According to the 2006–2010 NSFG, the combined oral contraceptive pill is the leading contraceptive method among women, with 28% of women between the ages of 15–44 choosing the pill. The availability of lower-dose combination oral contraceptives (COCs) (<50 μg ethinyl estradiol) has provided many women a highly effective, safe, and tolerable method of contraception.
Combined oral contraceptives suppress ovulation by diminishing the frequency of gonodotropin-releasing hormone pulses and halting the luteinizing hormone surge. They also alter the consistency of cervical mucus, affect the endometrial lining, and alter tubal transport. Most of the antiovulatory effects of COCs derive from the action of the progestin component. The estrogen doses are not sufficient to produce a consistent antiovulatory effect. The estrogenic component of COCs potentiates the action of the progestin and stabilizes the endometrium so that breakthrough bleeding is minimized. When administered correctly and consistently, they are >99% effective at preventing pregnancy. However, failure rates are as high as 8–10% during the first year of typical use. Noncompliance is the primary reason cited for the difference between these rates, frequently secondary to side effects such as abnormal bleeding and nausea.
The estrogenic agent most commonly used in COCs is ethinyl estradiol (EE), in doses ranging from 20 to 35 μg. Mestranol, which is used infrequently, is less potent than ethinyl estradiol such that a 50-μg dose of mestranol is equivalent to 30–35 μg of ethinyl estradiol. It appears that decreasing the dose of estrogen to 20 μg reduces the frequency of estrogen-related side effects, but increases the rate of breakthrough bleeding. In addition, there may be less margin for error with low-dose preparations such that missing pills may be more likely to result in breakthrough ovulation.
Multiple progestins are used in COC formulations. Biphasic and triphasic oral contraceptives, which vary the dose of progestin over a 28-day cycle, were developed to decrease the incidence of progestin-related side effects and breakthrough bleeding, although there is no convincing evidence that multiphasics indeed cause fewer adverse effects. As with estrogens, some progestins (norethindrone and levonorgestrel) are biologically active, while others are prodrugs that are activated by metabolism. Norethindrone acetate is converted to norethindrone, and norgestimate is metabolized into several active steroids, including levonorgestrel. Progestins that do not require hepatic transformation tend to have better bioavailability and a longer serum half-life. For example, levonorgestrel has a longer half-life than norethindrone. Norgestimate and desogestrel have lower androgenic potential than other progestins.
Drospirenone, a derivative of spironolactone, differs from other progestins because it has mild antimineralocorticoid activity. Contraceptive efficacy, metabolic profile, and cycle control are comparable to other COCs. The clinical implications of the diuretic like potential of drospirenone are not yet clear. Because of its antimineralocorticoid effects and the potential for hyperkalemia, drospirenone should not be used in women with severe renal disease or hepatic dysfunction.
Combination oral contraceptives are traditionally dosed cyclically with 21 days of hormone and 7 days of placebo during which a withdrawal bleed occurs. To address the potential of escape ovulation in the lowest estrogen formulations (20 μg), many regimens reduce the number of hormone-free days to 2–4 days. Extended cycle regimens or continuous hormonal regimens are safe and acceptable forms of contraception and may be more efficacious than cyclic regimens. Extended cycle regimens result in fewer scheduled bleeding episodes; however, they also result in more unscheduled bleeding and/or spotting episodes that decrease with time. Women who may particularly benefit from these regimens are those who have symptoms exacerbated by their menses. These include women who have seizure disorders, endometriosis, menstrual headaches, premenstrual dysphoric disorder, menorrhagia, or dysmenorrhea. There are several extended cycle regimens approved by the FDA (Sasonal, Seasonique, Lybrel); however, traditionally packaged COCs may also be prescribed as extended cycle regimens. Women are advised to use the active pills and then start a new pack, ignoring the placebo pills. This regimen gives women the option of cycling as they desire, modifying the timing of individual periods on a month-by-month basis for personal reasons.
Side effects may be due either to the estrogen component, the progestin component, or both. Side effects attributable to progestin include androgenic effects, such as hair growth, male-pattern baldness, and nausea. Switching to an agent with lower androgenic potential may decrease or resolve these problems. Estrogenic effects include nausea, breast tenderness, and fluid retention. Weight gain is commonly assumed to be a side effect of COCs; however, multiple studies have failed to confirm a significant effect. Weight gain can be managed by switching to a different formulation; however, appropriate diet and exercise should be emphasized.
