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History of oral contraceptive drugs and their use worldwide
Best Practice & Research Clinical Endocrinology & Metabolism 27 (2013) 3–12
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Best Practice & Research Clinical Endocrinology & Metabolism journal homepage: www.elsevier.com/locate/beem
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History of oral contraceptive drugs and their use worldwide Sophie Christin-Maitre, MD, PhD, Professor a, b, * a b
Department of Endocrinology, AP-HP, Hospital Saint-Antoine, University Pierre et Marie Curie, Paris VI, France Inserm U 933, Paris, France
Keywords: hormonal contraceptives oral contraceptive drugs combined oral contraceptive vaginal ring implants microprogestins
The first hormonal pill, called EnovidÒ, was approved by the Federal Drug Administration (FDA) in May 1960. It contained mestranol and norethisterone. Over the years, oral contraceptives have evolved through gradual lowering of ethinyl estradiol (EE) content, introduction of 17b estradiol, and many different progestins. The standard regimen allows for 21 days of pill containing steroids and a pill-free interval of 7 days. Recently, continuous or extended regimens have been approved. In order to improve compliance, alternative routes of combined oral contraceptive (COC) administration have been developed such as vaginal or transdermal routes. In 2009, according to the United Nations, the mean global percentage using contraception in women who are married or in union was 62.7%. COC represented 8.8% of contraceptive prevalence, reaching 15.4% in more developed countries. More than 100 million women worldwide use COCs. However, each year, many unintended pregnancies occur, indicating that contraception still needs to be promoted. Ó 2012 Elsevier Ltd. All rights reserved.
History Egyptians are recognized as one of the first civilizations using birth control.1 From as early as 3000 BC ancient drawings depict men wearing condoms. However, the earliest known illustration of a man using a condom during sexual intercourse is painted on the wall of a cave in France and is 12,000 to 15,000 years old.1 Egyptians developed many contraceptive strategies, such as vaginal pessaries or
* Department of Endocrinology, Hôpital Saint-Antoine, 184 rue du faubourg Saint-Antoine, 75012 Paris, France. Tel.: þ33 1 49282400; Fax: þ33 1 49283195. E-mail address: [email protected]. 1521-690X/$ – see front matter Ó 2012 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.beem.2012.11.004
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vaginal sponges. Pessaries were made of crocodile dung, honey and sodium bicarbonate. Women used cotton-lint tampons soaked in the fermented juice of acacia plants to prevent pregnancy. In order to be spermicidal, vaginal sponges used to be soaked in lemon juice or vinegar. In the 4th century BC, Aristotle was the first Greek writer to mention contraception. The philosopher recommended that women “anoint that part of the womb on which the seed falls” with olive oil in order to prevent pregnancy. Another method recommended by the ancient Greeks was to exert pressure on the abdomen in order to expulse semen from the vagina. Various plants were used by Greek women to prevent pregnancy such as pomegranate, pennyroyal, and pine. Later, Peter of Spain, who was elected Pope John XXI in 1276, offered advice on birth control by giving recipes using different herbs that induced menstruation.2 Women in Sri Lanka are reported to eat a papaya a day to prevent pregnancy. It contains an enzyme papain which interacts with progesterone. Centuries ago, Chinese women used to drink lead and mercury to control fertility which often resulted in sterility or death. Intrauterine devices (IUDs) have been used as a method of contraception for over 2000 years, although their use became more common in the second half of the 20th century. In Europe, condoms were used from the 16th century, firstly to prevent syphilis and then to prevent pregnancy. They were originally made from fish or animal gut. However, in 1944 Charles Goodyear patented the vulcanization of rubber. This procedure facilitated the mass production of condoms. Other than the use of condoms, the main methods of birth control used before the 20th century included mainly abstinence, infrequent coitus, coitus interruptus, breastfeeding and induced abortion. Real improvements in birth control occurred in the 20th century, thanks to several women, including Dr Marie Stopes from Scotland. She wrote a guide to contraception entitled “Wise Parenthood” and opened the first of her birth control clinics in Holloway, Northern London in 1921. The dawning of hormonal contraception involved two women, the Americans Margaret Sanger and Katharine McCormick, and a man Gregory Pincus. Margaret Sanger founded the American Birth Control League which became Planned Parenthood. She was probably highly motivated as her mother had 18 pregnancies, 11 children and died at the early age of 50. She claimed that “No woman can call herself free who does not own and control her body. No woman can call herself free until she can choose consciously whether she will or will not be a mother”.3 She met Katharine McCormick, the wife of the inventor of the mechanical harvester, as they were both involved in women’s rights. McCormick, who had a large fortune, funded Gregory Pincus’s research into developing a birth control pill. He is considered as the creator of the first contraceptive pill. The total of McCormick’s gifts to the research reached $2,000,000.1 She funded the first clinical trials of the Pill, which were conducted by Dr John Rock, an eminent Catholic gynecologist. He first treated his patients in his private practice. Rock, who came to be regarded as a co-developer of the Pill, worked with Planned Parenthood staff on a closely reasoned book, The Time Has Come: A Catholic Doctor’s Proposals to End the Battle over Birth Control. Pincus and Rock were able to benefit from Carl Djerassi’s research on steroids. Djerassi had synthesized a progestin, called norethisterone, in his laboratory in Mexico City which remained effective when taken orally, and was much stronger than natural progesterone. Doses over 5 mg of progestin in a 21day regimen could suppress ovulation but caused unacceptable bleeding. With the discovery that the contaminant mestranol reduced breakthrough bleeding, mestranol, and subsequently its active metabolite ethinyl estradiol (EE), were added to contraceptive pills. The first hormonal pill was called EnovidÒ. It was approved by the Federal Drug Administration (FDA) in 1957 as treatment of menstrual disorders. Its capacity to regulate birth was only recognized several years later and it was not until 1959 that the pharmaceutical company Searle applied to the FDA for approval of a pill that would be marketed as a contraceptive. In May 1960, approval was granted.4 Nowadays, COCs are used by more than 100 million women worldwide. Combined oral contraceptives The first combined contraceptive pill, called EnovidÒ contained mestranol and norethynodrel.5 Mestranol is an estrogen, the 3-methyl ether of EE. It is a prodrug as it is demethylated to EE in the liver. Its dose in the first pill was 150 mg. Knowing that 50 mg of mestranol is pharmacokinetically bioequivalent to 35 mg of EE, the initial dose of estrogen contained in the pill was very high. Norethynodrel is a progestin; its initial dose was 9.85 mg per pill.
