-ferdinand-peeters-de-vergeten-stiefvader-van-de-pil, live, JOURNAL,www.flanderstoday.eu/living/little-pill-could, Hope A, 24 May 2010, The little pill that could, Flanders Today, 28 December 2014, 1 January 2021,www.flanderstoday.eu/living/little-pill-could," title="web.archive.org/web/20210101051858www.flanderstoday.eu/living/little-pill-could,">web.archive.org/web/20210101051858www.flanderstoday.eu/living/little-pill-could, dead,United Kingdom
Before the mid-1960s, the United Kingdom did not require pre-marketing approval of drugs. The British Family Planning Association (FPA) through its clinics was then the primary provider of family planning services in the UK and provided only contraceptives that were on its Approved List of Contraceptives (established in 1934). In 1957, Searle began marketing Enavid (Enovid 10 mg in the US) for menstrual disorders. Also in 1957, the FPA established a Council for the Investigation of Fertility Control (CIFC) to test and monitor oral contraceptives which began animal testing of oral contraceptives and in 1960 and 1961 began three large clinical trials in Birmingham, Slough, and London.JOURNAL, Mears E, Clinical trials of oral contraceptives, British Medical Journal, 2, 5261, 1179–83, November 1961, 14471934, 1970272, 10.1136/bmj.2.5261.1179, In March 1960, the Birmingham FPA began trials of noretynodrel 2.5 mg + mestranol 50 μg, but a high pregnancy rate initially occurred when the pills accidentally contained only 36 μg of mestranol—the trials were continued with noretynodrel 5 mg + mestranol 75 μg (Conovid in the UK, Enovid 5 mg in the US).JOURNAL, Eckstein P, Waterhouse JA, Bond GM, Mills WG, Sandilands DM, Shotton DM, The Birmingham oral contraceptive trial, British Medical Journal, 2, 5261, 1172–9, November 1961, 13889122, 1970253, 10.1136/bmj.2.5261.1172, In August 1960, the Slough FPA began trials of noretynodrel 2.5 mg + mestranol 100 μg (Conovid-E in the UK, Enovid-E in the US).JOURNAL, Pullen D, “Conovid-E” as an oral contraceptive, British Medical Journal, 2, 5311, 1016–9, October 1962, 13972503, 1926317, 10.1136/bmj.2.5311.1016, In May 1961, the London FPA began trials of Schering’s Anovlar.JOURNAL, Mears E, Grant EC, “Anovlar” as an oral contraceptive, British Medical Journal, 2, 5297, 75–9, July 1962, 14471933, 1925289, 10.1136/bmj.2.5297.75, In October 1961, at the recommendation of the Medical Advisory Council of its CIFC, the FPA added Searle’s Conovid to its Approved List of Contraceptives.JOURNAL, Annotations, British Medical Journal, 2, 5258, 1007–9, October 1961, 20789252, 1970146, 10.1136/bmj.2.3490.1009, JOURNAL, 10.1136/bmj.2.5258.1032, 2, Medical News, 1961, BMJ, 5258, 1032–1034, 51696624, In December 1961, Enoch Powell, then Minister of Health, announced that the oral contraceptive pill Conovid could be prescribed through the NHS at a subsidized price of 2s per month.JOURNAL, Chà vez L, Takahashi A, Yoshimoto T, Su CC, Sugawara T, Fujii Y, 8849008, Morphological changes in normal canine basilar arteries after transluminal angioplasty, Neurological Research, 12, 1, 12–6, March 1990, 10.1136/bmj.2.5266.1584, 1970619, NEWS, 15 December 1961, Subsidizing birth control, Time (magazine), Time, 78, 24, 55,www.time.com/time/magazine/article/0,9171,827091,00.html,www.time.com/time/magazine/article/0,9171,827091,00.html," title="web.archive.org/web/20080205155642www.time.com/time/magazine/article/0,9171,827091,00.html,">web.archive.org/web/20080205155642www.time.com/time/magazine/article/0,9171,827091,00.html, dead, 5 February 2008, In 1962, Schering’s Anovlar and Searle’s Conovid-E were added to the FPA’s Approved List of Contraceptives.France
In December 1967, the Neuwirth Law legalized contraception in France, including the pill.JOURNAL, Dourlen Rollier AV, [Contraception: yes, but...], Fertilité, Orthogénie, 4, 4, 185–8, October 1972, 12306278, The pill is the most popular form of contraception in France, especially among young women. It accounts for 60% of the birth control used in France. The abortion rate has remained stable since the introduction of the pill.WEB, The Aids Generation: the pill takes priority?, Science Actualities, 2000, 7 September 2006,www.cite-sciences.fr/francais/ala_cite/science_actualites/sitesactu/question_actu.php?langue=an&id_article=263, 1 December 2006,www.cite-sciences.fr/francais/ala_cite/science_actualites/sitesactu/question_actu.php?langue=an&id_article=263," title="web.archive.org/web/20061201112340www.cite-sciences.fr/francais/ala_cite/science_actualites/sitesactu/question_actu.php?langue=an&id_article=263,">web.archive.org/web/20061201112340www.cite-sciences.fr/francais/ala_cite/science_actualites/sitesactu/question_actu.php?langue=an&id_article=263, dead,Japan
