Introduction

The development of combined hormonal oral contraception has been hailed as one of the most important public health achievements of the twentieth century . Since 1960, “the pill” has been used by hundreds of millions of women worldwide to prevent unintended pregnancy and its accompanying downstream consequences such as unsafe abortion and maternal morbidity and mortality. In 2013, the UNDP reported that 9% of women between the ages of 15 to 49 years who are married or in union use combined oral contraception (COC) . Globally, COC is the second most commonly used form of reversible contraception and has the widest geographic distribution of all modern methods.

Combined oral contraception confers a number of significant benefits to users. Not only do COCs offer safe, effective and reversible protection against pregnancy, but women also derive additional non-contraceptive health benefits from their use. COC use is also associated with well-studied risks. Common side effects are generally self-limiting and improve with increasing duration of use while serious adverse events, notably venous thromboembolism, are rare among healthy COC users. Contraceptive decision-making should include consideration of both the risks and benefits of a given method versus the consequences of unintended pregnancy.

Combined oral contraception: past, present and future

Correct, consistent use of COC interrupts the usual functioning of the hypothalamic-pituitary-gonadal axis by suppressing secretion of luteinizing hormone (progestogen) and follicle stimulating hormone (estrogen) to primarily prevent ovulation . Additional contraceptive effects attributable to progestogen exposure include endometrial atrophy, cervical mucus thickening and decreased tubal motility. Although progestogens provide the dominant contraceptive benefit, estrogen importantly stabilizes the endometrium to minimize breakthrough bleeding and potentiates the action of progestogens, allowing lower doses for contraceptive protection .

While the early birth control pills provided effective protection against pregnancy, they were far from perfect. The first combined hormonal oral contraceptive pill contained high doses of both synthetic estrogen (mestranol 150 mcg) and progestogen (norethynodrel 10 mg) and use was associated with significant side effects and unacceptable cardiovascular health risks . Subsequent modifications have maintained COC effectiveness while improving safety and tolerability. Additionally, the diverse formulations and variations in pill-taking regimens currently on offer provide expanded choices to women considering COC use.

Once the dose-dependent association between estrogens in COC and thromboembolism became apparent, COC with progressively lower doses were developed, resulting in significant decreases in venous thrombosis and cardiovascular risk . Most available pills today are manufactured with 20 to 35 mcg of ethinyl estradiol (EE), but some containing EE doses as low as 10 mcg are available . While there are no differences in contraceptive effectiveness among COC containing ≤ 20 mcg EE and higher dose (up to 50 mcg) pills, women using the former may discontinue more frequently and earlier as well as experience more bleeding disturbances . Theoretically, the lower estrogen content might translate to further reductions in the rare risk of arterial and venous thromboembolism associated with modern COC use but this trend has not been consistently observed in large, population-based studies .

Contemporary COC typically contain EE paired with one of a number of progestational agents that vary in potency, affinity for steroid receptors, interaction with estrogens, and physiological effects . Older progestins derived from testosterone (e.g. norethindrone, levonorgestrel) are typically associated with more androgenic side effects including acne, excess hair growth and altered carbohydrate and lipid metabolism. Newer progestins derived from progesterone and spironolactone (e.g. chlormadinone acetate, drospirenone) have been designed to bind more selectively to progesterone receptors and minimize androgenic, estrogenic and glucocorticoid side effects. In addition, some progestins, like drospirenone, have a partial antiandrogenic effect . COCs containing 35 mcg EE or less in combination with any one of the existing progestins do not demonstrate obvious differences in contraceptive effectiveness, side effects, cycle control or continuation rates, but further studies are needed . Whether or not there are differences in risk for venous thromboembolism (VTE) across COC formulations with various progestogens remains a point of debate .