Bleeding irregularities is the side effect most frequently cited as the reason for discontinuing COCs. Patients should be counseled that irregular bleeding/spotting is common in the first 3 months of COC use and will diminish with time. Spotting is also related to missed pills. Patients should be counseled regarding the importance of taking the pill daily. If the bleeding does not appear to be related to missed pills, the patient should be evaluated for other pathology such as infection, cervical disease, or pregnancy. If this evaluation is negative, the patient may be reassured. Another approach would be to change the pill formulation to increase the estrogen or progestin component. The doses can be tailored to the time in the cycle when the bleeding occurs. If the bleeding precedes the menses, consider a triphasic pill that increases the dose of estrogen (eg, Estrostep) or progestin (eg, Ortho-Novum 7/7/7) sequentially through the cycle. If the bleeding follows the menses, consider Mircette, which has only 2 hormone-free days. Increase the estrogen and/or the progestin midcycle for midcycle bleeding (eg, Triphasil).
Combined oral contraceptives may cause a small increase in blood pressure in some patients. The risk increases with age. The blood pressure usually returns to normal within 3 months if the COC is discontinued. Both estrogens and progestins are known to affect blood pressure. Therefore, switching to a lower estrogen formulation or a progestin-only pill may not resolve the problem.
Combined oral contraceptives can be safely prescribed after a thorough medical history (including the use of tobacco products) and blood pressure documentation. While a breast examination, Pap smear, and sexually transmitted disease screening may be indicated in a particular patient, these procedures are not required before a first prescription of COCs.
The use of most oral contraceptives with <50 μg of estrogen approximately triples one’s risk of venous thromboembolism (VTE). COCs containing third-generation progestogens (desogestrel, gestodene, but not norgestimate) or the progestin drospirenone have a greater risk of VTE (1.5–3.0 fold) over COCs containing levonorgestrel. Bias and confounding in these studies do not explain the consistent epidemiologic findings of increased risk. Obesity, increasing age, and the factor V Leiden mutation are contributing risk factors. The best approach to identify women at higher risk of VTE before taking COCs is controversial. Universal screening for factor V Leiden is not cost-effective. Furthermore, family history of VTE has unsatisfactory sensitivity and positive predictive value for identifying carriers of other common defects. Although the absolute risk of VTE remains low, women using COCs containing desogestrel, gestodene, and drospirenone should be counseled regarding potential increased risk. An FDA Advisory Committee has concluded that the benefits of COCs likely outweigh the risks in most women.
The risk of thrombotic or ischemic stroke among users of COCs appears to be relatively low. There is no evidence that the type of progestin influences risk or mortality associated with ischemic stroke. The risk of ischemic stroke does appear to be directly proportional to estrogen dose, but even with the newer low-estrogen preparations there is still a slightly increased risk compared with nonusers. Hypertension and cigarette smoking interact with COC use to substantially increase the risk of ischemic stroke. The risk of hemorrhagic stroke in young women is low and is not increased by the use of COCs. History of migraine without focal neurologic signs is not a contraindication to hormonal contraception.
Current use of COCs is associated with an increased risk of acute myocardial infarction (AMI) among women with known cardiovascular risk factors (diabetes, cigarette smoking, hypertension) and among those who have not been effectively screened for risk factors, particularly for blood pressure. The risk for AMI does not increase with increasing duration of use or with past use of COCs.
Many epidemiologic studies have reported an increased risk of breast cancer among COC users. For current users of COCs, the relative risk of breast cancer compared with never-users is 1.24. This small risk persists for 10 years, but essentially disappears after this time period. Although COC users have a modest increase in risk of breast cancer, the disease tends to be localized. The pattern of disappearance of risk after 10 years coupled with the tendency toward localized disease suggests that the overall effect may represent detection bias or perhaps a promotional effect.
Noncontraceptive Health Benefits
Most studies evaluating the relationship between COCs and ovarian cancer have shown a protective effect for oral contraceptives. There appears to be a 40–80% overall decrease in risk among users, with protection beginning 1 year after starting use, with a 10–12% decrease annually in risk for each year of use. Protection persists between 15 and 20 years after discontinuation. The mechanisms by which COCs may produce these protective effects include suppression of ovulation and the suppression of gonadotropins.
The use of COCs conveys protection against endometrial cancer as well. The reduction in risk of ≤50% begins 1 year after initiation, and persists for ≤20 years after COCs are discontinued. The mechanism of action is likely reduction in the mitotic activity of endometrial cells because of progestational effects.
Numerous epidemiologic studies demonstrate that the use of COCs will reduce the risk of salpingitis by 50–80% compared with the risk to women not using contraception or who use a barrier method. The purported mechanism for protection includes progestin-induced thickening of the cervical mucus so that ascent of bacteria is inhibited, and a decrease in menstrual flow resulting in less retrograde flow to the fallopian tubes. There is no protective effect against the acquisition of lower genital tract sexually transmitted diseases. Other noncontraceptive benefits of COCs include decreased incidence of benign breast disease, relief from menstrual disorders (dysmenorrhea and menorrhagia), reduced risk of uterine leiomyomata, protection against ovarian cysts, reduction of acne, improvement in bone mineral density, and a reduced risk of colorectal cancer.
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