From the Guidelines
Synthetic estrogens like ethinyl estradiol can cause several adverse effects, ranging from mild to severe, including blood clots, cardiovascular events, and an increased risk of certain cancers. The most recent and highest quality study 1 emphasizes the importance of considering the risks associated with synthetic estrogens, particularly in relation to cardiovascular events and stroke. Some of the common side effects of synthetic estrogens include:
- Nausea
- Headaches
- Breast tenderness
- Bloating
- Mood changes More serious risks associated with synthetic estrogens include:
- Blood clots (venous thromboembolism)
- Deep vein thrombosis
- Pulmonary embolism
- Stroke
- Cardiovascular events such as heart attack
- Increased risk of certain cancers, including breast cancer It is essential to note that the risks vary based on dosage, duration of use, age, and individual health factors, so medical supervision is crucial when using medications containing synthetic estrogens 1. The American Heart Association recommends that individuals considering hormonal contraception, such as synthetic estrogens, should be aware of the potential increased stroke risk and take steps to minimize it, including using lower doses of ethinyl estradiol 1. Overall, while synthetic estrogens can be effective for contraception and other medical uses, it is crucial to carefully weigh the potential benefits against the risks and to monitor patients closely for any adverse effects.
From the FDA Drug Label
An increased risk of the following serious adverse reactions has been associated with the use of oral contraceptives: Thrombophlebitis and venous thrombosis with or without embolism Arterial thromboembolism Pulmonary embolism Myocardial infarction Cerebral hemorrhage Cerebral thrombosis Hypertension Gallbladder disease Hepatic adenomas or benign liver tumors Benign hepatic adenomas are associated with oral contraceptive use, although the incidence of benign tumors is rare in the United States. Rupture of rare, benign, hepatic adenomas may cause death through intra-abdominal hemorrhage Studies from Britain have shown an increased risk of developing hepatocellular carcinoma in long-term (>8 years) oral contraceptive users Risk of Liver Enzyme Elevations with Concomitant Hepatitis C Treatment Ocular lesions There have been clinical case reports of retinal thrombosis associated with the use of oral contraceptives. Oral contraceptive use before or during early pregnancy Extensive epidemiologic studies have revealed no increased risk of birth defects in women who have used oral contraceptives prior to pregnancy Gallbladder disease Earlier studies have reported an increased lifetime relative risk of gallbladder surgery in users of oral contraceptives and estrogens Carbohydrate and lipid metabolic effects Oral contraceptives have been shown to cause a decrease in glucose tolerance in a significant percentage of users Progestogens increase insulin secretion and create insulin resistance, this effect varying with different progestational agents Elevated blood pressure An increase in blood pressure has been reported in women taking oral contraceptives Headache The onset or exacerbation of migraine or development of headache with a new pattern which is recurrent, persistent, or severe requires discontinuation of oral contraceptives and evaluation of the cause. Bleeding irregularities Breakthrough bleeding and spotting are sometimes encountered in patients on oral contraceptives, especially during the first three months of use Depression Carefully observe women with a history of depression and discontinue Kariva® if depression recurs to a serious degree. Hereditary Angioedema In females with hereditary angioedema, exogenous estrogens may induce or exacerbate symptoms of angioedema. Chloasma Chloasma may occur with Kariva® use, especially in females with a history of chloasma gravidarum.
The adverse effects of synthetic estrogens, such as ethinyl estradiol, include:
- Thrombophlebitis and venous thrombosis with or without embolism
- Arterial thromboembolism
- Pulmonary embolism
- Myocardial infarction
- Cerebral hemorrhage and thrombosis
- Hypertension
- Gallbladder disease
- Hepatic adenomas or benign liver tumors
- Ocular lesions, including retinal thrombosis
- Elevated blood pressure
- Headache, including migraine
- Bleeding irregularities, such as breakthrough bleeding and spotting
- Depression
- Hereditary Angioedema
- Chloasma
- Carbohydrate and lipid metabolic effects, including decreased glucose tolerance and increased insulin resistance
- Liver enzyme elevations with concomitant hepatitis C treatment 2
- Post-marketing experience has also reported other adverse reactions, including breast cancer risk, change in weight, change in cervical erosion and secretion, diminution in lactation, cholestatic jaundice, migraine, rash, mental depression, reduced tolerance to carbohydrates, vaginal candidiasis, change in corneal curvature, intolerance to contact lenses, pre-menstrual syndrome, cataracts, changes in appetite, cystitis-like syndrome, nervousness, dizziness, hirsutism, loss of scalp hair, erythema multiforme, erythema nodosum, hemorrhagic eruption, vaginitis, porphyria, impaired renal function, hemolytic uremic syndrome, acne, changes in libido, colitis, Budd-Chiari syndrome 2
From the Research
Adverse Effects of Synthetic Estrogens
The use of synthetic estrogens, such as ethinyl estradiol, has been associated with several adverse effects. Some of the key concerns include:
- Increased risk of venous thrombosis, with estrogen-containing methods increasing the risk from 2 to 10 venous thrombotic events per 10 000 women-years to 7 to 10 venous thrombotic events per 10 000 women-years 3
- Thromboembolic events, which can be life-threatening 4, 5
- Cardiovascular disease, including pulmonary embolism and deep vein thrombosis 6
- Discontinuation rates and adverse outcomes due to potential risks and side effects 4
Risk Assessment and Contraceptive Choices
When considering the use of synthetic estrogens, it is essential to assess the individual's risk factors and medical history. This includes:
- Evaluating the risk of thrombosis, particularly in women with a personal history of thrombosis or thrombophilia 6, 7
- Considering alternative contraceptive methods, such as progestin-only or nonhormonal options, which may have lower risks 3, 7
- Discussing patient values and preferences to determine the most suitable contraceptive method 3
Alternatives to Ethinyl Estradiol
Research has led to the development of alternative estrogens, such as estetrol, which may have a lower risk of side effects and thromboembolic events. These alternatives include: