Oral Contraceptives, Combinations
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The primary action of estrogen-progestin combination contraception is inhibition of ovulation via suppression of the hypothalamic-pituitary system, and both the estrogen and progestin contribute to contraceptive effectiveness. Combined hormonal contraception reduces secretion of gonadotropin-releasing hormone from the hypothalamus resulting in decreased release of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) from the pituitary. This reduction in FSH and LH levels prevents the midcycle surge that is necessary for follicular development, maturation, and ovulation. Estrogen-progestin contraceptive use also increases cervical mucus viscosity reducing sperm motility, and use also reduces endometrial thickness which can help prevent embryo implantation. 
Progestin Classifications Based on Structure     
Oral Contraceptive Comparative Efficacy and Safety Trials of Interest
Population-based case-control study in premenopausal women (18 - 50 years of age) taking oral contraceptive (OC) therapy to evaluate the impact of estrogen dose and progestin type on the risk of venous thromboembolism.
Case patients (n=1524) were women who experienced a first episode of deep venous thrombosis or pulmonary embolism between March 1999 and September 2004.
Controls (n=1760) were women 18-70 years of age with no history of deep venous thromboembolism.
Case - 72.4%
Controls - 37.4%
Thrombosis Risk and OC use (OR [95% CI])
Case - 5 [4.2 to 5.8]
Levonorgestrel-containing OCs most common in cases and controls; 44% and 57%, respectively.
Thrombosis Risk and Progestin Type (OR [95% CI])a
Levonorgestrel - 3.6 [2.9 to 4.6]
Desogestrel - 7.3 [5.3 to 10]
Norethindrone - 3.9 [1.4 to 10.6]
Norgestimate - 5.9 [1.7 to 21]
Drospirenone - 6.3 [2.9 to 13.7]
Thrombotic Risk Compared to Levonorgestrel (OR [95% CI])
Desogestrel - 2 [1.4 to 2.8]
Drospirenone - 1.7 (0.7 to 3.9]
Risk of venous thromboembolism similar for monophasic and triphasic OCs.
Thrombotic Risk Compared to Estrogen 30 mcg (OR [95% CI])b
Estrogen 20 mcg - 0.8 [0.5 to 1.2]
Estrogen 50 mcg - 1.9 [1.1 to 3.4]
Deep Venous Thrombosis Risk (Leg) and Progestin Type (OR [95% CI])
Levonorgestrel - 6.6 [5.4 to 8]
Desogestrel - 8.7 [6.1 to 12.4]
Norethindrone - 5.4 [1.8 to 16.6]
Norgestimate - 8.7 [2.1 to 35.5]
Drospirenone - 9.1 [3.9 to 21.5]
Pulmonary Embolism Risk and Progestin Type (OR [95% CI])c
Levonorgestrel - 3.9 [3.2 to 4.8]
Desogestrel - 7.1 [4.9 to 10.4]
Norethindrone - 3.1 [0.8 to 11.5]
Norgestimate - 5.2 [1.1 to 23.7]
Drospirenone - 6.2 [2.2 to 17.6]
Risk of venous thromboembolism highest in the first 3 months of therapy (12.6 [7.1 to 22.4])
Desogestrel and drospirenone are associated with a higher risk of venous thromboembolism.
Risk of venous thrombosis higher with estrogen 50 mcg.
Total women years: 10.4 million
Current use of OC: 3.4 million years
Past use of OC: 2.3 million years
Never use of OC: 4.8 million years
First Time Thrombotic Events
Total - 4213
Current OC Users - 2045
The incidence of venous thrombosis increased with age.
Rate of venous thrombosis per 10,000 women-years was 3.01 and 6.29 for never or former use of OC and current OC use, respectively.
Rate of venous thrombosis was higher during the first year of OC use (4.17 per 10,000 women-years) and decreased with continued use.
Higher estrogen doses associated with higher rate of venous thrombosis.