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In the first clinical studies, EnovidÒ’s contraceptive efficacy was excellent; reaching 100% but this drug induced many side effects. In studies performed in Puerto Rico under the supervision of Dr Edris Rice-Wray, 17% of women presented with nausea, dizziness, headaches, stomachaches and vomiting. The dose of northynodrel was lowered to 5 mg and the dose of mestranol to 75 mg. However, in 1961, the Lancet reported the death of a woman from thrombosis who was taking the pill. In less than a year, the FDA had received reports of 6 deaths and 20 non-fatal cases of thromboembolism. Over the years, oral contraceptives have evolved through gradual lowering of estrogen content, introduction of new progestins, new regimens of biphasic, triphasic or quadriphasic Pills as well as fixed or flexible extended regimen and alternative routes of COC administration, such as vaginal or transdermal, have been developed. Estrogen in COC Over the years, in order to decrease the cardiovascular risk of the pill, the dose of estrogen has progressively decreased. In the majority of COCs available nowadays, the estrogen component is EE or 17a estradiol. In the 1970s, the dose of EE decreased from 50 to 30–35 mg. Subsequently, formulations containing 20 and even 15 mg were developed. Pills available nowadays are usually sorted into concentrations of EE higher or lower than 30 mg, with pills containing less than 30 mg considered as low dose Pills. This decrease has been made possible thanks to the availability of new progestins. The concept of using the natural 17b estradiol (17 bE2) in combined pills arose in the 1970s. More than 15 different attempts were made by different companies.6–9 However, no satisfactory combinations were available for many years. In many cases, the pills containing 17 bE2 were contraceptive but their tolerance was low, as women experienced bleedings. Mono-, bi- or triphasic combinations have failed over the years. However, two formulations delivering estradiol (E2) have recently been marketed. A quadriphasic COC combining E2 valerate and dienogest has been newly approved in Europe and USA. E2 valerate is a synthetic estrogen, which is metabolized into 17 bE2. The second pill is a monophasic COC combining 17b E2 with nomegestrol acetate, a progesterone-derived progestin. It is now available in several European countries.10,11 A pill containing estetrol, a synthetic estrogen identical to an endogenous fetal estrogen, is currently under development.12 This molecule is a Selective Estrogen Receptor Modulator (SERM) and has estrogenic activity on bone and on the endometrium but anti-estrogenic activity on the breast. Progestins in COCs In the different combined pills available nowadays, the progestin component in the pill inhibits luteinizing hormone (LH) peak, decreases ovarian sensibility to follicle stimulating hormone (FSH) and therefore decreases estradiol production. The estrogenic component regulates endometrium proliferation and compensates estrogenic deficiency induced by the anti-gonadotropic effect of the progestin. Progestins are classically characterized according to their structural origins. They bind to progesterone receptors, but progestins may also bind to other steroid receptors, such as androgen, glucocorticoid and mineralocorticoid receptors. Most of the progestins contained in COCs were initially derived from testosterone, and are called 19-nortestosterone derivatives. Norethisterone is an estrane, and norethisterone acetate and norethynodrel are gonanes. Few pills containing first generation progestins are still available. Their side effects, such as acne, oily skin and decreased high density lipoprotein (HDL), mainly due to their androgenic proprieties, are the main cause for their progressive withdrawal. Over the years, progestins with less androgenic effects have been developed. Among them, are the second and third generation progestins. Levonorgestrel and norgestrel are second generation progestins. Third generation progestins include desogestrel, with its active metabolite 3-keto-desogestrel (also named etonogestrel), norgestimate (and its active 17-deacetylated metabolite, norelgestromin) and gestodene. The most recent were released in the mid 1980s.13 Different progestins used in COCs are derived from progesterone. Molecules such as chlormadinone acetate, cyproterone acetate and medroxyprogesterone acetate are called pregnane derivatives, as they are derived from 17OH progesterone.14 Some newer progestins have been available more recently in oral contraceptives, such as drospirenone. This progestin possesses anti-mineralocorticoid and weak
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anti-androgen proprieties. Dienogest, is referred to as a hybrid progestin, as it is derived from the estrane group but does not exert the androgenic effects of the testosterone derivatives. A Cochrane Review evaluated the effectiveness and side effects of different progestogens.15 Thirty trials with a total of 13,923 participants were included, generating 16 comparisons. Overall the quality of trials was low. The conclusion of this Cochrane Review mentions that women using COCs containing second generation progestogens may be less likely to discontinue than those using COCs containing first generation progestogens. Based on one small double-blind trial, third-generation progestogens may be preferable to second generation preparations with regard to bleeding patterns but further evidence is needed. Sequence of COC Combination pills are categorized as monophasic, or multiphasic, depending on the different levels of hormones contained in each pill per cycle. The initial pill was monophasic but biphasic and triphasic pills were introduced in the 1980s. They were initially designed to decrease potential side effects, such as nausea and headaches. A Cochrane review showed that tolerance is identical between mono- or multiphasic pills.16,17 A second goal was to mimic the natural human cycle more closely. Most COCs have a 28-day cycle. The standard regimen allows for 21 pills containing steroids and a pill-free interval of 7 days, for eliciting regular withdrawal bleeding and for reassuring women that they are not pregnant. However, monthly bleeding is not necessary for contraceptive efficacy or safety issues. Furthermore, several studies have illustrated that ovarian activity occurs during the pill free interval,18 potentially reducing the efficacy of the pill as follicular growth may occur followed by ovulation. This phenomenon is mainly observed with the newest pills, as they contain lower doses of steroids and therefore less gonadotropin inhibition. This threat of contraceptive failure is even higher in the case of pill omission just after the pill free interval.18 Therefore, in some new pills, the pill-free interval has been reduced to 4 days. This reduction has been shown to diminish the mean follicular size. For instance, with the pill containing nomegestrol acetate and 17b E2, the largest follicle diameter was significantly smaller in the 24/4 day group than in the 21/7 day group [mean (SD) mm in cycle 2: 9.0 (3.0) versus 11.3 (5.3) (p¼ 0.02); in cycle 3: 9.2 (3.0) versus 11.5 (6.0) (p ¼ 0.04)].19 Mean FSH plasma levels were significantly lower in the 24-day versus the 21 day group on day 24 of cycles 1 and 2. Over the past years, a strategy has been to add placebo pills instead of having a pill-free interval. The Coraliance study, enrolling 617 gynecologists in France, followed 3316 patients and showed that during their previous cycle of COC, 23% women missed a pill at least once.20 Among women on the pill involving a treatment-free interval, 42% of instances of missing a pill occurred during the first week following the treatment-free interval. Therefore, a continuous regimen without a treatment free interval may improve compliance. In order to reduce the number of unwanted pregnancies, the immediate start or “quick-start” strategy has been developed. It implies that COCs are started immediately after the healthcare provider’s visit instead of waiting for the next menses. It has to be associated with back-up birth control for the first seven days. A Cochrane Review reported limited evidence that immediate start reduces unwanted pregnancies.21 Another change in the cycle regimen, developed in the past 10 years, is the extended cycle COC.22 This consists of 3 or 4 months of active pill use with a 7-day pill free interval. When the pill-free interval is avoided it is named continuous regimen as opposed to cyclical regimen. The rationale of extended or continuous regimens was to avoid menstrual related side effects, such as premenstrual syndrome, dysmenorrhea or migraine. The second goal was to reduce the number of days of bleeding. In 2003, the FDA approved an extended cycle COC in an 84/7 dosing regimen, EE 30 mg/levonorgestrel (LNG) 150 mg (SeasonaleÒ; Duramed Pharmaceuticals, Cincinnati, Ohio), with 84 active pills and 7 placebos. In 2007, it approved LybrelÒ (Wyeth Pharmaceuticals, Philadelphia, Pennsylvania), which is administered as a combined active pill containing LNG 90 mg and EE 20 mg in a continuous fashion, 365 days per year. Several studies have shown that those regimens’ contraceptive efficacy is comparable with the traditional 21/7 regimen. However, continuous regimens are often associated with increased risk of breakthrough bleeding versus cyclical COC.
