Combined Oral Estrogen-Progestin Contraceptives (COC)

COCs contain derivatives of the hormones estrogen and progestin, which work by inhibiting follicular development, ovulation, and sperm penetration of a mature egg. These hormones also thicken the cervical mucus, further inhibiting sperm motility through the female reproductive tract. The optimal use failure rate is approximately 0.3%; however, actual usage has a failure rate of 7% due to compliance.^18*

Combined oral contraceptives come in either monophasic or multiphasic pack formulations. Monophasic pills each contain a consistent dose of estrogen and progestin. Multiphasic packs may be biphasic, triphasic, or quadriphasic, depending on the varying amount of estrogen present. Many combined oral contraceptives contain inactive or placebo pills to mimic a monthly period; however, others allow a woman to select when or if she wants to have a period.

Current preparations allow for no, monthly, or every three months withdrawal bleeding. A systemic review found that continuous or extended dosing had greater improvement in headaches, genital irritation, tiredness, bloating, and menstrual pain. Vaginal bleeding patterns were equivalent or slightly improved using continuous dosing.¹⁹ Some women may experience more unscheduled bleeding with continuous regimens, especially during the initial three to six months of therapy.

Unscheduled bleeding typically decreases over time.²⁰ Pregnancy may be difficult to ascertain with continuous dosing; a pregnancy test is recommended if unexplained breast tenderness, fatigue, or morning sickness occurs.

The lowest dosage of hormones should be used to provide contraception. Doses of estrogen should not exceed 35 mcg of ethinyl estradiol (EE) equivalent, and most often, 20 mcg is chosen as a starting dose. Formulations with even lower doses, ten mcg, have been developed. Higher doses are associated with an increased risk of adverse events, but not to the degree to endorse 20 mcg doses as having a superior safety profile.

The absolute risk of thrombosis or myocardial infarction (MI) with hormonal contraceptives is low, but the risk was increased by 0.9 to 1.7 times with EE doses less than 20 mcg and by 1.3 to 2.3 for doses of 30 to 40 mcg. Many practitioners will start with a monophasic COC containing 20 mg of ethinyl estradiol.^21,22

The dosage of EE can be increased if unscheduled vaginal bleeding or spotting is an issue. Issues such as breast tenderness, nausea, vomiting, and headaches may indicate that a lower dose of EE is necessary.

The type of progestin can influence thrombosis risk. Gestodene, desogestrel, cyproterone acetate and drosperinone may have a 50% to 80% higher risk of thrombosis compared to levonorgestrel. Norgestimate was found to have a lower risk of thrombosis and MI than gestodene, desogestrel, and drospirenone.

The absolute risk of thrombosis is small and should not be used as a sole guide for therapy.^22* Third-generation progestins have less androgenic potential than earlier-generation progestins. New fourth-generation progestins have antiandrogenic properties. A different progestin or a lower dose can be used if women develop side effects related to androgenic activity (oily skin, acne, central obesity, alopecia, hirsutism, deep voice).

Alternatively, a higher estrogen-containing product may alleviate these symptoms by shifting the hormone balance towards estrogen dominance. Drospirenone is a progestin with mineralocorticoid activity similar to spironolactone. Three mg of drospirenone is equivalent to 25 mg of spironolactone. Healthy women taking this are unlikely to develop potassium retention; however, women on other medications that may increase potassium retention (NSAIDs, diuretics, ACE inhibitors, angiotensin antagonists, aldosterone antagonists) should have potassium monitored during the first month of therapy.²³

Drospirenone/EE is FDA approved for premenstrual syndrome (PMS) and premenstrual dysphoric disorder (PMDD). Many practitioners will start with a COC containing norgestimate or levonogestrol.^22,23*

The efficacy of monophasic compared to multiphasic preparations with equal adherence is the same; however, monophasic COCs may have increased adherence because of simplicity. Multiphasic COCs must be taken in sequential order because of the different hormone doses throughout the dosage cycle.

Multiphasic COCs should not be used for the extended or continuous COC method. Multiphasic COCs may also exacerbate mood symptoms more than monophasic COCs in women with premenstrual syndrome or premenstrual dysphoric disorder.

Table 4 – Progestins by Class²⁴

Table 5 – Advantages & Disadvantages of COCs^18*

Nausea, abdominal bloating, breast tenderness, and headaches may occur after initiation but usually resolve within the first month of therapy. Taking a COC with food may improve gastric tolerability.

Unscheduled bleeding is common after COC initiation and may affect up to 50% of women starting therapy.^25,26 Formulations with 24/4 dosing have higher bleeding rates than 21/7 formulations due to the lower estrogen content.²⁷ COCs were not associated with weight change in a meta-analysis of 49 trials.²⁸

COC use is not associated with an increase in all-cause mortality.²⁹ COCs are associated with elevations in blood pressure in susceptible patients; however, the blood pressure typically returns to normal after discontinuation of therapy. COCs can increase fluid retention by activating the renin-angiotensin system (RAS), elevating blood pressure.

Higher doses are associated with an increased risk of developing hypertension. The relative risk of developing hypertension for COC users compared to non-users was 1.9 (95 CI 1.5-2.5). The absolute increase in systolic and diastolic blood pressure was 0.7 mmHg (95 CI 0.4-1.0) and 0.4 mmHg (95% CI 0.2-0.6), respectively.³⁰

Estrogens increase the hepatic synthesis of clotting factors. The absolute risk of VTE is approximately 0.06 per 100 pill years. Per 10,000 individuals, the risk of VTE is one to five for non-COC users and 3 to 12 for users. This risk is higher in the first few months of therapy. Obesity, smoking, polycystic ovarian syndrome, immobilization, and age are factors that increase the risk of VTE.^31,32 Estrogen content has been reduced since COCs were first approved, reducing the risk of stroke and MI.