Adjusted Rate Ratio (95%CI) of Venous Thrombosis With Levonorgestrel As Referenced
Norethindrone - 0.98 (0.71 to 1.37)
Levonorgestrel - 1
Norgestimate - 1.19 (0.96 to 1.47)
Desogestrel - 1.82 (1.49 to 2.22)
Drospirenone - 1.64 (1.47 to 2.10)
Desogestrel and drospirenone associated with higher risk of venous thrombosis compared to levonorgestrel.
Risk of venous thrombosis higher with higher doses of estrogen.
aOnly results for progestins available within the United States of America are presented. Comparison based on regimens containing estrogen 30 mcg for levonorgestrel and desogestrel. Norethindrone reported as norethisterone in the study; bAnalysis restricted to monophasic OCs containing levonorgestrel, desogestrel, and gestodene; cOnly results for progestins available within the United States of America are presented. Comparison based on regimens containing estrogen 30 mcg for levonorgestrel and desogestrel. Patients with pulmonary embolism may or may not have had deep venous thrombosis; dOnly results for progestins available within the United States of America are presented. Norethindrone reported as norethisterone in the study. All progestins were given in combination with estrogen 30 - 40 mcg.
Common adverse effects of combined oral contraceptives (COCs) may occur with initial use, but are usually mild and should resolve after a few months of use. Breakthrough bleeding or spotting is common during the first 3 months of therapy. Common estrogenic adverse effects include breast tenderness, nausea/vomiting, headache, and melasma. More common adverse effects associated with the progestin component include acne, mood changes, and weight gain. Symptoms only need evaluation if prolonged or bothersome. For example, if breakthrough bleeding or spotting continues beyond 3 months, switching to a COC with greater progestational activity can be helpful.
Thromboembolism and thrombus formation are serious adverse reactions related to combined oral contraceptive (COC) therapy and may include deep venous thrombosis, pulmonary embolism, retinal thrombosis, myocardial infarction or stroke. Should any of these events occur or be suspected, the COC should be discontinued immediately. The risk for thromboembolism due to COCs is approximately 4 to 10 per 10,000 woman-years, which is still lower than the risk during pregnancy or the immediate post-partum period. Heart attack and ischemic stroke are rare in women without co-existing risk factors. Women with high risk for thromboembolism, such as presence of thrombophilia, systemic lupus erythematosus (SLE), diabetes mellitus with vascular complications or more than a 20-year history of diabetes mellitus, certain types of cardiovascular disease, or history of migraine with aura are generally not suitable candidates for COCs. Risk factors such as tobacco smoking, increasing age (more than 35 years), hypertension, obesity, and prolonged immobilization influence the risk for thromboembolism. Women who smoke have significantly increased risk, and especially if over the age of 35 years. There is a positive association between dosage of estrogen and risk for thromboembolism, as estrogens increase the production of clotting factors. Oral contraceptives containing ethinyl estradiol 50 mcg/day or more are associated with a higher risk compared to those containing 35 mcg/day or less. The risk may vary based on progestin component in combination oral contraceptives, but the data are not clear and require further consideration. Some evidence suggests that the risk of venous thromboembolism is higher with newer progestins (e.g., desogestrel, drospirenone, and dienogest) in COCs versus the usual risk for older progestins in COC products, and other evidence does not. Many of the retrospective observational studies available vary in their ability to control for preexisting confounding risk factors and prescribing bias. For example, prospective observational studies have not found an increased risk for products containing drospirenone relative to products containing levonorgestrel.            
Because female cancers can be hormonally responsive, do not use combined oral contraceptives in patients with a history of such cancers, including cancers of the breast, reproductive organs, or genitals.
