8.1.3 Hormonal contraception

The first widely available hormonal contraceptive method, the birth control pill, was first introduced in the 1960s. It was both a response to, and a reflection of, the societal and philosophical currents of the time. The idea that fertility could be controlled, pregnancy planned, and population stabilized to decrease poverty, manifested reason and rationalism, as well as the concept that science could be used to improve life. Indeed, the increased utilization of various hormonal contraceptive methods over the last four decades is now regarded as one of the most successful public health ventures of our time. Money spent on family planning services has been estimated to result in more than triple the savings in prenatal and neonatal costs (1).

Although it is now viewed as one of the great inventions of the 20th century, hormonal contraception has also been controversial. It allowed for the separation of sex from pregnancy and reproduction, and is cited by many as a catalyst to the sexual revolution. Consequently, hormonal contraceptives have been some of the best studied and closely scrutinized medications in history.

Hormonal contraceptives can be divided into two major categories, the progestin-only methods and combined hormonal contraception, which contains an oestrogen and progestin component. With all hormonal contraceptives, the progestin component has the dominant hormonal effect. The progestin component is also responsible for the mechanism of contraceptive action with the oestrogen component of the combined methods serving mainly to regulate bleeding (2). The combined hormonal methods have been constituted in the form of a pill, injection, transdermal patch, and ring. Progestin-only methods have been formulated to be delivered in the form of a pill, injection, subdermal implant, and intrauterine device (IUD).

Overall, hormonal contraception has been shown to be remarkably safe, especially when compared with pregnancy, which is one of the most medically-threatening times in a woman’s life. The World Health Organization (WHO) has published evidence-based guidelines to help assist in contraceptive decision-making. The WHO Medical Eligibility Criteria utilizes a grading system to provide information about the safety of a particular method in women with medical conditions (1 = no restrictions for use; 2 = the advantages generally outweigh the risks; 3 = the risks outweigh the benefits; 4 = the risk is unacceptable). This grading system is based on an extensive review of the literature, as well as expert consensus statements (3).

Because there are only a few contraindications to progestins, progestin-only methods have an excellent safety profile and are appropriate for most women, including those with medical comorbidities. In addition, the levonorgestrel-releasing IUD (Mirena) and the contraceptive implants(Implanon), are two of the most effective, but reversible methods with typical failure rates of less than 0.1% (4).

Worldwide, the intrauterine device (IUD) is the most commonly utilized form of reversible contraception (4). The classic nonhormonal IUD worked as a potent spermicide by inducing a sterile inflammatory response in the endometrium. The levonorgestrel-releasing IUD adds a progestational effect to the foreign body reaction. The result is markedly decidualized endometrium with atrophic glands that inhibit sperm capacitation and survival (5). The levonorgestrel-releasing IUD also thickens cervical mucus creating a barrier to sperm penetration. Because it produces very low serum concentrations of progestin, cycles continue to be ovulatory in 50–75% of women (6). The scientific literature indicates that the levonorgestrel-releasing IUD does not work as an abortifacient or by preventing implantation (7).

With studies uniformly reporting an efficacy in the order of 99.9%, the levonorgestrel-releasing IUD is comparable with female sterilization in pregnancy prevention (8). The levonorgestrel-releasing IUD is effective for at least 5 years. Patient satisfaction also appears to be high with one year continuation rates reported to be 81% (9).

The levonorgestrel-releasing IUD also has a good safety record. The risk of perforation at the time of insertion is less than 1% and the risk of expulsion is less than 3% (10). No increased risk of pelvic inflammatory disease has been noted in IUD users outside the first 20 days after insertion (11). Even in the first 20 days, the risk of infection is less than 1% (12). Insertion and use of the levonorgestrel-releasing IUD also appears to be safe in nulliparous women (2). The levonorgestrel-releasing IUD is effective in preventing ectopic pregnancy; however, if a pregnancy occurs with the IUD in place, it is more likely to be an ectopic pregnancy. Regardless of the duration of use, return to fertility is rapid after removal and fertility rates after IUD use are no different from the general population.

Contraindications to IUD insertion based on the WHO Medical Eligibility Criteria are listed in Box 8.1.3.1. Antibiotic prophylaxis is not indicated before or after IUD insertion (13). In women without any signs or symptoms of cervicitis or a pelvic infection, screening for sexually transmitted infections is not required before IUD placement. For those patients who are at a higher risk for a sexually transmitted infection, such as a woman with a new sexual partner, age younger than 25 years, or a recent history of sexually transmitted infection, screening can be performed at the time of insertion. If the screening test turns out to be positive, treatment can commence with the IUD in place.

In the past, clinicians were trained to insert IUDs during menses to ensure that a woman was not pregnant at the time of insertion. Anecdotally, insertion was also reported to be easier when it took place at this time. However, there is a study that suggests that the rate of expulsion may be higher when the IUD is inserted during menses (14).