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In some extended regimens, placebo pills have been replaced by low dose of EE. The rationale is to provide the potential for greater gonadotropin secretion. Furthermore, EE could stabilize the endometrium and reduce bleeding. In May 2006 and October 2008, the FDA approved respectively, a pill containing 84 active pills with LNG 150 mg and EE 30 mg, followed by 7 days of 10 mg EE pills, and a pill containing 84 active pills with LNG 100 mg and EE 20 mg, followed by 7 days of 10 mg EE pills. A recent review has shown that this new extended cycle OC provides patients a low dose, extended regimen OC option without sacrificing efficacy or tolerability.23 In the past few years, it has been hypothesized that a regimen that extended more than 28 days and could give women the opportunity to manage their intracyclic breakthrough bleeding would be appreciated. It was called flexible extended regimen or MIB, for “Manage Intracyclic Bleeding”. Klipping et al. conducted a multicenter randomized, open-label, parallel group study comparing EE 20 mg/ drospirenone (DRSP) 3 mg in a flexible extended regimen versus a cyclical or a fixed extended regimen of 124 days.24 With the flexible MIB regimen, women received EE/DRSP for a flexible number of cycles (minimum three, maximum 13 in 1 year), each of which was separated by a 4-day tablet-free interval. Over a period of 1 year, the mean number of bleeding/spotting days was significantly lower in the flexible MIB regimen than with the cyclical regimen (41.0 29.1 (95% CI 38.8–43.3; n ¼ 640) versus 65.8 27.0 (95% CI 62.2–69.4; n ¼ 215) days, p < 0.0001). The mean number of bleeding/spotting days with the fixed extended regimen was 60.9 51.1 (95% CI 53.9–67.9) days (n ¼ 209). The Pearl Index for the flexible MIB regimen was 0.64, indicating good contraceptive efficacy. These data have been confirmed by Jensen et al.25 The management of intracyclic bleeding represents an interesting concept that could be more developed over the next years. Non-oral routes of COC In order to increase efficacy, compliance and tolerance, alternative routes of combined contraception have been developed, such as vaginal or transdermal routes. Increased bioavailability implies that lower steroid doses are needed in these systems. The contraceptive vaginal ring named NuvaringÒ releases 15 mg of EE, and 120 mg of etonogestrel per day.26 It is a flexible, transparent ring with a diameter of 54 mm and a cross section of 4 mm. It is self-administered for 3 weeks, followed by 1 week ring-free period. It works by inhibiting ovulation. The skin patch called EvraÒ delivers 20 mg EE and 150 mg norelgestromin daily to the systemic circulation.27 It is a once-weekly self-administered patch and its efficacy is based on ovulation suppression. Both regimens have been approved since the mid 2000s. COC as emergency contraception COCs were first used as emergency contraception, as advised by Dr Albert Yuzpe, a Canadian obstetrician/gynecologist who first published in 1974. This method must be initiated within 72 h following sexual intercourse. Several COC pills have to be taken 12 h apart.28 This method has been used by millions of women; however, its tolerance is low, and nausea, vomiting, spotting and headaches are frequent side effects. Therefore, in 1999 it was replaced by progestin only emergency contraception and, more recently, by Selective Progesterone Receptor Modulators (SPRM). Other types of hormonal contraception Progestin only pills should be distinguished from COCs. This type of pill does not contain estrogens, only synthetic progestogens, and are called progestin only mini-pills. These pills have been available since 1973 and are currently proposed to women with contraindications to use of estrogens, as their efficacy is lower than combined pills and their tolerance is not always very good, inducing bleedings such as spotting as well as acne and ovarian cysts.29 The dose of progestin contained in this type of pill is lower than in COCs. They inconsistently inhibit ovulation and rely mainly on their progestogenic effect of thickening the cervical mucus, thereby reducing sperm viability and penetration. Therefore, their ovulation inhibition is lower than with COC. Injectable progestins were developed a few years after the pill in order to make it possible for women to use an effective method without taking a pill once a day. Depot medroxyprogesterone
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acetate (DMPA) was first submitted to the FDA for contraceptive use in 1967. However, although it has been widely used all over the world, it was not approved until 1992 by the FDA. This long acting formula needs to be injected every three months.1 Another form of progestin only contraception are implants. The first developed was Norplant, a multi unit system containing 6 rods, then came Jadelle containing 2 rods.30 Since then several single or double-rod systems have been developed using four different types of progestin: levonogestrel, etonogestrel, nestorone and nomegestrol acetate. The most recent one to be launched on the market was NexplanonÒ. It is a single-rod subdermal implant that is inserted just under the skin of a woman’s upper arm. The 4 cm by 2 mm rod, named ImplanonÒ, contains 68 mg of etonogestrel which is released over a three year period. It was first approved in 1988 in Indonesia and in the US in 2006. It has been replaced by NexplanonÒ because of cases of incorrect insertion of ImplanonÒ by medical personnel.31 It is essentially identical to ImplanonÒ except that it is radiopaque. The first IUD containing progesterone was introduced in 1976. However, it was abandoned as its life-span was only 1 year. In the late 1970s Dr Luukainen designed an IUD delivering levonorgestrel, called MirenaÒ. It was first approved in Finland in 1990 and has a lifespan of 5 years. Levonorgestrel is released into the endometrial cavity initially at a daily dose of 20 mg and then at a dose of 10 mg.32 Progestin pills can be used as emergency contraception. The most popular form for emergency contraception is levonorgestrel. Initially two pills of 0.75 mg were administered 12 h apart, although this regimen has now been replaced by a single pill containing 1.5 mg of levonorgestrel.33 More recently, SPRMs have been developed as emergency contraception. Initially low doses of mifepristone have been tested.34 The SPRM available as emergency contraception is ulipristal acetate (UPA), previously known as VA 29-14 or CDB-2914.35 It is a derivative of 19-norprogesterone and is administered as a single dose of 30 mg. It was approved in May 2009 by the European Commission and marketed as an emergency contraceptive within 5 days of unprotected sexual intercourse. This molecule has also been developed as daily contraceptive; a daily oral administration of UPA is able to suppress ovulation in a majority of women.36 It is an “estrogen-free” contraceptive with possibly fewer side effects than contraceptives delivering EE. Currently the Population Council in collaboration with National Institute of Child Health and Human Development (NICHD) is developing a 3-month contraceptive vaginal ring containing UPA.37 Prevalence of contraception use At the 2005 World Summit, Governments committed themselves to “achieving universal access to reproductive health by 2015, as set out at the International Conference on Population and Development” (General Assembly resolution 60/1). This goal is not achieved yet, as illustrated in Fig. 1, reporting the percentage of women between 15 and 49 years old using contraception according to the most recent data published by United Nation in 2011.38 Disparities are obvious. In 2009, the mean global percentage using contraception in women who are married or in union was 62.7%. In more developed regions, it was as high as 72.4% and as low as 31.4% in lesser developed countries. Looking more precisely at modern contraceptive methods, the prevalence was 60% for Asia, 67% for the Latin American and Caribbean region, but only 22% for Africa as a whole and 16% for sub-Saharan Africa.38 Furthermore, in at least 46 countries, 20% or more of the women of reproductive age who are married or in a union have an unmet need for contraception. However, a major improvement in contraceptive prevalence has been observed since 1960. In developing countries this prevalence reached 10% in 1960 and was close to 70% in 2009. The fertility rate has decreased from 4.7 births in the early 1970s to 2.6 births in the late 2000s, predominantly due to contraceptive use.39 Using a mathematical model, Ahmed et al. estimated that worldwide, in 2008, 342,203 women died from maternal causes, but that contraceptive use averted 272,040 maternal deaths (uncertainty interval 127,937–407,134), a 44% reduction, so without contraceptive use, the number of maternal deaths would have been 1$8 times higher than the 2008 total.39 Contraceptive use improves perinatal outcomes and child survival by widening the interval between pregnancies.40 In developing countries, risk of death in infancy (age < 1 year) would fall by 10% and in ages 1–4 years by 21% if all children were spaced by a gap of 2 years.