In Japan, lobbying from the Japan Medical Association prevented the pill from being approved for general use for nearly 40 years. The higher dose “second generation” pill was approved for use in cases of gynecological problems, but not for birth control. Two main objections raised by the association were safety concerns over long-term use of the pill, and concerns that pill use would lead to decreased use of condoms and thereby potentially increase sexually transmitted infection (STI) rates.PRESS RELEASE, Djerassi on birth control in Japan – abortion ‘yes,’ pill ‘no’, Stanford University News Service, 14 February 1996,www.stanford.edu/dept/news/pr/96/960214japanabort.html, 23 August 2006,www.stanford.edu/dept/news/pr/96/960214japanabort.html," title="web.archive.org/web/20070106173620www.stanford.edu/dept/news/pr/96/960214japanabort.html,">web.archive.org/web/20070106173620www.stanford.edu/dept/news/pr/96/960214japanabort.html, 6 January 2007, dead, However, when the Ministry of Health and Welfare approved Viagra’s use in Japan after only six months of the application’s submission, while still claiming that the pill required more data before approval, women’s groups cried foul.NEWS,www.nytimes.com/1999/04/27/science/japan-s-tale-of-two-pills-viagra-and-birth-control.html, Japan’s Tale of Two Pills: Viagra and Birth Control, 27 April 1999, The New York Times, Wudunn S, 15 February 2017, 19 April 2023,web.archive.org/web/20230419121521/https://www.nytimes.com/1999/04/27/science/japan-s-tale-of-two-pills-viagra-and-birth-control.html, live, The pill was subsequently approved for use in June 1999, when Japan became the last UN member country to do so.WEB, Efron S, 3 June 1999, Japan OKs Birth Control Pill After Decades of Delay,www.latimes.com/archives/la-xpm-1999-jun-03-mn-43662-story.html, 31 August 2022, Los Angeles Times, 31 August 2022,web.archive.org/web/20220831131415/https://www.latimes.com/archives/la-xpm-1999-jun-03-mn-43662-story.html, live, However, the pill has not become popular in Japan.NEWS,articles.latimes.com/1999/jun/03/news/mn-43662, Japan OKs Birth Control Pill After Decades of Delay, Efron S, 3 June 1999, Los Angeles Times, 15 January 2015, 10 August 2014,articles.latimes.com/1999/jun/03/news/mn-43662," title="web.archive.org/web/20140810011111articles.latimes.com/1999/jun/03/news/mn-43662,">web.archive.org/web/20140810011111articles.latimes.com/1999/jun/03/news/mn-43662, live, According to estimates, only 1.3 percent of 28 million Japanese females of childbearing age use the pill, compared with 15.6 percent in the United States. The pill prescription guidelines the government has endorsed require pill users to visit a doctor every three months for pelvic examinations and undergo tests for sexually transmitted diseases and uterine cancer. In the United States and Europe, in contrast, an annual or bi-annual clinic visit is standard for pill users. However, beginning as far back as 2007, many Japanese OBGYNs have required only a yearly visit for pill users, with multiple checks a year recommended only for those who are older or at increased risk of side effects.NEWS, Hayashi A,www.cbsnews.com/stories/2004/08/20/health/main637523.shtml, Japanese Women Shun The Pill, CBS News, 20 August 2004, 12 June 2006, 29 June 2006,www.cbsnews.com/stories/2004/08/20/health/main637523.shtml," title="web.archive.org/web/20060629074107www.cbsnews.com/stories/2004/08/20/health/main637523.shtml,">web.archive.org/web/20060629074107www.cbsnews.com/stories/2004/08/20/health/main637523.shtml, live, As of 2004, condoms accounted for 80% of birth control use in Japan, and this may explain Japan’s comparatively low rates of AIDS.Society and culture