After insertion, intrauterine device users should be encouraged to periodically check their IUD strings. If the strings are not palpated, they should seek medical attention to determine if the IUD has been inadvertently dislodged or expelled. An ultrasound should be performed initially to confirm intrauterine placement and if not present, an abdominal X-ray can help to determine if the IUD is intra-abdominal or truly expelled. However, it should be noted that a levonorgestrel-releasing IUD usually only demonstrates an acoustic shadow by ultrasonography (Fig. 8.1.3.1, panel b) and does not have the bright echogenic appearance that the copper IUD does (Fig. 8.1.3.1, panel a).

The full suppressive effect of levonorgestrel on the endometrium can take several months and it is not uncommon in the first 3–6 months of use for women to have irregular, unplanned bleeding. This can be bothersome to women and women should be cautioned about this side effect prior to insertion of the device. However, bleeding patterns do improve over time with approximately 40% of users eventually becoming amenorrhoeic and the remainder typically having light menstrual periods (15, 16).

This bleeding pattern has made the levonorgestrel releasing IUD efficacious in the treatment of menorrhagia and dysmenorrhoea, as well as pain due endometriosis and adenomyosis (17–19). Menstrual bleeding is decreased by an average 75% in women with heavy bleeding (20). Other reported ‘off-label’ uses include management of endometrial hyperplasia in poor surgical candidates (21), endometrial protection from tamoxifen (22), and postmenopausal oestrogen therapy (23).

Contraceptive implants are safe, highly effective, reversible methods of contraception. Norplant® was the first contraceptive implant to be utilized widely. This highly effective contraceptive method was composed of six silicone capsules, each filled with 36 mg of levonorgestrel. It was placed subdermally in the upper arm and was effective for more than 5 years (7 years in normal-weight women). Because of complications associated with removal, Norplant was withdrawn from the UK market in 1999, the US market in 2002, and was phased out of production in 2008.

There are two progestin containing subdermal implants that have taken the place of Norplant®. The etonorgestrel implant (Implanon) is a 4 cm single rod implant made of ethylene vinyl acetate that releases 58 mg of etonorgestrel, the active metabolite of desogestrel. Implanon™ provides 3 years of effective contraception. Jadelle® (Bayer Schering Pharma Oy, Finland), a two-rod silastic levonorgestrel containing system is effective for 5 years (2). Removal of any contraceptive implants should be performed by a trained individual and removal should not be attempted if the implant cannot be definitively palpated.

With a 1-year failure rate of 0.09% for the etonorgestrel implant and 0.08–0.10% for the levonorgestrel implant, the contraceptive implants are highly effective (24, 25). The contraceptive implants work through a combination of three mechanisms; ovulation suppression, cervical mucus thickening to prevent sperm penetration, and thinning of the endometrium to create an inhospitable uterine environment (4). With the etonorgestrel implant, ovulation suppression occurs within a day of insertion and lasts for approximately 2 years. Between years 2 and 3, ovulation sometimes resumes, but the other progestin effects are substantial enough to ensure high contraceptive efficacy. After implant removal, return to fertility is rapid with 90% of women ovulating within 3 weeks (26).

Because of the suppressed oestrogen levels that accompany contraceptive implant insertion, concern has been raised about the contraceptive implant’s effect on bone mineral density. Some studies have shown no change in bone mineral density while others have demonstrated a decrease in bone mineral density at the radius but not the ulna (27, 28). Importantly, no studies have demonstrated an increased risk of osteopenia, osteoporosis or fracture with the etonorgestrel and the levonorgestrel implant (27, 28).

Menstrual disturbances with the contraceptive implants are common and are the most frequently cited reason for method discontinuation. When using the contraceptive implant, women do not typically have regular menstrual periods. Bleeding patterns can range from amenorrhoea to prolonged and frequent bleeding, but not usually heavy enough to cause anaemia. Over a 90-day period, 20% of women are amenorrhoeic with the remainder experiencing 7.5–10 days of bleeding (29). Bleeding patterns can change do not typically improve over time (i.e. achieve amenorrhoea). Consequently, women should be counselled about this side effect before insertion of the implant.

With typical failure rates between 0.3 and 3.0%, depo medroxyprogesterone acetate (DMPA) represents another highly effective form of contraception. DMPA was first utilized in 1967. There are currently two formulations of DMPA available. The original and more commonly utilized injection consists of a 150 mg intramuscular dose that is administered every 12 weeks (±7 days). A subcutaneous 104 mg formulation is also available. It was hoped that the subcutaneous formulation would be less painful to administer and women could learn to self administer these prefilled syringes, thus eliminating the need for repeated visits to a health care provider.