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Fig. 1. Percentage of women using any modern method of contraception among those aged 15–49 years who are married or in a union, in 2009.
What is the prevalence of COC use and types of COC used? The global mean percentage using contraception among women who are married or in union of 62.7% breaks down as follows: 56.1% using modern methods, and 6.6% using any traditional methods. Modern methods are female sterilization (18.9%), male contraception (2.4%), pill or COC (8.8%), injection (3.5%), implants (0.3%), IUD (14.3%), condoms (7.6%) and vaginal barrier methods (0.2%). In 2009, COCs represented only 8.8% of contraceptive prevalence, reaching 15.4% in more developed countries. It is currently used by more than 100 millions of women worldwide, with large variations depending on country, age and education. According to a recent study by Hall et al., the proportion of women using sexual and reproductive health services (SRHs) in the US, increased from 50% (2006–2007) to 54% (2007–2008) and 57% (2008– 2010) [all year odds ratios (ORs) 1.4, p values < 0.03]. Among sexually experienced women, the proportions using SRH and contraceptive services were unchanged, while sexually transmitted infection (STI) service use increased from 22% (2006–2007) to 33% (2008–2009) (OR 1.7, confidence interval 1.1–2.4, p ¼ 0.009).41 Lower proportions of service were used among women of social disadvantage. A recent American study from Princeton University sought to estimate the prevalence of types of COCs used among US women. Data were collected by interviewing 12,279 women aged 15–44 years participating in the National Survey of Family Growth.42 Analyses focused on COC use overall, by pill type, across socio-demographic and health factors. The prevalence of current COC use (88 different brands) was 17%. The majority of COC users used earlier-formulation COCs: 30 mg (67%) versus <30 mg estrogen (33%), monophasic (67%) versus multiphasic (33%) dosages and traditional 21/7 regimens (88%) versus extended or other cycle regimens (12%). Norgestimate (32%) and norethindrone (20%) were the most commonly used progestins. Socio-demographic, gynecological and health risk factors were associated with type of COC use. Conclusion In 2009, COC use remained low, accounting for 8.8% of global contraceptive prevalence. Although studies have demonstrated that long acting methods such as IUDs and implants have a very low failure rate and that their effectiveness is superior to that of contraceptive pills, ring or patch,43 there is still
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room for COCs. Their failure rate is among the lowest, ranging from 1/5 to 1/100 woman per year. Furthermore, non-contraceptive benefits of COCs have been reported, such as improved acne, headaches, menorrhagia, dysmenorrhea and premenstrual menstrual syndrome.44 A recent review of the literature has reported that fertility after using COC is broadly similar to those reported following discontinuation of barrier methods or use of no contraceptive method.45 In summary, the health benefits of COC far outweigh the health risks. The European Society of Human Reproduction and Embryology (ESHRE) Capri Workshop group recently concluded that although great advances have been made in recent years in increasing contraceptive needs in women in many countries where contraceptive prevalence is low or there is a high unmet need for contraception,46 much more can, and needs to be done. Healthcare providers should be more informed about contraception47 and women and couples need to make informed choice concerning their contraception. Practice points - The first hormonal contraceptive pill, EnovidÒ, was approved by FDA in 1960. - Doses of ethinyl estradiol have been progressively lowered in order to avoid thrombotic events. - The standard regimen of 21 pills containing steroids and a pill-free interval of 7 days is progressively being replaced by continuous regimens to improve compliance. - Non-contraceptive benefits of COCs, such as improvement of acne, headaches, menorrhagia, dysmenorrhea and premenstrual menstrual syndrome should be considered when choosing a contraceptive method. - In 2009, COC represented 8.8% of contraceptive prevalence. More than 100 million women used COCs.
Research agenda - Research needs to be performed in order to understand the method failures of COC. - Trials are necessary to test educational programs explaining how benefits outweigh the risks of COCs. - Development of new molecules such as progestins or Selective Progesterone Receptor Modulators for new contraceptive pills, rings or patches. Funding None. Conflict of interest None declared.
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Efficacy and tolerability of a monophasic combined oral contraceptive containing nomegestrol acetate and 17b-oestradiol in a 24/4 regimen, in comparison to an oral contraceptive containing ethinylestradiol and drospirenone in a 21/7 regimen. European Journal of Contraception and Reproductive Health Care 2011; 16: 430–443. 12. Visser M & Coelingh-Bennink HJT. Clinical implications of estetrol. Journal of Steroid Biochemistry and Molecular Biology 2009; 114: 85–89. 13. Sitruk-Ware R. Pharmacological profile of progestins. Maturitas 2008; 61: 151–157. *14. Sitruk-Ware R & Nath A. The use of newer progestins for contraception. Contraception 2010; 82: 410–417. 15. Lawrie TA, Helmerhorst FM, Maitra NK et al. Types of progestogens in combined oral contraception: effectiveness and sideeffects. The Cochrane Database of Systematic Reviews 2011; 11. CD004861. 16. Van Vliet HA, Grimes DA, Helmerhorst FM et al. Biphasic versus monophasic oral contraceptives for contraception. The Cochrane Database of Systematic Reviews 2006; 3. CD002032. 17. Van Vliet HA, Grimes DA, Lopez LM et al. Triphasic versus monophasic oral contraceptives for contraception. The Cochrane Database of Systematic Reviews 2011; 11. CD003553. *18. van Heusden AM & Fauser B. Residual ovarian activity during oral steroid contraception. Human Reproduction Update 2002; 8: 345–358. 19. Christin-Maitre S, Serfaty D, Chabbert-Buffet N et al. Comparison of a 24-day and a 21-day pill regimen for the novel combined oral contraceptive, nomegestrol acetate and 17 b estradiol (NOMAC/E2): a double-blind, randomized study. Human Reproduction 2011; 26: 1338–1347. 20. Aubeny E, Buhler M, Colau JC et al. Oral contraception: patterns of non-compliance. The Coraliance study. European Journal of Contraception and Reproductive Health Care 2002; 7: 155–161. 21. Lopez LM, Newmann SJ, Grimes DA et al. Immediate start of hormonal contraceptives for contraception. The Cochrane Database of Systematic Reviews 2008; 2. CD006260. 22. Read CM. New regimens with combined oral contraceptive pills-moving away from traditional 21/7 cycles. The European Journal of Contraception and Reproductive Health Care 2010; 15: 32–41. 23. Krishnan S & Kiley J. The lowest-dose, extended-cycle combined oral contraceptive pill with continuous ethinyl estradiol in the United States: a review of the literature on ethinyl estradiol 20 mg/levonorgestrel 100 mg þ ethinyl estradiol 10 mg. International Journal of Women’s Health 2010; 2: 235–239. 24. Klipping C, Duijkers I, Fortier MP et al. Contraceptive efficacy and tolerability of ethinylestradiol 20 mg/drospirenone 3 mg in a flexible extended regimen: an open-label, multicentre, randomized, controlled study. Journal of Familial Planning and Reproductive Health Care 2012; 38: 73–83. 25. Jensen JT, Garie SG, Trummer D et al. Bleeding profile of a flexible extended regimen of ethinylestradiol/drospirenone in US women: an open-label, three-arm, active controlled, muticenter study. Contraception 2012; 86: 110–118. 26. Roumen FJME, Apter D, Mulders TMT et al. Efficacy, tolerability and acceptability of a novel contraceptive vaginal ring releasing etonogestrel and ethinyl estradiol. Human Reproduction 2001; 16: 469–475. 27. Goa KL, Warner GT & Easthope SE. Transdermal ethinylestradiol/norelgestromin: a review of its use in hormonal contraception. Treatments in Endocrinology 2003; 2: 191–206. 28. Yuzpe AA, Thurlow HJ, Ramzy I et al. Post coital contraception – a pilot study. Journal of Reproductive Medicine 1974; 13: 53–58. *29. ESHRE Capri Workshop Group. Ovarian and endometrial function during hormonal contraception. Human Reproduction 2001; 16: 1527–1535. 30. Croxatto HB. Progestin implants. Steroids 2000; 65: 681–685. 