The link between combined oral contraceptive (COC) use and breast cancer has been controversial. There is substantial evidence that COCs do not significantly increase the incidence of breast cancer. Some past studies have suggested that COCs might increase the incidence of breast cancer; more recent studies have not confirmed such findings. Data suggest a small increased risk of breast cancer, if any, and no increased risk in breast cancer death. From one large study published in 2017, the risk of breast cancer was higher among women who currently or recently used contemporary hormonal contraceptives than among women who had never used hormonal contraceptives, and this risk increased with longer duration of use; however, absolute increases in risk were small. The absolute risk of breast cancer associated with any hormonal contraceptive use was 13 per 100,000 women-years, which corresponds to 1 extra case of breast cancer for every 7,690 COC users in 1 year. The same study data suggest that an increased risk of breast cancer usually disappears rapidly after an interruption in the use of COCs. There continues to be controversy regarding the risk of COC use in women with a family history of breast cancer (e.g., BRCA mutations). Patients should be instructed to perform a monthly self-breast examination and report any breast changes, lumps or breast discharge to their healthcare professional.   
In general, the data suggest an increased risk of cervical cancer among combined oral contraceptive (COC) users. Some studies suggest that COC use has been associated with an increase in the risk of cervical cancer or intraepithelial neoplasia; however, such findings may be due to differences in sexual behavior, the presence of the human papillomavirus (HPV) and other factors. HPV is thought to be the cause of more than 90% of all cervical cancers, although, hormonal factors may influence risk. The relative risk of invasive cervical cancer of 1.37 after 4 years of use; relative risk increased to 1.6 after 8 years of use. Because a potential for cervical dysplasia may exist, regularly evaluate patients taking COCs via cervical cytology screening as recommended per standards of care.  
Endometrial and Ovarian
In general, the data suggest a decreased risk of endometrial and ovarian cancer among combined oral contraceptive (COC) users, except for hereditary forms of ovarian cancer (e.g., women who carry BRCA1 or BRCA2 gene alterations).  
Studies have shown an increased risk of developing hepatocellular carcinoma in long-term (more than 8 years) COC users. However, these cancers are rare in the United States, and the attributable risk (the excess incidence) of liver cancers in oral contraceptive users approaches less than 1 per million users. 
Combined oral contraceptive (COC) therapy has been reported to cause elevations in blood pressure and the incidence increases with duration of use, patient age and, possibly, progestin concentration. If the patient's blood pressure rises significantly during use, the COC should generally be discontinued. Patients with pre-existing hypertension or hyperlipidemias should be monitored and managed appropriately during COC use.
Mental depression and mood changes have all been reported with oral contraception, but are infrequent.
Gallbladder disease, biliary obstruction, cholestatic jaundice, cholelithiasis, and cholecystitis have been reported. Hepatitis, elevated hepatic enzymes, peliosis hepatis, enlargement of hepatic hemangiomas, and pancreatitis are rare adverse reactions. Cases of bowel ischemia have been reported during combined estrogen and progesterone use; mesenteric vein thrombosis due to hypercoagulability is the proposed mechanism. Oral contraceptives should be discontinued, and patient evaluated if jaundice, cholestasis, or severe abdominal pain occur.
Headaches/migraines may be hormonally mediated; thus, COC use may result in the development of headaches/migraines, alter the frequency, duration, or severity of existing headache patterns, or decrease the occurrence of migraines. A headache or migraine with focal symptoms or vision changes should be evaluated immediately, since such symptoms can be related to cerebrovascular events or retinal thrombosis.
Melasma and photosensitivity, as well as various infrequent dermatological reactions, such as maculopapular rash, urticaria, erythema, alopecia or hirsutism, have been reported with combined hormonal contraception. Oral contraceptive use may be associated with aggravation of acne, but in some patients, acne may improve.
Factors to Consider
Persistent breakthrough bleeding
If no cause found, consider the following for cyclic regimens:
For extended/continuous regimens:
Lack of Withdrawal Bleeding
Occurs during the pill-free/withdrawal period,
Mild-moderate and occurs with active pills:
Severe, presence of focal neurological symptoms (i.e., dizziness, slurred speech, flashing lights, loss of vision), persistent headache despite alterations in contraceptive or patient at risk of stroke
Depression, Mood Swings, Emotional Lability
Estrogens and progestins are partially metabolized by CYP3A4; therefore, coadministration with CYP3A4 inhibitors or inducers may result in increased or decreased plasma concentrations of estrogens/progestins, respectively. Concomitant therapy with CYP3A4 inducers increases the risk of contraceptive failure, and these drug interactions may require adjustments to the patient's birth control choices and regimens. Epileptic women on concomitant therapy with oral contraceptives and anticonvulsants may be at higher risk for folate deficiency.