Monophasic COC regimens provide a uniform dose of estrogen and progestin in all active pills during a cycle. In contrast, multiphasic COC vary the dose of either or both steroid hormones. The intention behind this innovation, initiated in the 1980s, was to reduce both total hormone exposure as well as side effects by producing cycles that more closely mimic normal physiology. Several systematic reviews have concluded, however, that multiphasic regimens do not offer superior contraceptive protection or clearly demonstrate any clinical advantage over monophasic formulations . Rather, in the absence of greater benefits, use of monophasic regimens over multiphasic regimens may be preferred. Multiphasic COC require stricter adherence to a specific sequential pill-taking order given the variation in steroid hormones, potentially increasing the likelihood of incorrect use and subsequent unintended pregnancy.

Another strategy to improve safety and tolerability and possibly promote COC adherence has focused on manipulation of the interval between active pill cycles. Traditional pill packs provide active pills for twenty-one consecutive days followed by seven days of placebo to induce cyclic withdrawal bleeding, similar to a natural menstrual cycle. To reduce the duration of withdrawal bleeding and side effects like migraines and dysmenorrhea associated with the hormone free interval, monthly regimens with a shortened placebo period and/or low doses of estrogen were developed . Various studies note that use of 24/4 regimens either resulted in lighter scheduled bleeding of lesser duration or no difference and more frequent or no different incidents of unscheduled bleeding while maintaining contraceptive efficacy compared with 21/7 regimens . Extended or continuous COC regimens allow women to plan withdrawal bleeding quarterly, on a flexible schedule, or eliminate them entirely . Existing clinical trials suggest similar contraceptive efficacy, safety, satisfaction and either equivalent or somewhat improved bleeding patterns with extended regimens compared to cyclic use. Additionally, women randomized to extended use report greater relief from menstrual symptoms such as headaches, bloating, and menstrual pain . Generally, extended and continuous COC users experience fewer scheduled bleeding events, but may have more unpredictable spotting and bleeding episodes to navigate.

The newest COC formulations replace synthetic hormones with steroid components that more closely resemble endogenous molecules. In theory, natural estrogens and progestogens may have fewer metabolic and decreased thrombotic effects, further improving on safety . A four-phasic COC containing estradiol valerate (E2V), a compound metabolized to the natural estrogen, estradiol, paired with dienogest, a selective synthetic progestin derived from nortestosterone, effectively suppresses ovulation, maintains cycle control and exhibits favorable metabolic and hemostatic effects . Another monophasic COC formulated with the natural estrogen, estradiol (E2), and nomegestrel acetate (NOMAC), a potent synthetic progestin structurally similar to naturally occurring progesterone, has recently been approved in Europe and appears similarly safe and performs well in protecting against unintended pregnancy . Further surveillance is necessary to determine whether the promising characteristics of these formulations translate to greater efficacy and safety (e.g. decreases in VTE) over prior products.

Despite decades of pioneering research that have produced a diverse array of effective hormonal methods, including COC, contraceptive development continues to evolve. For example, new molecules (e.g. progesterone antagonists, progesterone receptor modulators), pill-taking regimens (e.g. peri-coital administration), targets (e.g. multi-purpose technologies, contraceptive vaccines, male contraception, genetic/proteomic molecules) and alternative delivery systems (e.g. intrauterine devices, implants, patches, rings, gels) are under investigation with the potential for even greater contraceptive protection, tolerability, non-contraceptive benefits and safer choices .

Combined oral contraception: past, present and future

Correct, consistent use of COC interrupts the usual functioning of the hypothalamic-pituitary-gonadal axis by suppressing secretion of luteinizing hormone (progestogen) and follicle stimulating hormone (estrogen) to primarily prevent ovulation . Additional contraceptive effects attributable to progestogen exposure include endometrial atrophy, cervical mucus thickening and decreased tubal motility. Although progestogens provide the dominant contraceptive benefit, estrogen importantly stabilizes the endometrium to minimize breakthrough bleeding and potentiates the action of progestogens, allowing lower doses for contraceptive protection .

While the early birth control pills provided effective protection against pregnancy, they were far from perfect. The first combined hormonal oral contraceptive pill contained high doses of both synthetic estrogen (mestranol 150 mcg) and progestogen (norethynodrel 10 mg) and use was associated with significant side effects and unacceptable cardiovascular health risks . Subsequent modifications have maintained COC effectiveness while improving safety and tolerability. Additionally, the diverse formulations and variations in pill-taking regimens currently on offer provide expanded choices to women considering COC use.