Although DMPA thickens cervical mucus and thins the endometrial lining, its primary mechanism of action is the profound inhibition of ovulation. If it is administered within the first 5 days of normal menses, immediately postabortion, immediately postpartum, or 6 weeks postpartum in exclusively breastfeeding women, it is effective immediately and there is no need for back-up contraception. However, if it is administered outside this window or if a woman returns more than 7 days after her scheduled injection, a back-up method of contraception is required for 5 days. A pregnancy test should be performed and the woman should be counselled about the possibility of a very early pregnancy. There is no evidence to suggest teratogenicity if DMPA is administered during pregnancy in humans, but it could delay the diagnosis of a pregnancy. In primate studies, malformations in the external genitalia of offspring has only been noted at doses above 10 times the human dose equivalent (30).

The only absolute contraindications to DMPA use is current pregnancy and breast cancer (3). Some of the relative contraindications cited by the WHO and Royal College of Obstetricians and Gynecologists are listed in Box 8.1.3.2. Although DMPA does not affect a woman’s baseline fertility potential, return to fertility following discontinuation can be slower than with other methods. It takes an average of 6–8 months to resume normal cycles and up to 22 months for fertility to return after discontinuation of intramuscular DMPA (4). With subcutaneous DMPA the return fertility takes a median of 7 months with 97% of women returning to ovulatory status at 1 year (31). Thus, this method may not be appropriate for women who wish to conceive in the next 1–2 years.

Menstrual changes occur in all women using DMPA (2, 31). Unscheduled bleeding and spotting secondary to atrophy of the endometrial lining occurs in 70% of women in the first year (2). Although bleeding is rarely heavy, 25% of users will discontinue DMPA in the first year because of dissatisfaction with bleeding patterns (8). Counselling regarding bleeding patterns prior to DMPA use increases continuation rates and decreases discontinuation due to bleeding. With continued use, the most common bleeding pattern is no bleeding. Rates of amenorrhoea after 1 and 5 years of use are 50 and 80%, respectively (32). Bleeding patterns are not significantly different between women using the subcutaneous and intramuscular formulations of DMPA (32).

Because the frequency and duration of unscheduled bleeding decreases with continued administration of DMPA, many women find it acceptable to wait for spontaneous resolution of breakthrough bleeding. Several interventions such as supplemental oral or transdermal oestrogen (1), cyclo-oxygenase 2 inhibitors (33, 34), and the antiprogestin mifepristone (18) have been studied as possible treatments for irregular bleeding. However, they have not been shown to definitively improve bleeding patterns.

DMPA has several noncontraceptive benefits. DMPA appears to raise the seizure threshold and unlike the combined hormonal contraceptives, its efficacy is unaffected by concomitant use of anti-seizure medications (35). This makes it an appropriate contraceptive choice for many women with seizures. DMPA may also be an ideal contraceptive for women with sickle cell anaemia as it stabilizes the red cell membrane and increases blood counts by decreasing menstrual blood loss (36). Because the most frequent pattern with prolonged use of DMPA is amenorrhoea, it is also an effective treatment for menorrhagia, dysmenorrhoea, endometriosis, and ovarian cyst formation (37).

Use of DMPA leads to an inhibition of gonadotropin secretion. In addition to providing an excellent contraceptive effect, inhibition of gonadotropins results in suppression of ovarian oestradiol production which leads to an increase in osteoclast activity. As a result, DMPA has been noted to cause a reversible decrease in bone mineral density on the order of 3–6% after 24 months of use (38, 39). Decreased bone mineral density in current users of DMPA has led to some to question whether DMPA use could lead to osteoporosis and an increased risk of fracture. Many debates have focused on teenage users who are in the process of attaining peak bone mass and perimenopausal women who may be starting to lose bone mineral density.

The scientific literature suggests that decreases in bone mineral density in DMPA users is completely reversible (38). The largest longitudinal study of DMPA use and bone mineral density showed that former users and never users had similar spine and hip bone mineral density 3 years after discontinuation (40). Indeed, DMPA has never been shown to increase the risk of fracture, osteoporosis, or osteopenia (38). Although there are few studies examining DMPA and bone mineral density in teens (41, 42) and perimenopausal women (43), the available literature does not suggest an increased risk of fracture.

Based on the scientific literature, the WHO has recommended that there should be no restriction on the use or duration of use of DMPA among women 18–45 years of age. Among adolescents and women over the age of 45, the advantages of using DMPA typically outweigh concerns regarding fracture risk (44). In many cases, the benefit of preventing unwanted pregnancy in these groups of women will outweigh theoretical concerns. There are certain populations of women in whom DMPA should be used with caution. This includes women already at risk for osteopenia, such as heavy smokers, women with anorexia nervosa, amenorrhoeic elite athletes, and women who chronically require steroids. Use of DMPA is not an indication for bone mineral density monitoring.

Progestin-only pills or ‘mini-pills’ are appropriate for women who want to prevent pregnancy with a birth control pill, but cannot take oestrogen. There are two clinical situations in which acceptable efficacy is achieved, women over 40 and lactating women. Typical progestin-only pills contain 0.35 mg of a progestin, such as norethindrone or levonorgestrel.