The pill was approved by the FDA in the early 1960s; its use spread rapidly in the late part of that decade, generating an enormous social impact. Time magazine placed the pill on its cover in April 1967.MAGAZINE,www.time.com/time/covers/0,16641,1101670407,00.html,web.archive.org/web/20050219124757/https://time.com/time/covers/0,16641,1101670407,00.html, 19 February 2005, The Pill, Time, 7 April 1967, dead, 16 June 2020, WEB, Westhoff C, 15 December 2015, How Obamacare Explains the Rising Popularity of IUDs,www.publichealth.columbia.edu/public-health-now/news/how-obamacare-explains-rising-popularity-iuds, 17 June 2020, Public Health Now at Columbia University, 23 December 2021,web.archive.org/web/20211223112423/https://www.publichealth.columbia.edu/public-health-now/news/how-obamacare-explains-rising-popularity-iuds, live, In the first place, it was more effective than most previous reversible methods of birth control, giving women unprecedented control over their fertility.WEB,www.plannedparenthood.org/files/1514/3518/7100/Pill_History_FactSheet.pdf, The Birth Control Pill: A History, 20 October 2018, 9 December 2021,web.archive.org/web/20211209221721/https://www.plannedparenthood.org/files/1514/3518/7100/Pill_History_FactSheet.pdf, dead, Its use was separate from intercourse, requiring no special preparations at the time of sexual activity that might interfere with spontaneity or sensation, and the choice to take the pill was a private one. This combination of factors served to make the pill immensely popular within a few years of its introduction.Claudia Goldin, among others, argue that this new contraceptive technology was a key player in forming women’s modern economic role, in that it prolonged the age at which women first married allowing them to invest in education and other forms of human capital as well as generally become more career-oriented. Soon after the birth control pill was legalized, there was a sharp increase in college attendance and graduation rates for women.JOURNAL, Claudia, Goldin, Claudia Goldin, Lawrence F., Katz, Lawrence F. Katz, 2002, The Power of the Pill: Oral Contraceptives and Women’s Career and Marriage Decisions, Journal of Political Economy, 110, 4, 730–770, 10.1086/340778,dash.harvard.edu/bitstream/handle/1/2624453/Goldin_PowerPill.pdf, 10.1.1.473.6514, 221286686, 1 November 2017, 29 May 2023,web.archive.org/web/20230529052311/https://dash.harvard.edu/bitstream/handle/1/2624453/Goldin_PowerPill.pdf, live, From an economic point of view, the birth control pill reduced the cost of staying in school. The ability to control fertility without sacrificing sexual relationships allowed women to make long term educational and career plans.NEWS,equalityarchive.com/history/the-pill/, The Pill, 1 March 2017, Equality Archive, 9 March 2017, 23 December 2021,equalityarchive.com/history/the-pill/," title="web.archive.org/web/20211223112416equalityarchive.com/history/the-pill/,">web.archive.org/web/20211223112416equalityarchive.com/history/the-pill/, dead, Because the pill was so effective, and soon so widespread, it also heightened the debate about the moral and health consequences of pre-marital sex and promiscuity. Never before had sexual activity been so divorced from reproduction. For a couple using the pill, intercourse became purely an expression of love, or a means of physical pleasure, or both; but it was no longer a means of reproduction. While this was true of previous contraceptives, their relatively high failure rates and their less widespread use failed to emphasize this distinction as clearly as did the pill. The spread of oral contraceptive use thus led many religious figures and institutions to debate the proper role of sexuality and its relationship to procreation. The Roman Catholic Church in particular, after studying the phenomenon of oral contraceptives, re-emphasized the stated teaching on birth control in the 1968 papal encyclical Humanae vitae. The encyclical reiterated the established Catholic teaching that artificial contraception distorts the nature and purpose of sex.BOOK, Weigel G, The Courage to Be Catholic: Crisis, Reform, and the Renewal of the Church, 2002, Basic Books, On the other side Anglican and other Protestant churches, such as the Protestant Church in Germany (EKD), accepted the combined oral contraceptive pill.WEB,www.focus.de/regional/muenchen/kirche-pillenverbot-bleibt-streitfrage-zwischen-den-konfessionen_id_4426875.html, Pillenverbot bleibt Streitfrage zwischen den Konfessionen, Focus Online, 22 March 2016, 6 July 2021,web.archive.org/web/20210706162710/https://www.focus.de/regional/muenchen/kirche-pillenverbot-bleibt-streitfrage-zwischen-den-konfessionen_id_4426875.html, live, The United States Senate began hearings on the pill in 1970 and where different viewpoints were heard from medical professionals. Dr. Michael Newton, President of the College of Obstetricians