Once the dose-dependent association between estrogens in COC and thromboembolism became apparent, COC with progressively lower doses were developed, resulting in significant decreases in venous thrombosis and cardiovascular risk . Most available pills today are manufactured with 20 to 35 mcg of ethinyl estradiol (EE), but some containing EE doses as low as 10 mcg are available . While there are no differences in contraceptive effectiveness among COC containing ≤ 20 mcg EE and higher dose (up to 50 mcg) pills, women using the former may discontinue more frequently and earlier as well as experience more bleeding disturbances . Theoretically, the lower estrogen content might translate to further reductions in the rare risk of arterial and venous thromboembolism associated with modern COC use but this trend has not been consistently observed in large, population-based studies .

Contemporary COC typically contain EE paired with one of a number of progestational agents that vary in potency, affinity for steroid receptors, interaction with estrogens, and physiological effects . Older progestins derived from testosterone (e.g. norethindrone, levonorgestrel) are typically associated with more androgenic side effects including acne, excess hair growth and altered carbohydrate and lipid metabolism. Newer progestins derived from progesterone and spironolactone (e.g. chlormadinone acetate, drospirenone) have been designed to bind more selectively to progesterone receptors and minimize androgenic, estrogenic and glucocorticoid side effects. In addition, some progestins, like drospirenone, have a partial antiandrogenic effect . COCs containing 35 mcg EE or less in combination with any one of the existing progestins do not demonstrate obvious differences in contraceptive effectiveness, side effects, cycle control or continuation rates, but further studies are needed . Whether or not there are differences in risk for venous thromboembolism (VTE) across COC formulations with various progestogens remains a point of debate .

Monophasic COC regimens provide a uniform dose of estrogen and progestin in all active pills during a cycle. In contrast, multiphasic COC vary the dose of either or both steroid hormones. The intention behind this innovation, initiated in the 1980s, was to reduce both total hormone exposure as well as side effects by producing cycles that more closely mimic normal physiology. Several systematic reviews have concluded, however, that multiphasic regimens do not offer superior contraceptive protection or clearly demonstrate any clinical advantage over monophasic formulations . Rather, in the absence of greater benefits, use of monophasic regimens over multiphasic regimens may be preferred. Multiphasic COC require stricter adherence to a specific sequential pill-taking order given the variation in steroid hormones, potentially increasing the likelihood of incorrect use and subsequent unintended pregnancy.

Another strategy to improve safety and tolerability and possibly promote COC adherence has focused on manipulation of the interval between active pill cycles. Traditional pill packs provide active pills for twenty-one consecutive days followed by seven days of placebo to induce cyclic withdrawal bleeding, similar to a natural menstrual cycle. To reduce the duration of withdrawal bleeding and side effects like migraines and dysmenorrhea associated with the hormone free interval, monthly regimens with a shortened placebo period and/or low doses of estrogen were developed . Various studies note that use of 24/4 regimens either resulted in lighter scheduled bleeding of lesser duration or no difference and more frequent or no different incidents of unscheduled bleeding while maintaining contraceptive efficacy compared with 21/7 regimens . Extended or continuous COC regimens allow women to plan withdrawal bleeding quarterly, on a flexible schedule, or eliminate them entirely . Existing clinical trials suggest similar contraceptive efficacy, safety, satisfaction and either equivalent or somewhat improved bleeding patterns with extended regimens compared to cyclic use. Additionally, women randomized to extended use report greater relief from menstrual symptoms such as headaches, bloating, and menstrual pain . Generally, extended and continuous COC users experience fewer scheduled bleeding events, but may have more unpredictable spotting and bleeding episodes to navigate.