With progestin-only pills, ovulation is not consistently inhibited. Rather, the contraceptive effect of comes from thickening of the cervical mucus, decreased tubal motility, and a thinning of the endometrial lining. A back-up method, such as condoms should be utilized for 7 days after starting a progestin-only pill. Because the contraceptive effect of this method is sensitive to serum progestin levels, pills need to be taken at the same time every day. If a woman is more than 3 h late in taking a pill, a back-up method of contraception, such as condoms should be utilized for 48 h. The time sensitive nature of the progestin-only pill is reflected in the 1-year failure rate with typical use of 1.1% in some groups of women to 13% in others (2, 4).

Progestin-only pills are taken in a continuous fashion without a hormone-free interval or a scheduled withdrawal bleed. Although women continue to ovulate, the endometrium remains thin. Thus, 40–50% of women who use progestin-only s have normal menstrual cycles with the remainder having irregular cycles (40%) or spotting and amenorrhoea (10%) (1).

The only absolute contraindications to progestin-only pills are current pregnancy and breast cancer. However, a different method should be chosen in women taking rifampin, anti-epileptics (phenytoin, carbamazepine, barbiturates, primidone, topiramate, and oxcarbazepine), and St. John’s Wort because of increased hormonal metabolism and consequent decreased efficacy (2).

The first hormonal contraceptive was a combined oestrogen and progestin pill called Enovid (G.D. Searle, USA) that was introduced in the 1960s (39). This pill contained 150 µg of mestranol and 9.85 mg of norethynodrel. In the last four decades, pill dosages have dramatically decreased and combined hormonal contraception is now also delivered through transdermal patches, intramuscular injections, and transvaginal contraceptive rings.

Combined hormonal contraception works by suppressing ovulation, thickening cervical mucus, and thinning the endometrium. Typical use failure rates are 7% or less for these methods (9). Women can start on combined hormonal contraception anytime in their menstrual cycle as long as they use a back-up method of contraception for 7 days. If a woman starts on a combined method within 5 days of the start of menses, a back-up method is unnecessary. Some irregular bleeding is common in the first several months after initiating a combined hormonal contraceptive method. Starting a combined method using ‘quick start’ where the contraceptive is started as soon it can be obtained regardless of where a woman is in her cycle, does not seem to increase the risk of breakthrough bleeding compared with a traditional Sunday start (45). Combined hormonal contraception has no teratogenic effect if a woman discovers she is pregnant after she has already started on a combined method.

Contraindications to combined hormonal contraception are related largely to the oestrogen component of these medications. A list of relative and absolute contraindications to combined hormonal contraception is presented in Box 8.1.3.3. Although there are no randomized controlled trials exploring the relationship between oral contraceptives and cardiovascular disease, oestrogen is known to have effects on the cardiovascular system and, even in low doses, increases the risk of venous thromboembolism. It is important to note that historical cohort studies such as the Royal College of General Practitioners Oral Contraception Study from which we derive much of our data, studied women taking pills 50 µg doses of oestrogen, higher than the doses utilized today (46). Overall, the incidence of venous thromboembolism in reproductive aged women is quite low on the order of 1 per 10 000 women per year. The available literature indicates that this rate is increased to 2–3 per 10 000 women per year in women using combined hormonal contraception and 6 per 10 000 women per year in women who are pregnant (47).

In healthy nonsmoking women, combined hormonal contraception can be used until menopause. In women who have a risk factor for cardiovascular disease, such as smokers, use should cease at the age of 35 (3). Women with a number of stable medical conditions including well controlled hypertension, diabetes mellitus without vascular disease, connective tissue disorders, migraine without aura, and gall bladder disease can continue to use combined hormonal contraception as long as their comorbidities remain stable (3). When selecting a contraceptive method, it is important to consider that a woman’s highest risk for thromboembolic disease occurs during pregnancy and the postpartum period and the benefit of preventing pregnancy in women with medical problems often outweighs the risk of combined hormonal contraception.

There are multiple noncontraceptive benefits to combined hormonal contraception. Women using combined hormonal contraception experience a reduction of menstrual associated symptoms, duration of bleeding, and blood loss at the time of menses. Consequently, combined hormonal contraception can be used to treat dysmenorrhoea, dysfunctional uterine bleeding, endometriosis, and menorrhagia. Because combined hormonal contraceptives decrease-free testosterone levels by increasing sex hormone-binding globulin, combined hormonal methods have also been used to treat acne (4).

Combined oral contraceptive pills are one of the most commonly utilized hormonal contraceptive methods (4). When used consistently, they are effective, safe, and provide many short and long term noncontraceptive health benefits (48). Standard low dose oral contraceptive pills contain 20–35 µg of ethinyl oestradiol. There is no evidence that the side effect or safety profile is different between pills containing 35 µg and 20 µg of ethinyl oestradiol. They also seem to be similar in cycle control and contraceptive efficacy when taken correctly. Pills containing more than 35 µg of oestrogen are still manufactured and are usually reserved for certain groups of women, such as those using medications that increase hepatic metabolism, such as anti-epileptics.