and Gynecologists said:{{blockquote|The evidence is not yet clear that these still do in fact cause cancer or related to it. The FDA Advisory Committee made comments about this, that if there wasn’t enough evidence to indicate whether or not these pills were related to the development of cancer, and I think that’s still thin; you have to be cautious about them, but I don’t think there is clear evidence, either one way or the other, that they do or don’t cause cancer.WEB,www.upi.com/Audio/Year_in_Review/Events-of-1970/Apollo-13/12303235577467-2/#title, 1970 Year in Review, UPI, 8 April 2009, 23 May 2009,www.upi.com/Audio/Year_in_Review/Events-of-1970/Apollo-13/12303235577467-2/#title," title="web.archive.org/web/20090523010239www.upi.com/Audio/Year_in_Review/Events-of-1970/Apollo-13/12303235577467-2/#title,">web.archive.org/web/20090523010239www.upi.com/Audio/Year_in_Review/Events-of-1970/Apollo-13/12303235577467-2/#title, live, }}Another physician, Dr. Roy Hertz of the Population Council, said that anyone who takes this should know of “our knowledge and ignorance in these matters” and that all women should be made aware of this so they can decide to take the pill or not.The Secretary of Health, Education, and Welfare at the time, Robert Finch, announced the federal government had accepted a compromise warning statement which would accompany all sales of birth control pills.Result on popular culture
The introduction of the birth control pill in 1960 allowed more women to find employment opportunities and further their education. As a result of women getting more jobs and an education, their husbands had to start taking over household tasks like cooking.JOURNAL, Winnick C, 1968, The Beige Epoch: Depolarization of Sex Roles in America, 1037799, The Annals of the American Academy of Political and Social Science, 376, 18–24, 10.1177/000271626837600103, 145158114, Wanting to stop the change that was occurring in terms of gender norms in an American household, many films, television shows, and other popular culture items portrayed what an ideal American family should be. Below are listed some examples:Poem
- The Pill Versus the Springhill Mine Disaster is the title poem of a 1968 collection by Richard Brautigan.JOURNAL,www.brautigan.net/pill.html, Richard, Brautigan, The Pill versus The Springhill Mine Disaster, Brautigan, 2007, 1 December 2017, 10.7273/nvgh-ca61, 14 January 2009,www.brautigan.net/pill.html," title="web.archive.org/web/20090114231634www.brautigan.net/pill.html,">web.archive.org/web/20090114231634www.brautigan.net/pill.html, dead,
Music
- Singer Loretta Lynn commented on how women no longer had to choose between a relationship and a career in her 1974 album with a song entitled “The Pill”, which told the story of a married woman’s use of the drug to liberate herself from her traditional role as wife and mother.WEB,gender.stanford.edu/news/2011/pill-and-marriage-revolution, The pill and the marriage revolution, The Clayman Institute for Gender Research, 1 December 2017,gender.stanford.edu/news/2011/pill-and-marriage-revolution," title="web.archive.org/web/20171212220618gender.stanford.edu/news/2011/pill-and-marriage-revolution,">web.archive.org/web/20171212220618gender.stanford.edu/news/2011/pill-and-marriage-revolution, 12 December 2017, dead,
Environmental impact
A woman using COCPs excretes in her urine and feces natural estrogens, estrone (E1) and estradiol (E2), and synthetic estrogen ethinylestradiol (EE2).JOURNAL, Williams RJ, Johnson AC, Smith JJ, Kanda R, Steroid estrogens profiles along river stretches arising from sewage treatment works discharges, Environmental Science & Technology, 37, 9, 1744–50, May 2003, 12775044, 10.1021/es0202107, 2003EnST...37.1744W, These hormones can pass through water treatment plants and into rivers.JOURNAL, Not Quite Worry-Free, Environment, 45, 1, 6–7, Jan–Feb 2003, 10.1080/00139150309604545, 218496430, Other forms of contraception, such as the contraceptive patch, use the same synthetic estrogen (EE2) that is found in COCPs, and can add to the hormonal concentration in the water when flushed down the toilet.JOURNAL, Batt S, Pouring Drugs Down the Drain, Herizons, 18, 4, 12–3, Spring 2005,www.macalester.edu/environmentalstudies/students/projects/endocrinedisrupterswebsite/articles/16183034.pdf, 4 December 