The absolute risk for reproductive-age women for stroke is 5 to 10 per 100,000 women-years and doubles with COC use.^33,34 A 2015 meta-analysis reported a 1.6 times higher risk of arterial thrombosis when COC users were compared to non-users. The risk did not appear to change by progestin type.³⁵

COCs can increase triglycerides and HDL and lower LDL; however, this effect is small and not considered a clinical concern. Triglycerides may increase by 25 mg/dL, and HDL and LDL may go up by 12% or down by 5%, depending on the formulation.^36,37 COCs are contraindicated with migraine disorders because of a two to four-fold increased risk of stroke.^33* COCs are associated with a small increased risk of inflammatory bowel disorders (OR 1.32, 95% CI 1.17 to 1.49), perhaps through thrombotic effects on the intestinal microvasculature.³⁸

COCs are not associated with an increase in the overall risk of cancer. COC use is associated with decreases in ovarian, endometrial, and colorectal cancers. Breast and cervical cancer use increases while COCs are actively used but return to normal two to five years after discontinuation. The oncoprotective effect persisted for over 30 years (ovarian cancer OR 0.72, 95% CI 0.65-0.81 and endometrial cancer incidence ratio 0.66, 99% CI 0.48-0.89).^39,40 Studies are mixed on the risk of COC and breast cancer, but the studies showing an association show a small increased risk RR of 1.19 (95 CI 1.13 to 1.26). The risk increased with a longer duration of use; however, the absolute risk increase was small. COC use was associated with approximately one additional breast cancer case per 7690 person-years. For women under 35, the absolute risk increase was 2 per 1000,000 person-years.⁴¹ COC use increases the risk of cervical cancer for approximately ten years after discontinuation, with a peak incidence ratio of 2.32 (99% CI 1.24-4.34). After ten years, the risk equilibrates to women who have never used COCs.^40*,42 COCs are associated with focal nodular hyperplasia, hepatic adenomas, and hepatocellular carcinoma. The strongest association is with hepatic adenomas.⁴³

Significant drug-drug interactions exist, which can decrease the efficacy of estrogen and progestin-containing formulations. Fosamprenavir (COC only) and efavirenz are associated with lower serum hormone levels and an increased risk of breakthrough pregnancy. Other protease inhibitors like ritonavir, darunavir, and lopinavir decrease norethindrone and EE levels.

Other protease inhibitors that are not boosted, like dolutegravir, talegravir, and bictegravir, do not affect hormone levels. Anticonvulsants such as phenytoin, carbamazepine, barbiturates, topiramate, and oxcarbazepine may reduce the efficacy of hormonal contraception by altering hormone levels. Gabapentin, levetiracetam, valproate, tiagabine, and zonisamide are appropriate alternatives.

Rifampin and rifabutin can decrease serum EE and progestin levels.^16*,44 Lamotrigine use is not recommended with COCs because concurrent use can lower lamotrigine levels resulting in increased seizure activity.⁴⁵

Estrogen can increase the concentration of thyroxine-binding globulin, cortisol-binding globulin, and sex hormone-binding globulin. The result is an increase in total thyroxine (T4), triiodothyronine (T3), cortisol, estradiol, and testosterone, but the free levels do not change. Patients with thyroid, adrenal and gonadal function issues may be adversely affected. Oral contraceptives have also been associated with the depletion of several nutrients, including folic acid, B vitamins (B2, B6, B12), magnesium, selenium, and zinc.

Pharmacists can recommend that patients take a high-quality multivitamin and eat a whole-food nutrition plan to prevent significant nutrient deficiencies.⁴⁶

The pharmacist should counsel the patient to take one pill daily, preferably at the same time each day. COCs may be started at any time in the month; however, if initiated > five days after menses, a backup method of contraception must be used for seven days.

Return to fertility is a concern for many COC users and varies depending on the method used. One trial revealed a 57% pregnancy rate at three months and an 81% pregnancy rate at 12 months after discontinuing CHCs. The median time to return to menses is 32 days after cessation of therapy.⁴⁷

Switching to another COC can be done immediately; the patient can start the day after taking the last dose of the previous COC. If there is no hormone-free interval (HFI), there is no need for backup contraception. Switching from a POC to CHC requires a backup method for seven days. If the patient is switching from an injectable progestin or implant to a CHC, no backup method is needed. Changing from a progestin IUD to COC requires backup contraception for seven days.

Suppose there was unprotected or inadequately protected vaginal intercourse within seven days of the switch date. In that case, the IUD should be retained until the patient has completed seven days of COC therapy. For copper IUDs, if it has been less than five days since the start of the menstrual cycle, no backup is necessary. However, seven days of contraceptive backup should be used during any other time in the reproductive cycle.⁴⁸

There are no specific follow-up examinations or lab work recommended for monitoring purposes while on COC therapy. Healthy patients typically get a year’s supply of medication refilled during routine physicals.

Table 6 – Example of COCs⁴⁹

Table 7 – Missed Dose Instructions For COCs⁵⁰

Table 8 – Switching From COC To Another Contraceptive Method^48*