The traditional oral contraceptive pill contained 21 days of hormonally active pills followed by 7 days of placebo in which women would have a withdrawal bleed. Biphasic and triphasic preparations of the pill, designed to mimic the endocrinology of the normal menstrual cycle vary the amount of hormone in the active pills. However, no real clinical advantage or improvement in side effect profile has been noted in the triphasic or biphasic pills. Some of the newer pill formulations contain 3–4 days of hormonally inactive pills, rather than the usual 7 and for a shorter, lighter period.

Epidemiological studies often classify combined oral contraceptives into ‘generations’. First generation products contain 50 µg or more of ethinyl oestradiol. The second generation products utilize 35 µg or less of ethinyl oestradiol and contain levonorgestrel, norgestimate, or other members of the norethindrone family for the progestin component. The third generation oral contraceptives utilize desogestrel or gestodene, and fourth generation products contain an aldosterone antagonist, drosperinone, which exerts both progestational and antiandrogenic activity (49). Additionally, a pill containing cyproterone acetate and ethinyl oestradiol that was initially designed as a treatment for acne, provides the additional benefit of hormonal contraception (50). Although the third and fourth generation progestins tend to be less androgenic, groupings are largely based on the timing of their introduction to the market and do not seem to necessarily result in a different clinical affect (4, 39). There was initially some concern that use of the third generation progestins resulted in a higher risk of venous thromboembolism than other combined hormonal contraceptives. However, it appears that most of this risk can be explained by prescription bias and confounding by age (51).

Despite a high contraceptive efficacy if taken correctly, the oral contraceptive pill requires a significant amount of compliance. It is estimated that method discontinuation and inconsistent pill use with standard oral contraceptives account for 20% of the 3.5 million annual unintended pregnancies that occur each year in the United States (52). The effect of missed pills on contraceptive efficacy depends on how many pills are missed, the dosage of the pill, and when in the cycle the pill is missed. The risk of contraceptive failure is greatest when hormonally active pills are missed near the placebo week so that the hormone free interval is extended (39).

The World Health Organization released practice guidelines regarding missed oral contraceptive pills in 2004 (53). These guidelines are summarized in Box 8.1.3.4. In general, if a woman taking 30–35-µg pills misses one or two pills, she should take them as soon as she remembers and continue taking the pills remaining in her pill pack. No back up method is necessary in this circumstance. If she misses three pills, she should consider taking emergency contraception, continue taking the remaining daily pills and use a back-up method for the remainder of the pill pack. Women taking 20 µg ethinyl oestradiol pills should use a back up method for the remainder of the pill pack if more than 1 hormonally active pill is missed (53).

The original oral contraceptive was designed around a 28-day cycle to improve its social acceptability. However, there is no biological basis for a monthly withdrawal bleed. In a woman taking combined hormonal contraceptives, the endometrium is typically thin, atrophic, and protected against future endometrial cancer. There is no risk of endometrial ‘build up’ and no need for monthly shedding. The monthly bleeding that does occur during the placebo week is a pseudomenstruation secondary to hormone withdrawal.

Extended administration of combined oral contraceptives refers to the practice of taking hormonally active pills for several months in order to minimize withdrawal bleeds to a few times a year. Continuous administration refers to the practice of taking hormonally active pills continuously to indefinitely postpone a withdrawal bleed. These dosing regimens initially gained legitimacy as a treatment for endometriosis, dysmenorrhoea and other menstrual-associated symptoms. Studies have demonstrated that prolonging the interval between periods is both acceptable and desirable to women (54).

Compared to the traditional cyclic regimen, continuous COCs decrease the overall number of scheduled bleeding days (55). However, they are associated with irregular bleeding and spotting (55). Rates of unscheduled bleeding are highest in the first 3 months and gradually decrease over time. In evaluation of bleeding patterns in women with standard cyclic or continuous dosing regimens of a low dose (20 µg EE/100 µg LNG) oral contraceptive, Miller et al. reported that amenorrhoea was achieved in only 16% of continuous use subjects during the first 3 months of treatment. This increased to 72% by months 10–12 (55).

Any monophasic contraceptive pill can be taken in an extended or continuous fashion. There are several commercially available products specifically manufactured for continuous and extended administration and the appearance of these products have popularized continuous and extended administration further.

The contraceptive patch (Ortho Evra),is placed every 7 days for 3 weeks in a row followed by a patch-free week during which time the woman usually has a withdrawal bleed. The currently marketed patch is 20 cm² and delivers 20 µg of ethinyl oestradiol and 150 µg of norelgestromin, the biologically active metabolite of norgestimate, per day (56). Mean serum concentrations of these hormones are not affected by heat, humidity, exercise, or cold water immersion (56). The patch can be applied anywhere except the breasts. If the contraceptive patch is left on, it continues to provide contraceptive coverage for 9 days. However, if it is left on for more than 9 days, a back-up method should be utilized for the remainder of the cycle. The patch is safe to use in latex allergic women.