2011,www.macalester.edu/environmentalstudies/students/projects/endocrinedisrupterswebsite/articles/16183034.pdf," title="web.archive.org/web/20120315121943www.macalester.edu/environmentalstudies/students/projects/endocrinedisrupterswebsite/articles/16183034.pdf,">web.archive.org/web/20120315121943www.macalester.edu/environmentalstudies/students/projects/endocrinedisrupterswebsite/articles/16183034.pdf, 15 March 2012, dead, This excretion is shown to play a role in causing endocrine disruption, which affects the sexual development and reproduction of wild fish populations in segments of streams contaminated by treated sewage effluents.JOURNAL, Zeilinger J, Steger-Hartmann T, Maser E, Goller S, Vonk R, Länge R, Effects of synthetic gestagens on fish reproduction, Environmental Toxicology and Chemistry, 28, 12, 2663–70, December 2009, 19469587, 10.1897/08-485.1, free, doi, A study done in British rivers supported the hypothesis that the incidence and the severity of intersex wild fish populations were significantly correlated with the concentrations of the E1, E2, and EE2 in the rivers.A review of activated sludge plant performance found estrogen removal rates varied considerably but averaged 78% for estrone, 91% for estradiol, and 76% for ethinylestradiol (estriol effluent concentrations are between those of estrone and estradiol, but estriol is a much less potent endocrine disruptor to fish).JOURNAL, Johnson AC, Williams RJ, Simpson P, Kanda R, What difference might sewage treatment performance make to endocrine disruption in rivers?, Environmental Pollution, 147, 1, 194–202, May 2007, 17030080, 10.1016/j.envpol.2006.08.032, 2007EPoll.147..194J, Several studies have suggested that reducing human population growth through increased access to contraception, including birth control pills, can be an effective strategy for climate change mitigation as well as adaptation.NEWS, Potts M, Marsh L, THE POPULATION FACTOR: How does it relate to climate change?,ourplanet.com/climate-adaptation/Potts_and_Marsh.pdf, 22 June 2015, OurPlanet.com, February 2010,ourplanet.com/climate-adaptation/Potts_and_Marsh.pdf," title="web.archive.org/web/20160304065641ourplanet.com/climate-adaptation/Potts_and_Marsh.pdf,">web.archive.org/web/20160304065641ourplanet.com/climate-adaptation/Potts_and_Marsh.pdf, 4 March 2016, dead, Malcolm Potts, WEB, Cafaro P, Alternative Climate Wedges – Population Wedge,www.philipcafaro.com/alternative-climate-wedges/population-wedge, Philip Cafaro, 22 June 2015, 22 June 2015,www.philipcafaro.com/alternative-climate-wedges/population-wedge," title="web.archive.org/web/20150622072109www.philipcafaro.com/alternative-climate-wedges/population-wedge,">web.archive.org/web/20150622072109www.philipcafaro.com/alternative-climate-wedges/population-wedge, live, According to Thomas Wire, contraception is the ‘greenest technology’ because of its cost-effectiveness in combating global warming — each $7 spent on contraceptives would reduce global carbon emissions by 1 tonne over four decades, while achieving the same result with low-carbon technologies would require $32.NEWS, Wire T, Contraception is ‘greenest’ technology,www.lse.ac.uk/newsAndMedia/news/archives/2009/09/Contraception.aspx, 22 June 2015, London School of Economics, 10 September 2009, 22 June 2015,www.lse.ac.uk/newsAndMedia/news/archives/2009/09/Contraception.aspx," title="web.archive.org/web/20150622070553www.lse.ac.uk/newsAndMedia/news/archives/2009/09/Contraception.aspx,">web.archive.org/web/20150622070553www.lse.ac.uk/newsAndMedia/news/archives/2009/09/Contraception.aspx, live,See also
- Estradiol-containing oral contraceptive
- Hormone replacement therapy (HRT)
- List of estrogens available in the United States
- List of progestogens available in the United States
- Progestogen-only injectable contraceptive
References
{{Reflist}}Further reading
- JOURNAL, Black A, Guilbert E, Costescu D, Dunn S, Fisher W, Kives S, Mirosh M, Norman WV, Pymar H, Reid R, Roy G, Varto H, Waddington A, Wagner MS, Whelan AM, No. 329-Canadian Contraception Consensus Part 4 of 4 Chapter 9: Combined Hormonal Contraception, Journal of Obstetrics and Gynaecology Canada, 39, 4, 229–268.e5, April 2017, 28413042, 10.1016/j.jogc.2016.10.005,
External links
- The Birth Control Pill—CBC Digital Archives
- www.life.com/image/first/in-gallery/42292/the-birth-of-the-pill" title="web.archive.org/web/20100511003522www.life.com/image/first/in-gallery/42292/the-birth-of-the-pill">The Birth of the Pill—slide show by Life magazine
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