Hormonal contraceptives should not be administered with amprenavir or fosamprenavir. Oral combination contraceptives may decrease the serum concentrations of certain antiretroviral medications, such as amprenavir and fosamprenavir, which could result in the loss of virologic response and possible viral resistance. Other protease inhibitors may increase (e.g., ritonavir, lopinavir; ritonavir, nelfinavir, saquinavir, tipranavir) or decrease (e.g., atazanavir, indinavir) the metabolism of hormonal contraceptives. Further, the use of hormonal contraceptives does not reduce the risk for transmission of the HIV virus or other sexually-transmitted diseases.
The use of estrogens, including estrogen-containing birth control is not recommended during aromatase inhibitor treatment (e.g., aminoglutethimide, anastrozole, exemestane, letrozole, testolactone, vorozole) due to opposing pharmacologic actions. The indications for use of the aromatase inhibitors generally preclude the use of estogen-containing hormonal contraception.
Subtherapeutic response to metyrapone is seen when given with estrogens; thus, it is recommended to avoid concomitant administration.
Anticoagulant effects of warfarin are usually reduced with coadministration of estrogen therapy; thus, concomitant therapy is generally avoided. If concurrent therapy given, warfarin dose adjustments should be based on either the prothrombin time or INR value. Oral contraceptives containing 50 mcg/day or more of ethinyl estradiol are associated with greatest risk of thromboembolic complications, and should be avoided in most patients. In general, hormonal contraceptives are contraindicated in patients with active or recent thromboembolic disease, or who have prominent risk factors for thromboembolism.
Antibiotics, such as penicillins, sulfonamides, tetracyclines, clindamycin, neomycin and nitrofurantoin, may affect the gut flora, resulting in lower estrogen reabsorption and reduced efficacy of oral estrogen/progestin contraceptives. An additional method of contraception during antibiotic use may be advisable with use of selected agents.
Generally, antiestrogenic selective estrogen receptor modulators (SERMS) such as tamoxifen and raloxifene are pharmacological opposites of estrogens, and the indication for use of the SERM precludes the use of estogen-containing hormonal contraception.
Drospirenone is a spironolactone derivative with antimineralocorticoid effects and may increase serum potassium levels. Thus concurrent administration of drospirenone and potassium containing products (e.g., potassium iodide, potassium salts, dietary salt substitutes), other potassium containing medications (e.g., antibiotics), potassium-sparing diuretics, angiotensin-converting enzyme inhibitors (ACE inhibitors), angiotensin II receptor antagonists or eplerenone may increase the risk of hyperkalemia, especially in the prescence of renal impairment. Monitor serum potassium levels if these drugs are use concurrently with drospirenone; estradiol, particularly during the first month of therapy.
Combined oral contraceptives (COCs) are contraindicated in patients with a current or history of stroke, coronary thrombosis, myocardial infarction, venous thromboembolic disease (VTE) or deep venous thrombosis. Thromboembolic disease, such as deep venous thrombosis, is associated with the use of hormonal contraceptives. Tobacco smoking greatly increases the risk of thromboembolism, including major cardiovascular events such as myocardial infarction and stroke, particularly in women more than 35 years of age or younger women who smoke 15 or more cigarettes per day. Combined hormonal contraceptives are contraindicated in women more than 35 years of age who smoke. Other risk factors for thromboembolism should be reviewed; any condition associated with an increased risk for thromboembolism generally contraindicates the use of estrogen-containing hormonal contraception. Also, to minimize the risk of VTE, hormonal contraception should be stopped at least 4 weeks before any elective surgery that may be associated with an increased risk of thromboembolism; patients should not restart the contraceptive until ambulatory. Also, discontinue use during any period of prolonged immobilization.