The newest COC formulations replace synthetic hormones with steroid components that more closely resemble endogenous molecules. In theory, natural estrogens and progestogens may have fewer metabolic and decreased thrombotic effects, further improving on safety . A four-phasic COC containing estradiol valerate (E2V), a compound metabolized to the natural estrogen, estradiol, paired with dienogest, a selective synthetic progestin derived from nortestosterone, effectively suppresses ovulation, maintains cycle control and exhibits favorable metabolic and hemostatic effects . Another monophasic COC formulated with the natural estrogen, estradiol (E2), and nomegestrel acetate (NOMAC), a potent synthetic progestin structurally similar to naturally occurring progesterone, has recently been approved in Europe and appears similarly safe and performs well in protecting against unintended pregnancy . Further surveillance is necessary to determine whether the promising characteristics of these formulations translate to greater efficacy and safety (e.g. decreases in VTE) over prior products.

Despite decades of pioneering research that have produced a diverse array of effective hormonal methods, including COC, contraceptive development continues to evolve. For example, new molecules (e.g. progesterone antagonists, progesterone receptor modulators), pill-taking regimens (e.g. peri-coital administration), targets (e.g. multi-purpose technologies, contraceptive vaccines, male contraception, genetic/proteomic molecules) and alternative delivery systems (e.g. intrauterine devices, implants, patches, rings, gels) are under investigation with the potential for even greater contraceptive protection, tolerability, non-contraceptive benefits and safer choices .

Non-contraceptive benefits associated with COC use

Improved acne and hirsutism

Because combined oral contraception decreases androgen levels and increases sex hormone binding globulin, they can be useful in preventing or reducing unwanted effects of excess androgen exposure such as acne and hirsutism . A recently updated Cochrane systematic review synthesized results from thirty-one randomized controlled trials with a total of over 12,000 participants . All of the COC formulations studied significantly reduced the appearance of both inflammatory and non-inflammatory facial acne lesions compared to placebo. Comparisons between COC formulations were limited and demonstrated mixed results, precluding determination of any superior formulation for this indication. Androgen-sensitive hair growth is also altered with COC use; hair shaft diameter is reduced, with maximal benefits being observed after one to two years of use .

Improved bone health

Perimenopausal and postmenopausal women (over the age of forty) using COC tend to gain or preserve bone mineral density (BMD) while non-users experience typical age-related bone losses . Other women with hypoestrogenic conditions (e.g. hypothalamic amenorrhea) treated with COC also demonstrate increases in BMD . COC use among adolescents may result in a net decrease in bone mineral density while premenopausal users experience no difference when compared to non-users of similar age . Although changes in BMD have been observed during hormonal contraceptive use, the clinical relevance of these changes and their impact on risk for subsequent bone fracture remain unclear. Most studies report no differences in risk among past COC users compared to never users, but several suggest mild protective effects .

Prevention of ovarian, endometrial and colorectal cancer

There is a substantial amount of epidemiological evidence demonstrating that COC use decreases a woman’s lifetime risk for ovarian, endometrial and colorectal cancer . A recent re-analysis of data from 45 studies across twenty-one countries found that COC use was associated with a reduction in lifetime mortality from ovarian cancers (both epithelial and non-epithelial) by over 50%. It also reported greater benefit with longer duration of use (1-4 years: RR 0.78 (95% CI, 0.73-0.83); 15 years or more: RR 0.42 (95% CI, 0.36-0.49). Protective effects persist for up to 30 years following COC discontinuation .

Risk for endometrial cancer is also reduced by upwards of 50% among COC users compared to never users. Data supporting this claim are derived from well-conducted large, population-based cohort studies . A systematic review and meta-analysis evaluating colorectal cancer and combined oral contraception noted nearly a 20% decrease in risk among ever use versus never use . No difference in effect was demonstrated according to duration of use; however, it appeared that protection was stronger relative to recent use (< 10 years since last use: OR 0.51, 95% CI 0.35-0.74) compared to more distant use (> 10 years since last use: OR 0.77, 95% CI, 0.60-0.99).

Reductions in mortality

Prevention of unintended pregnancy with use of effective, modern methods of contraception, including COC, can be a life-saving strategy during a woman’s reproductive years, particularly in regions with high rates of maternal mortality. Even after childbearing, large population-based studies suggest that a history of COC use may have an impact on reducing lifetime mortality from all causes compared to never users, supporting a strong overall health benefit associated with COC use .

Risks associated with COC use