Failure rates of the contraceptive patch have been reported to be less than 1% in clinical studies (57). In contraceptive patch trials, one-third of pregnancies occurred in the small group of women who weighed more than 198 lbs (58). Although the package labelling cautions against use in women with body weights greater than 198 lbs, it is likely that the overall contraceptive efficacy of the patch in these women is still high. If a women weighing more than 198 lbs does not want to utilize another hormonal method, they can use the contraceptive patch as long as they understand that the efficacy may be slightly decreased (58).

Approximately 20% of patients report some degree of skin reaction to the patch and 2% of women will discontinue the patch for this reason. Breast discomfort is also reported in approximately 20% of users, a rate that is significantly higher than with oral contraceptive users (57).

While the combined hormonal contraceptive pill and the ring have been studied in a continuous fashion, there is only one published study examining extended use of the contraceptive patch. This study of 239 women reported fewer bleeding days with the extended regimen, but higher rates of headache, nausea, and breast tenderness than traditional cyclic patch users (59).

Pharmacokinetic studies reveal that women are exposed to 60% more oestrogen with the contraceptive patch than the combined pill and the contraceptive ring (60) (Fig. 8.1.3.2). It is not known whether this affects the risk of serious adverse events related to oestrogen, such as venous thromboembolism. Three epidemiological studies evaluating insurance claims data have been published on this topic. Two showed no difference in thrombotic risk in patch users compared to combined oral contraceptive users while one found a slightly increased risk (OR 2.2, CI 1.3,3.8) (61–63). Because the risk of thromboembolism is low in reproductive aged women using combined hormonal contraception, even if the relative risk is increased by 2.2 times, the overall absolute risk continues to be low. There is no evidence suggest that the contraceptive patch cannot be used in women who do not have a contraindication to combined hormonal contraception in general.

Vaginal contraceptive rings have been studied for many years with some rings designed to provide as little as one week of hormone and others designed to provide as much as a year of hormone (4). There is currently only one contraceptive ring widely available (NuvaRing). This flexible ring is composed of ethylene vinyl acetate copolymer and releases 120 µg of etonorgestrel and 15 µg of ethinyl oestradiol a day. It is 54 mm in diameter and has a cross-sectional diameter of 4 mm (4).

Total oestrogen exposure with the contraceptive vaginal ring is lower than with both the contraceptive patch and the contraceptive pill (Fig. 8.1.3.2) (60). These levels are adequate to effectively inhibit ovulation with pregnancy rates of less than 1% in clinical trials (64). The low levels of hormone may explain the low incidence of oestrogen-related side effects such as nausea and breast tenderness (65). Relatively constant serum levels of hormone may explain why breakthrough bleeding is lower with the vaginal ring than with the low dose combined oral contraceptive pill (66). Two to four percent of women discontinued the ring in clinical trials, usually because of vaginal discomfort, unwanted awareness of the ring’s presence, coital problems or expulsion (67). Vaginal flora and cervical cytology is not affected by the presence of the contraceptive ring (68).

The contraceptive ring is usually left in place for 3 weeks then taken out for a week to induce a withdrawal bleed. If left in for a longer period of time, the ring will continue to provide coverage for a total of 5 weeks (64), and can be used in a continuous and extended fashion. The ring does not need to be fitted. It is inserted and removed by the user. Although it does not need to be removed during sexual intercourse, it can be taken out for up to 3 h without an effect on contraceptive efficacy (4). The contraceptive ring can be used with antimycotic medications, spermicides, and tampons without an impact on its contraceptive efficacy (69). Although ring expulsion occurs infrequently (2–3% of women experience expulsion), women should check for the ring after sexual intercourse, large valsalva, or tampon removal. The contraceptive ring is safe to use in latex allergic women (70)

Monthly injectable contraceptive combinations of oestrogen and progestin are most commonly utilized in China, Latin America, and Eastern Asia (4). Combined injectable methods contain 25 mg of depot medroxyprogesterone acetate with 5 mg of oestradiol or 150 mg of dihydroxyprogesterone acetophenide with 10 mg of oestradiol enanthate (4). These methods have an efficacy similar to DMPA but unlike DMPA, return to fertility after discontinuation is rapid (71). Women also have less irregular bleeding with the combined injectable methods. The same contraindications that apply to the other combined hormonal methods apply to the combined injection. The need for a monthly injection is one downside, although an automatic device for self administration is available (72).

Emergency contraception refers to the practice of taking a hormonal medication to prevent pregnancy after intercourse has already occurred. There are two hormonal options for emergency contraception that are currently available, the Yupze method and the progestin-only method. Although the non-hormonal copper IUD has also been used for emergency contraception, the levonoregestrel-releasing IUD cannot. The progestin-only method, consists of 2 pills, each with 0.75 mg of levonorgestrel. Although this medication was initially studied as 2 separate doses taken 12 h apart, studies have shown that taking the tablets at the same time is just as efficacious, does not lead to an increase in side effects, and may improve compliance (73).