31. Palomba S, Falbo A, Di Cello A et al. Nexplanon: the new implant for long-term contraception. A comprehensive descriptive review. Gynecological Endocrinology 2012; 28: 710–721. 32. Mansour D. The benefits and risks of using a levonorgestrel-releasing intrauterine system for contraception. Contraception 2012; 85: 224–234. 33. Sarkar NN. The emergency contraceptive drug, levonorgestrel: a review of post-coital oral and peri-coital vaginal administration for prevention of pregnancy. Journal of Obstetrics and Gynaecology 2011; 31: 703–707. 34. Glasier A, Thong KJ, Dewar M et al. Mifepristone (RU486) compared with high dose estrogen and progestogen for emergency postcoital contraception. New England Journal of Medicine 1992; 327: 1041–1044. *35. Glasier AF, Cameron ST, Fine PM et al. Ulipristal acetate versus levonorgestrel for emergency contraception: a randomised non-inferiority trial and meta-analysis. Lancet 2010; 375: 555–562. 36. Chabbert-Buffet N, Pintiaux-Kairis A, Bouchard P et al. Effects of the progesterone receptor modulator VA 2914 in a continuous low dose on the hypothalamic-pituitary-ovarian axis and endometrium in normal women: a prospective, randomized, placebo-controlled trial. Journal of Clinical Endocrinology and Metabolism 2007; 92: 3582–3589. 37. Brache V, Sitruk-Ware R, Williams A et al. Effects of a novel estrogen-free, progesterone receptor modulator contraceptive vaginal ring on inhibition of ovulation, bleeding patterns and endometrium in normal women. Contraception 2012; 85: 480–488. *38. http://www.un.org/esa/population/publications/contraceptive 2011. *39. Ahmed S, Li Q & Tsui AO. Maternal death averted by contraceptive use: an analysis of 172 countries. Lancet 2012; 380: 111–125. 40. Cleland J, Conde-Agudelo A, Peterson H et al. Contraception and health. Lancet 2012; 380: 149–156. 41. Hall K, Moreau C & Trussell J. Continuing social disparities despite upward trends in sexual and reproductive health service among young women in the United States. Contraception 2012; 86: 681–686.
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42. Hall K & Trussell J. Types of contraceptives used by US women. Contraception 2012; 86: 659–665. *43. Winner B, Peipert JF, Zhao Q et al. Effectiveness of long-acting reversible contraception. New England Journal of Medicine 2012; 366: 1998–2007. 44. Siedman D. Non-contraceptive benefits of hormonal contraception: time for renewed awareness. The European Journal of Contraception and Reproductive Health Care 2011; 16: 407–408. 45. Mansour D, Gemzell-Daniellsson K, Inki P et al. Fertility after discontinuation of contraception: a comprehensive review of literature. Contraception 2011; 84: 465–477. *46. The ESHRE Capri Working group. Family planning 2011: better use of existing methods, new strategies and more informed choices for female contraception. Human Reproduction Update 2012 advance access published June 13. 47. Meldrum M. The art of medicine women making contraceptive choices in 20th-century America. Lancet 2012; 380: 102–103.
Contents lists available at SciVerse ScienceDirect
Best Practice & Research Clinical Endocrinology & Metabolism journal homepage: www.elsevier.com/locate/beem
1
History of oral contraceptive drugs and their use worldwide Sophie Christin-Maitre, MD, PhD, Professor a, b, * a b
Department of Endocrinology, AP-HP, Hospital Saint-Antoine, University Pierre et Marie Curie, Paris VI, France Inserm U 933, Paris, France
Keywords: hormonal contraceptives oral contraceptive drugs combined oral contraceptive vaginal ring implants microprogestins
The first hormonal pill, called EnovidÒ, was approved by the Federal Drug Administration (FDA) in May 1960. It contained mestranol and norethisterone. Over the years, oral contraceptives have evolved through gradual lowering of ethinyl estradiol (EE) content, introduction of 17b estradiol, and many different progestins. The standard regimen allows for 21 days of pill containing steroids and a pill-free interval of 7 days. Recently, continuous or extended regimens have been approved. In order to improve compliance, alternative routes of combined oral contraceptive (COC) administration have been developed such as vaginal or transdermal routes. In 2009, according to the United Nations, the mean global percentage using contraception in women who are married or in union was 62.7%. COC represented 8.8% of contraceptive prevalence, reaching 15.4% in more developed countries. More than 100 million women worldwide use COCs. However, each year, many unintended pregnancies occur, indicating that contraception still needs to be promoted. Ó 2012 Elsevier Ltd. All rights reserved.
History Egyptians are recognized as one of the first civilizations using birth control.1 From as early as 3000 BC ancient drawings depict men wearing condoms. However, the earliest known illustration of a man using a condom during sexual intercourse is painted on the wall of a cave in France and is 12,000 to 15,000 years old.1 Egyptians developed many contraceptive strategies, such as vaginal pessaries or
* Department of Endocrinology, Hôpital Saint-Antoine, 184 rue du faubourg Saint-Antoine, 75012 Paris, France. Tel.: þ33 1 49282400; Fax: þ33 1 49283195. E-mail address: [email protected]. 1521-690X/$ – see front matter Ó 2012 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.beem.2012.11.004
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vaginal sponges. Pessaries were made of crocodile dung, honey and sodium bicarbonate. Women used cotton-lint tampons soaked in the fermented juice of acacia plants to prevent pregnancy. In order to be spermicidal, vaginal sponges used to be soaked in lemon juice or vinegar. In the 4th century BC, Aristotle was the first Greek writer to mention contraception. The philosopher recommended that women “anoint that part of the womb on which the seed falls” with olive oil in order to prevent pregnancy. Another method recommended by the ancient Greeks was to exert pressure on the abdomen in order to expulse semen from the vagina. Various plants were used by Greek women to prevent pregnancy such as pomegranate, pennyroyal, and pine. Later, Peter of Spain, who was elected Pope John XXI in 1276, offered advice on birth control by giving recipes using different herbs that induced menstruation.2 Women in Sri Lanka are reported to eat a papaya a day to prevent pregnancy. It contains an enzyme papain which interacts with progesterone. Centuries ago, Chinese women used to drink lead and mercury to control fertility which often resulted in sterility or death. Intrauterine devices (IUDs) have been used as a method of contraception for over 2000 years, although their use became more common in the second half of the 20th century. In Europe, condoms were used from the 16th century, firstly to prevent syphilis and then to prevent pregnancy. They were originally made from fish or animal gut. However, in 1944 Charles Goodyear patented the vulcanization of rubber. This procedure facilitated the mass production of condoms. Other than the use of condoms, the main methods of birth control used before the 20th century included mainly abstinence, infrequent coitus, coitus interruptus, breastfeeding and induced abortion. Real improvements in birth control occurred in the 20th century, thanks to several women, including Dr Marie Stopes from Scotland. She wrote a guide to contraception entitled “Wise Parenthood” and opened the first of her birth control clinics in Holloway, Northern London in 1921. The dawning of hormonal contraception involved two women, the Americans Margaret Sanger and Katharine McCormick, and a man Gregory Pincus. Margaret Sanger founded the American Birth Control League which became Planned Parenthood. She was probably highly motivated as her mother had 18 pregnancies, 11 children and died at the early age of 50. She claimed that “No woman can call herself free who does not own and control her body. No woman can call herself free until she can choose consciously whether she will or will not be a mother”.3 She met Katharine McCormick, the wife of the inventor of the mechanical harvester, as they were both involved in women’s rights. McCormick, who had a large fortune, funded Gregory Pincus’s research into developing a birth control pill. He is considered as the creator of the first contraceptive pill. The total of McCormick’s gifts to the research reached $2,000,000.1 She funded the first clinical trials of the Pill, which were conducted by Dr John Rock, an eminent Catholic gynecologist. He first treated his patients in his private practice. Rock, who came to be regarded as a co-developer of the Pill, worked with Planned Parenthood staff on a closely reasoned book, The Time Has Come: A Catholic Doctor’s Proposals to End the Battle over Birth Control. Pincus and Rock were able to benefit from Carl Djerassi’s research on steroids. Djerassi had synthesized a progestin, called norethisterone, in his laboratory in Mexico City which remained effective when taken orally, and was much stronger than natural progesterone. Doses over 5 mg of progestin in a 21day regimen could suppress ovulation but caused unacceptable bleeding. With the discovery that the contaminant mestranol reduced breakthrough bleeding, mestranol, and subsequently its active metabolite ethinyl estradiol (EE), were added to contraceptive pills. The first hormonal pill was called EnovidÒ. It was approved by the Federal Drug Administration (FDA) in 1957 as treatment of menstrual disorders. Its capacity to regulate birth was only recognized several years later and it was not until 1959 that the pharmaceutical company Searle applied to the FDA for approval of a pill that would be marketed as a contraceptive. In May 1960, approval was granted.4 Nowadays, COCs are used by more than 100 million women worldwide. Combined oral contraceptives The first combined contraceptive pill, called EnovidÒ contained mestranol and norethynodrel.5 Mestranol is an estrogen, the 3-methyl ether of EE. It is a prodrug as it is demethylated to EE in the liver. Its dose in the first pill was 150 mg. Knowing that 50 mg of mestranol is pharmacokinetically bioequivalent to 35 mg of EE, the initial dose of estrogen contained in the pill was very high. Norethynodrel is a progestin; its initial dose was 9.85 mg per pill.
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In the first clinical studies, EnovidÒ’s contraceptive efficacy was excellent; reaching 100% but this drug induced many side effects. In studies performed in Puerto Rico under the supervision of Dr Edris Rice-Wray, 17% of women presented with nausea, dizziness, headaches, stomachaches and vomiting. The dose of northynodrel was lowered to 5 mg and the dose of mestranol to 75 mg. However, in 1961, the Lancet reported the death of a woman from thrombosis who was taking the pill. In less than a year, the FDA had received reports of 6 deaths and 20 non-fatal cases of thromboembolism. Over the years, oral contraceptives have evolved through gradual lowering of estrogen content, introduction of new progestins, new regimens of biphasic, triphasic or quadriphasic Pills as well as fixed or flexible extended regimen and alternative routes of COC administration, such as vaginal or transdermal, have been developed. Estrogen in COC Over the years, in order to decrease the cardiovascular risk of the pill, the dose of estrogen has progressively decreased. In the majority of COCs available nowadays, the estrogen component is EE or 17a estradiol. In the 1970s, the dose of EE decreased from 50 to 30–35 mg. Subsequently, formulations containing 20 and even 15 mg were developed. Pills available nowadays are usually sorted into concentrations of EE higher or lower than 30 mg, with pills containing less than 30 mg considered as low dose Pills. This decrease has been made possible thanks to the availability of new progestins. The concept of using the natural 17b estradiol (17 bE2) in combined pills arose in the 1970s. More than 15 different attempts were made by different companies.6–9 However, no satisfactory combinations were available for many years. In many cases, the pills containing 17 bE2 were contraceptive but their tolerance was low, as women experienced bleedings. Mono-, bi- or triphasic combinations have failed over the years. However, two formulations delivering estradiol (E2) have recently been marketed. A quadriphasic COC combining E2 valerate and dienogest has been newly approved in Europe and USA. E2 valerate is a synthetic estrogen, which is metabolized into 17 bE2. The second pill is a monophasic COC combining 17b E2 with nomegestrol acetate, a progesterone-derived progestin. It is now available in several European countries.10,11 A pill containing estetrol, a synthetic estrogen identical to an endogenous fetal estrogen, is currently under development.12 This molecule is a Selective Estrogen Receptor Modulator (SERM) and has estrogenic activity on bone and on the endometrium but anti-estrogenic activity on the breast. Progestins in COCs In the different combined pills available nowadays, the progestin component in the pill inhibits luteinizing hormone (LH) peak, decreases ovarian sensibility to follicle stimulating hormone (FSH) and therefore decreases estradiol production. The estrogenic component regulates endometrium proliferation and compensates estrogenic deficiency induced by the anti-gonadotropic effect of the progestin. Progestins are classically characterized according to their structural origins. They bind to progesterone receptors, but progestins may also bind to other steroid receptors, such as androgen, glucocorticoid and mineralocorticoid receptors. Most of the progestins contained in COCs were initially derived from testosterone, and are called 19-nortestosterone derivatives. Norethisterone is an estrane, and norethisterone acetate and norethynodrel are gonanes. Few pills containing first generation progestins are still available. Their side effects, such as acne, oily skin and decreased high density lipoprotein (HDL), mainly due to their androgenic proprieties, are the main cause for their progressive withdrawal. Over the years, progestins with less androgenic effects have been developed. Among them, are the second and third generation progestins. Levonorgestrel and norgestrel are second generation progestins. Third generation progestins include desogestrel, with its active metabolite 3-keto-desogestrel (also named etonogestrel), norgestimate (and its active 17-deacetylated metabolite, norelgestromin) and gestodene. The most recent were released in the mid 1980s.13 Different progestins used in COCs are derived from progesterone. Molecules such as chlormadinone acetate, cyproterone acetate and medroxyprogesterone acetate are called pregnane derivatives, as they are derived from 17OH progesterone.14 Some newer progestins have been available more recently in oral contraceptives, such as drospirenone. This progestin possesses anti-mineralocorticoid and weak
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anti-androgen proprieties. Dienogest, is referred to as a hybrid progestin, as it is derived from the estrane group but does not exert the androgenic effects of the testosterone derivatives. A Cochrane Review evaluated the effectiveness and side effects of different progestogens.15 Thirty trials with a total of 13,923 participants were included, generating 16 comparisons. Overall the quality of trials was low. The conclusion of this Cochrane Review mentions that women using COCs containing second generation progestogens may be less likely to discontinue than those using COCs containing first generation progestogens. Based on one small double-blind trial, third-generation progestogens may be preferable to second generation preparations with regard to bleeding patterns but further evidence is needed. Sequence of COC Combination pills are categorized as monophasic, or multiphasic, depending on the different levels of hormones contained in each pill per cycle. The initial pill was monophasic but biphasic and triphasic pills were introduced in the 1980s. They were initially designed to decrease potential side effects, such as nausea and headaches. A Cochrane review showed that tolerance is identical between mono- or multiphasic pills.16,17 A second goal was to mimic the natural human cycle more closely. Most COCs have a 28-day cycle. The standard regimen allows for 21 pills containing steroids and a pill-free interval of 7 days, for eliciting regular withdrawal bleeding and for reassuring women that they are not pregnant. However, monthly bleeding is not necessary for contraceptive efficacy or safety issues. Furthermore, several studies have illustrated that ovarian activity occurs during the pill free interval,18 potentially reducing the efficacy of the pill as follicular growth may occur followed by ovulation. This