In general, combined hormonal contraceptive use is contraindicated in women with headaches, such as migraine, that include focal neurological symptoms, such as aura. The risk for cerebral thromboembolic events may be increased. Patients with new onset or exacerbation of migraines, visual disturbances or focal neurologic symptoms, or who develop headache with a new pattern which is recurrent, persistent or severe should be evaluated to identify the cause. In some cases, such symptoms may be warning signs for stroke.
Combined hormonal contraceptives are associated with elevations in blood pressure; as such, they are generally contraindicated in patients with uncontrolled hypertension and should be used with caution in patients with controlled hypertension or kidney disease. Oral products containing 50 mcg ethinyl estradiol should not be used unless medically necessary. Blood pressure should be monitored; any significant increase in blood pressure may require discontinuation of hormonal contraceptives.
Hormonal combined oral contraceptives (COCs) are contraindicated in patients with known, suspected or personal history of breast cancer, endometrial cancer, cervical cancer, ovarian cancer, uterine cancer, vaginal cancer, other estrogen-responsive tumors, and undiagnosed, abnormal vaginal bleeding. Use with caution in patients with uterine leiomyomata (fibroids). Evaluation of patients via pelvic examinations and cervical cytology screening should be performed as per standards of care during COC use.
Hormone replacement therapy is contraindicated in patients with a history of cholestatic jaundice/pruritus of pregnancy or jaundice due to prior hormonal treatments or in the presence of hepatocellular cancer, hepatic adenoma, jaundice, hepatic insufficiency or hepatic disease. Caution should be utilized with administration in patients with acute or intermittent prophyria.
Hormonal contraceptives are contraindicated during pregnancy. There appears to be little or no increased risk of birth defects in children born to women who have used estrogens and progestins from combined oral contraceptives (COCs) inadvertently during early pregnancy. Discontinue the COC if pregnancy is confirmed. Estradiol and other estrogens freely cross the placenta to the fetus. Increased risk of a wide variety of fetal abnormalities, including modified development of sexual organs, cardiovascular anomalies and limb defects, have been reported following the continued use of estrogens in pregnant women.
Both progestins and estrogens appear to be excreted into breast milk. Manufacturers recommend avoidance of combined hormonal oral contraceptives (COCs) if possible until a mother has completely weaned her child. Small amounts of oral contraceptive steroids have been identified in the milk of nursing mothers and a few reports of effects on the infant exist, including jaundice and breast enlargement. Other experts often recommend avoidance of estrogen-containing hormonal contraceptives, in the first 21 days postpartum (or longer, if other risks for thromboembolism exist) due to maternal post-partum clot risks following obstetric delivery, and the potential for estrogen-containing hormonal contraceptives to interfere with the establishment of lactation. It is generally accepted that estrogen-containing combined contraceptives may be used after this period in healthy women without other risk factors; general monitoring of the infant for effects such as appetite changes, breast changes and proper weight gain and growth should occur. Estrogens, including ethinyl estradiol, have been reported to interfere with milk production and duration of lactation in some women, particularly at doses of 30 mcg/day EE or more. One study found that lower dose oral combined contraceptives (e.g., 10 mcg/day EE) may not affect lactation. However, a systematic review concluded that the available evidence, even from randomized controlled trials, is limited and of poor quality; the authors concluded that properly designed and conducted trials are needed to make determinations on the appropriateness of hormonal contraception during lactation and the effects on the health and growth of the infant.
Drospirenone has antimineralocorticoid activity, which may increase serum potassium levels or impair adrenal function; thus, it is contraindicated in patients with renal impairment, renal failure, renal disease or adrenal insufficiency. Monitor serum potassium levels in patients at risk for elevations, particularly during the first month of therapy with a drospirenone-containing hormonal contraceptive. Drospirenone may cause hyponatremia in high-risk patients.
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