The Yupze method is the classically described emergency contraceptive. However, it is less efficacious than the progestin-only method and is associated with significantly more nausea and vomiting (42 vs. 16%) (74). Thus, the Yupze method should only be used if the progestin-only method is unavailable. The Yupze method consists of 2 doses of 100 µg of ethinyl oestradiol and 0.5 mg of levonorgestrel. An anti-emetic should be prescribed with these pills. The Yupze method is marketed as a four-pill pack. However, it is more commonly administered by taking several pills in a conventional combined oral contraceptive pill pack. For example, 4 pills containing 30 µg of ethinyl oestradiol and 0.15 mg of levonorgestrel can be taken, followed by another 4 pills 12 h later.

The scientific literature suggests that both emergency contraceptive regimens work by delaying ovulation. There is no evidence to suggest that these medications will disrupt an already established pregnancy (39). Both the Yupze method and Plan B can be taken at any stage of the menstrual cycle. There is no evidence to suggest that emergency contraceptives increase the risk of ectopic pregnancy (75). With the exception of pregnancy, there are no contraindications to the use of emergency contraceptives. Even if a woman takes these medications while pregnant, there is no evidence to suggest an abortifacient or teratogenic effect (76).

The efficacy of the emergency contraceptives is related to the amount of time which has passed since between intercourse and pill ingestion. Pills should be taken as soon as they can be obtained and may be used up to 120 h after intercourse. Studies suggest that the progestin-only method reduces the risk of pregnancy by 85–89% (73, 74) and the Yupze method reduces the risk of pregnancy by 74% (77). Early studies of some of the antiprogestin agents, such as mifepristone suggest that these methods may be even more effective at preventing pregnancy after intercourse; however, these medications are not yet available for this purpose (73).

There is no limit to the number of times women can take EC during a single cycle. However, women who frequently utilize this method would benefit from a more effective contraceptive. Indeed, women should be advised to start birth control immediately after emergency contraception is administered.

Studies examining the long-term effects of combined oral contraceptives have uniformly noted a decreased risk of ovarian cancer. It has been hypothesized that this decreased risk is secondary to a reduction in the inflammatory and reparative process in the ovarian capsule that accompanies ovulation. Although the combined hormonal contraceptive patch and ring have not been utilized long enough to examine whether these agents also confer a protective effect against ovarian cancer, it is hypothesized that the reduction in risk will be similar as their hormonal effects are similar. Interestingly, studies indicate that DMPA, which also effectively prevents ovulation, does not decrease the risk of ovarian cancer (78).

The protective effects of combined oral contraceptives is evident with as little as 3–6 months of use and continues for up to 20 years after discontinuation (79). In general, the risk of ovarian cancer is reduced by 40% in users of combined hormonal contraception compared to non users (80, 81). However, the reduction of risk increases with increased duration of use and after more than 10 years of use, the risk is reduced by 80% (82, 83). This protective effect is particularly pronounced in women at increased risk of ovarian cancer such as nulliparous women and women with a family history of ovarian cancer. Use of combined oral contraceptives in these women can reduce the risk of ovarian cancer to a level equal to or less than women without a family history (84). The protective effect of combined oral contraceptives has not been consistently noted in studies of women with BRCA1 or BRCA2 mutations, but is still often recommended in this group until prophylactic oophorectomy is performed (85, 86).

By inducing a thin, decidualized endometrium, both combined oral contraceptive pills (87) and DMPA (88) have been shown to decrease the risk of endometrial cancer for several years after use. Because all hormonal contraceptives have a thinning effect on the endometrium, this protective effect is thought to extend to all of the hormonal contraceptives. After 4 years of use, the incidence of endometrial cancer is reduced by 56% and after 12 years of use, this risk is reduced by 72% (39, 89, 90). DMPA decreases the risk of endometrial cancer by 80% with these protective effects continuing for 8 years after discontinuation (91).

Studies suggest that the risk of cervical dysplasia and cervical cancer is increased with long term use of combined oral contraceptive pills (92, 93). While it has been established that the human papilloma virus (HPV) is the primary causative agent in cervical cancer, the combined oral contraceptive pill is hypothesized to act as a cofactor (94). The relationship between cervical cancer and hormonal contraceptive use is difficult to study because of confounders and screening bias. Nevertheless, the available literature suggests an increased risk of cervical cancer in women who use oral contraceptives for more than 5 years users (5–9 years of use: OR 2.82, 95% CI 1.46–5.42, >10 years of use: OR = 4.04, 95% CI 2.09–8.02). The mechanism for this association is unclear. The progestin-only contraceptives, such as DMPA do not appear to affect the risk of cervical cancer making the mechanism likely to be related to the oestrogen component of the contraceptive (95).