phenomenon is mainly observed with the newest pills, as they contain lower doses of steroids and therefore less gonadotropin inhibition. This threat of contraceptive failure is even higher in the case of pill omission just after the pill free interval.18 Therefore, in some new pills, the pill-free interval has been reduced to 4 days. This reduction has been shown to diminish the mean follicular size. For instance, with the pill containing nomegestrol acetate and 17b E2, the largest follicle diameter was significantly smaller in the 24/4 day group than in the 21/7 day group [mean (SD) mm in cycle 2: 9.0 (3.0) versus 11.3 (5.3) (p¼ 0.02); in cycle 3: 9.2 (3.0) versus 11.5 (6.0) (p ¼ 0.04)].19 Mean FSH plasma levels were significantly lower in the 24-day versus the 21 day group on day 24 of cycles 1 and 2. Over the past years, a strategy has been to add placebo pills instead of having a pill-free interval. The Coraliance study, enrolling 617 gynecologists in France, followed 3316 patients and showed that during their previous cycle of COC, 23% women missed a pill at least once.20 Among women on the pill involving a treatment-free interval, 42% of instances of missing a pill occurred during the first week following the treatment-free interval. Therefore, a continuous regimen without a treatment free interval may improve compliance. In order to reduce the number of unwanted pregnancies, the immediate start or “quick-start” strategy has been developed. It implies that COCs are started immediately after the healthcare provider’s visit instead of waiting for the next menses. It has to be associated with back-up birth control for the first seven days. A Cochrane Review reported limited evidence that immediate start reduces unwanted pregnancies.21 Another change in the cycle regimen, developed in the past 10 years, is the extended cycle COC.22 This consists of 3 or 4 months of active pill use with a 7-day pill free interval. When the pill-free interval is avoided it is named continuous regimen as opposed to cyclical regimen. The rationale of extended or continuous regimens was to avoid menstrual related side effects, such as premenstrual syndrome, dysmenorrhea or migraine. The second goal was to reduce the number of days of bleeding. In 2003, the FDA approved an extended cycle COC in an 84/7 dosing regimen, EE 30 mg/levonorgestrel (LNG) 150 mg (SeasonaleÒ; Duramed Pharmaceuticals, Cincinnati, Ohio), with 84 active pills and 7 placebos. In 2007, it approved LybrelÒ (Wyeth Pharmaceuticals, Philadelphia, Pennsylvania), which is administered as a combined active pill containing LNG 90 mg and EE 20 mg in a continuous fashion, 365 days per year. Several studies have shown that those regimens’ contraceptive efficacy is comparable with the traditional 21/7 regimen. However, continuous regimens are often associated with increased risk of breakthrough bleeding versus cyclical COC.
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In some extended regimens, placebo pills have been replaced by low dose of EE. The rationale is to provide the potential for greater gonadotropin secretion. Furthermore, EE could stabilize the endometrium and reduce bleeding. In May 2006 and October 2008, the FDA approved respectively, a pill containing 84 active pills with LNG 150 mg and EE 30 mg, followed by 7 days of 10 mg EE pills, and a pill containing 84 active pills with LNG 100 mg and EE 20 mg, followed by 7 days of 10 mg EE pills. A recent review has shown that this new extended cycle OC provides patients a low dose, extended regimen OC option without sacrificing efficacy or tolerability.23 In the past few years, it has been hypothesized that a regimen that extended more than 28 days and could give women the opportunity to manage their intracyclic breakthrough bleeding would be appreciated. It was called flexible extended regimen or MIB, for “Manage Intracyclic Bleeding”. Klipping et al. conducted a multicenter randomized, open-label, parallel group study comparing EE 20 mg/ drospirenone (DRSP) 3 mg in a flexible extended regimen versus a cyclical or a fixed extended regimen of 124 days.24 With the flexible MIB regimen, women received EE/DRSP for a flexible number of cycles (minimum three, maximum 13 in 1 year), each of which was separated by a 4-day tablet-free interval. Over a period of 1 year, the mean number of bleeding/spotting days was significantly lower in the flexible MIB regimen than with the cyclical regimen (41.0 29.1 (95% CI 38.8–43.3; n ¼ 640) versus 65.8 27.0 (95% CI 62.2–69.4; n ¼ 215) days, p < 0.0001). The mean number of bleeding/spotting days with the fixed extended regimen was 60.9 51.1 (95% CI 53.9–67.9) days (n ¼ 209). The Pearl Index for the flexible MIB regimen was 0.64, indicating good contraceptive efficacy. These data have been confirmed by Jensen et al.25 The management of intracyclic bleeding represents an interesting concept that could be more developed over the next years. Non-oral routes of COC In order to increase efficacy, compliance and tolerance, alternative routes of combined contraception have been developed, such as vaginal or transdermal routes. Increased bioavailability implies that lower steroid doses are needed in these systems. The contraceptive vaginal ring named NuvaringÒ releases 15 mg of EE, and 120 mg of etonogestrel per day.26 It is a flexible, transparent ring with a diameter of 54 mm and a cross section of 4 mm. It is self-administered for 3 weeks, followed by 1 week ring-free period. It works by inhibiting ovulation. The skin patch called EvraÒ delivers 20 mg EE and 150 mg norelgestromin daily to the systemic circulation.27 It is a once-weekly self-administered patch and its efficacy is based on ovulation suppression. Both regimens have been approved since the mid 2000s. COC as emergency contraception COCs were first used as emergency contraception, as advised by Dr Albert Yuzpe, a Canadian obstetrician/gynecologist who first published in 1974. This method must be initiated within 72 h following sexual intercourse. Several COC pills have to be taken 12 h apart.28 This method has been used by millions of women; however, its tolerance is low, and nausea, vomiting, spotting and headaches are frequent side effects. Therefore, in 1999 it was replaced by progestin only emergency contraception and, more recently, by Selective Progesterone Receptor Modulators (SPRM). Other types of hormonal contraception Progestin only pills should be distinguished from COCs. This type of pill does not contain estrogens, only synthetic progestogens, and are called progestin only mini-pills. These pills have been available since 1973 and are currently proposed to women with contraindications to use of estrogens, as their efficacy is lower than combined pills and their tolerance is not always very good, inducing bleedings such as spotting as well as acne and ovarian cysts.29 The dose of progestin contained in this type of pill is lower than in COCs. They inconsistently inhibit ovulation and rely mainly on their progestogenic effect of thickening the cervical mucus, thereby reducing sperm viability and penetration. Therefore, their ovulation inhibition is lower than with COC. Injectable progestins were developed a few years after the pill in order to make it possible for women to use an effective method without taking a pill once a day. Depot medroxyprogesterone
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acetate (DMPA) was first submitted to the FDA for contraceptive use in 1967. However, although it has been widely used all over the world, it was not approved until 1992 by the FDA. This long acting formula needs to be injected every three months.1 Another form of progestin only contraception are implants. The first developed was Norplant, a multi unit system containing 6 rods, then came Jadelle containing 2 rods.30 Since then several single or double-rod systems have been developed using four different types of progestin: levonogestrel, etonogestrel, nestorone and nomegestrol acetate. The most recent one to be launched on the market was NexplanonÒ. It is a single-rod subdermal implant that is inserted just under the skin of a woman’s upper arm. The 4 cm by 2 mm rod, named ImplanonÒ, contains 68 mg of etonogestrel which is released over a three year period. It was first approved in 1988 in Indonesia and in the US in 2006. It has been replaced by NexplanonÒ because of cases of incorrect insertion of ImplanonÒ by medical personnel.31 It is essentially identical to ImplanonÒ except that it is radiopaque. The first IUD containing progesterone was introduced in 1976. However, it was abandoned as its life-span was only 1 year. In the late 1970s Dr Luukainen designed an IUD delivering levonorgestrel, called MirenaÒ. It was first approved in Finland in 1990 and has a lifespan of 5 years. Levonorgestrel is released into the endometrial cavity initially at a daily dose of 20 mg and then at a dose of 10 mg.32 Progestin pills can be used as emergency contraception. The most popular form for emergency contraception is levonorgestrel. Initially two pills of 0.75 mg were administered 12 h apart, although this regimen has now been replaced by a single pill containing 1.5 mg of levonorgestrel.33 More recently, SPRMs have been developed as emergency contraception. Initially low doses of mifepristone have been tested.34 The SPRM available as emergency contraception is ulipristal acetate (UPA), previously known as VA 29-14 or CDB-2914.35 It is a derivative of 19-norprogesterone and is administered as a single dose of 30 mg. It was approved in May 2009 by the European Commission and marketed as an emergency contraceptive within 5 days of unprotected sexual intercourse. This molecule has also been developed as daily contraceptive; a daily oral administration of UPA is able to suppress ovulation in a majority of women.36 It is an “estrogen-free” contraceptive with possibly fewer side effects than contraceptives delivering EE. Currently the Population Council in collaboration with National Institute of Child Health and Human Development (NICHD) is developing a 3-month contraceptive vaginal ring containing UPA.37 Prevalence of contraception use At the 2005 World Summit, Governments committed themselves to “achieving universal access to reproductive health by 2015, as set out at the International Conference on Population and Development” (General Assembly resolution 60/1). This goal is not achieved yet, as illustrated in Fig. 1, reporting the percentage of women between 15 and 49 years old using contraception according to the most recent data published by United Nation in 2011.38 Disparities are obvious. In 2009, the mean global percentage using contraception in women who are married or in union was 62.7%. In more developed regions, it was as high as 72.4% and as low as 31.4% in lesser developed countries. Looking more precisely at modern contraceptive methods, the prevalence was 60% for Asia, 67% for the Latin American and Caribbean region, but only 22% for Africa as a whole and 16% for sub-Saharan Africa.38 Furthermore, in at least 46 countries, 20% or more of the women of reproductive age who are married or in a union have an unmet need for contraception. However, a major improvement in contraceptive prevalence has been observed since 1960. In developing countries this prevalence reached 10% in 1960 and was close to 70% in 2009. The fertility rate has decreased from 4.7 births in the early 1970s to 2.6 births in the late 2000s, predominantly due to contraceptive use.39 Using a mathematical model, Ahmed et al. estimated that worldwide, in 2008, 342,203 women died from maternal causes, but that contraceptive use averted 272,040 maternal deaths (uncertainty interval 127,937–407,134), a 44% reduction, so without contraceptive use, the number of maternal deaths would have been 1$8 times higher than the 2008 total.39 Contraceptive use improves perinatal outcomes and child survival by widening the interval between pregnancies.40 In developing countries, risk of death in infancy (age < 1 year) would fall by 10% and in ages 1–4 years by 21% if all children were spaced by a gap of 2 years.
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Fig. 1. Percentage of women using any modern method of contraception among those aged 15–49 years who are married or in a union, in 2009.
What is the prevalence of COC use and types of COC used? The global mean percentage using contraception among women who are married or in union of 62.7% breaks down as follows: 56.1% using modern methods, and 6.6% using any traditional methods. Modern methods are female sterilization (18.9%), male contraception (2.4%), pill or COC (8.8%), injection (3.5%), implants (0.3%), IUD (14.3%), condoms (7.6%) and vaginal barrier methods (0.2%). In 2009, COCs represented only 8.8% of contraceptive prevalence, reaching 15.4% in more developed countries. It is currently used by more than 100 millions of women worldwide, with large variations depending on country, age and education. According to a recent study by Hall et al., the proportion of women using sexual and reproductive health services (SRHs) in the US, increased from 50% (2006–2007) to 54% (2007–2008) and 57% (2008– 2010) [all year odds ratios (ORs) 1.4, p values < 0.03]. Among sexually experienced women, the proportions using SRH and contraceptive services were unchanged, while sexually transmitted infection (STI) service use increased from 22% (2006–2007) to 33% (2008–2009) (OR 1.7, confidence interval 1.1–2.4, p ¼ 0.009).41 Lower proportions of service were used among women of social disadvantage. A recent American study from Princeton University sought to estimate the prevalence of types of COCs used among US women. Data were collected by interviewing 12,279 women aged 15–44 years participating in the National Survey of Family Growth.42 Analyses focused on COC use overall, by pill type, across socio-demographic and health factors. The prevalence of current COC use (88 different brands) was 17%. The majority of COC users used earlier-formulation COCs: 30 mg (67%) versus <30 mg estrogen (33%), monophasic (67%) versus multiphasic (33%) dosages and traditional 21/7 regimens (88%) versus extended or other cycle regimens (12%). Norgestimate (32%) and norethindrone (20%) were the most commonly used progestins. Socio-demographic, gynecological and health risk factors were associated with type of COC use. Conclusion In 2009, COC use remained low, accounting for 8.8% of global contraceptive prevalence. Although studies have demonstrated that long acting methods such as IUDs and implants have a very low failure rate and that their effectiveness is superior to that of contraceptive pills, ring or patch,43 there is still
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room for COCs. Their failure rate is among the lowest, ranging from 1/5 to 1/100 woman per year. Furthermore, non-contraceptive benefits of COCs have been reported, such as improved acne, headaches, menorrhagia, dysmenorrhea and premenstrual menstrual syndrome.44 A recent review of the literature has reported that fertility after using COC is broadly similar to those reported following discontinuation of barrier methods or use of no contraceptive method.45 In summary, the health benefits of COC far outweigh the health risks. The European Society of Human Reproduction and Embryology (ESHRE) Capri Workshop group recently concluded that although great advances have been made in recent years in increasing contraceptive needs in women in many countries where contraceptive prevalence is low or there is a high unmet need for contraception,46 much more can, and needs to be done. Healthcare providers should be more informed about contraception47 and women and couples need to make informed choice concerning their contraception. Practice points - The first hormonal contraceptive pill, EnovidÒ, was approved by FDA in 1960. - Doses of ethinyl estradiol have been progressively lowered in order to avoid thrombotic events. - The standard regimen of 21 pills containing steroids and a pill-free interval of 7 days is progressively being replaced by continuous regimens to improve compliance. - Non-contraceptive benefits of COCs, such as improvement of acne, headaches, menorrhagia, dysmenorrhea and premenstrual menstrual syndrome should be considered when choosing a contraceptive method. - In 2009, COC represented 8.8% of contraceptive prevalence. More than 100 million women used COCs.
Research agenda - Research needs to be performed in order to understand the method failures of COC. - Trials are necessary to test educational programs explaining how benefits outweigh the risks of COCs. - Development of new molecules such as progestins or Selective Progesterone Receptor Modulators for new contraceptive pills, rings or patches. Funding None. Conflict of interest None declared.
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