A history of HPV or an abnormal pap smear should not deter women from using hormonal contraceptives. The overall risk of cervical cancer continues to be low in women using combined oral contraceptives and we have excellent screening tools for cervical dysplasia. As with ovarian cancer, studies have not examined the risk of cervical cancer with the contraceptive patch and ring.

There is a growing body of literature that suggests that combined oral contraceptives have a protective effect against colorectal cancer. The overall estimated relative risk of colon cancer in combined oral contraceptive users was 0.82 (95% CI 0.74–0.92) with the protective effect being greater in women who had used combined oral contraceptives within the previous 10 years (RR = 0.46; 95% CI, 0.30–0.71) (96, 97).

Because of the oestrogen component of combined hormonal contraceptives, multiple studies have focused on breast cancer risk in women who utilize combined hormonal contraceptives. Because there are no randomized controlled trials exploring this risk, the majority of the scientific information comes from large observational studies. After considerable debate and analysis it appears that there is a small increase in the relative risk of being diagnosed with breast cancer in women currently using oral contraceptive pills and this risk seems to persist for the first 10 years after discontinuing use (RR 1.24, 95% CI 1.15–1.33) (98).

After 10 years, the risk of being diagnosed with breast cancer is not increased in women who have ever used combined hormonal contraception compared to non users (RR 1.01, CI (0.96, 1.05) (98). There is also no evidence of an increase in lifetime risk of breast cancer among combined oral contraceptive users (39). Because the breast cancers diagnosed in ever-users of combined hormonal contraception are less advanced clinically than those diagnosed in never-users of combined hormonal contraceptive (RR = 0.88, 95% CI 0.81–0.95), it has been suggested that combined hormonal contraceptives accelerate growth of already exiting tumours rather than inciting de novo disease (98).

Obesity is a growing problem in many parts of the world. Obesity in and of itself is not a contraindication to combined hormonal contraception. The WHO Medical Eligibility Criteria considers use of combined hormonal contraception in obese women category 2 where the benefit generally outweighs the risk. However, it is important to be vigilant in this group for other co-morbidities and appropriate screening for hypertension and diabetes, especially over the age of 35, should be considered. While there is some concern that combined hormonal contraception may be metabolized differently in women of different body weights and body mass indices, hormonal contraception has not been extensively studied in these populations, and the use of contraception will always prevent more pregnancies than no contraception. As mentioned earlier, the efficacy of the contraceptive patch may be decreased in women who weigh more than 198 lbs (58).

There is a common perception among women that hormonal contraceptives, particularly the oral contraceptive pill, are associated with weight gain. However, the only contraceptive method that has been associated with a weight gain is DMPA and this association has not been definitively been established. Some studies of DMPA found no increase in weight while others found a small increase. On average, the weight gain was 4 kg over 5 years (99, 100). Other studies on this topic include placebo controlled experiments in which DMPA did not affect food intake, energy expenditure or body weight (101). With subcutaneous DMPA, the average weight gain was 1.5 kg after 1 year (102).

Despite the availability, safety, and ease of multiple hormonal contraceptive options, unplanned pregnancy continues to be a significant problem. Thus, it is important to extend contraceptive access to all women who desire it. Historically, contraceptive prescription was coupled with screening tests for sexually transmitted infections, breast cancer, and cervical cancer. While these are important parts of preventative health care, they are unrelated to the safe use of hormonal contraceptive methods. Many organizations such as the WHO now explicitly state that a pelvic and breast examination is not necessary before the provision of hormonal contraception (103). Additionally, women successfully using a hormonal contraceptive should not be ‘held hostage’ to their method by withholding a resupply of the method until an office visit is completed. Doing so could increase the risk of unintended pregnancy without demonstrable therapeutic or preventative value (103).

When counselling women about hormonal contraception, it is important to discuss side effect profiles. Continuation rates with many hormonal contraceptive methods are on the order of 50% at 1 year and this is thought to be related to inadequate counselling, and unexpected or poorly tolerated side effects. Women should not feel locked in to their initial birth control choice if they do not feel that it is appropriate for them.

In the last 50 years, we have made significant advances in hormonal contraception. Women now have many choices in hormonal formulations and routes of administration. Dosages of pills, side effects, and risks have also been markedly reduced. Many of the contraceptive devices provide many years of birth control, and require little maintenance outside of administration and removal. After close scientific scrutinization, hormonal contraception is considered to be both safe and effective. Patients often focus of the side effects and risks of medications and they should also be informed of the many noncontraceptive benefits of many of these methods.

Hormonal contraceptives have helped millions of women and families safely and effectively prevent unwanted pregnancy, and plan childbearing. In addition to the creation of new hormonal contraceptive methods, efforts should focus on expanding access to women around the world. Hormonal contraception represents one of the greatest inventions of our time and is a reflection of scientific initiative, innovation, and a commitment to improving the lives of women and their families.