Ethinylestradiol and Estradiol Formulations

Combined contraceptives use either ethinylestradiol, a synthetic oestrogen, or an oestradiol-type oestrogen: oestradiol valerate, oestradiol or estetrol. Ethinylestradiol is potent, resists first-pass breakdown and has strong effects on hepatic protein synthesis. Oestradiol-type products have weaker hepatic effects and are intended to give a different balance of cycle control and metabolic effects. All suppress ovulation and share the same eligibility categories.

Ethinylestradiol doses. 15 micrograms (with a gestodene progestin in some products), 20 micrograms (ultra-low), 30 to 35 micrograms (low), and 50 micrograms or more (high, rarely used). Venous thrombosis risk rises with dose, and cycle control improves with dose.

Oestradiol-type products.

Progestin partners. Levonorgestrel, norethisterone and norgestimate; desogestrel and gestodene; drospirenone, which has anti-mineralocorticoid action; dienogest; nomegestrol acetate; cyproterone acetate, which is anti-androgenic and not used for contraception alone.

Hepatic and metabolic effects. Ethinylestradiol raises sex hormone binding globulin, angiotensinogen and clotting factors and causes resistance to activated protein C. Oestradiol-type oestrogens cause smaller changes in these markers. Observational data suggest venous thrombosis risk with oestradiol valerate and dienogest or oestradiol and nomegestrol acetate is similar to or lower than with levonorgestrel and ethinylestradiol; long-term data on estetrol are limited.

Effectiveness. As a class, pills give 8 pregnancies in 100 women in the first year with typical use and 0.3 with perfect use. Registration studies of oestradiol-type pills show comparable efficacy. Return to fertility is without delay.

Eligibility. Medical eligibility categories do not change with the type of oestrogen. No oestradiol-type product is placed in a lower category than ethinylestradiol pills.

• Category 4: migraine with aura; breastfeeding under 6 weeks; blood pressure 160/100 or more; ischaemic heart disease or stroke; breast cancer; current or past deep vein thrombosis or pulmonary embolism; thrombogenic mutation; smoker 35 years or more with 15 or more cigarettes daily; diabetes with vascular disease; decompensated cirrhosis; liver adenoma or malignancy; lupus with positive or unknown antiphospholipid antibodies.
• Category 3: rifampicin, rifabutin, enzyme-inducing antiseizure medicines, symptomatic gall bladder disease, blood pressure 140/90 to 159/99.

When an oestradiol-type pill is considered. Intolerance of ethinylestradiol effects such as nausea or breast tenderness; heavy menstrual bleeding in a patient who wants contraception (the four-phase product); patient preference. Availability must be confirmed before prescribing.

Drospirenone cautions. Contraindicated in severe renal impairment, adrenal insufficiency and significant liver disease. Check potassium in the first cycle for patients taking potassium-sparing diuretics, angiotensin converting enzyme inhibitors, angiotensin receptor blockers, long-term NSAIDs or aldosterone antagonists.

Cyproterone acetate cautions. Venous thrombosis risk is higher than with levonorgestrel; it is used for acne or hirsutism, not as a first contraceptive choice, and withdrawn 3 to 4 cycles after the skin condition settles.

Interactions. Rifampicin, rifabutin, phenytoin, carbamazepine, barbiturates, primidone, topiramate, oxcarbazepine, griseofulvin and St John’s wort reduce effectiveness. Efavirenz, nevirapine and ritonavir-boosted regimens are category 2 and need added condoms. Lamotrigine levels fall.

Counselling points for the clinician. Oestradiol-type pills are not safer by category. Unscheduled bleeding is common in the first cycles of some products. Consent, no coercion, and assent from under 18 years.

Regimen line. Oral, one tablet daily at about the same time.

• Ethinylestradiol pills: 21 active tablets and 7 hormone-free days, or 24 active and 4 inactive tablets.
• Oestradiol-type pills: taken in the order of the pack.
• Start within 5 days of the start of menses with no backup; later starts need 7 days of backup.
• Grace: missing 1 or 2 pills carries little or no risk. Missing 3 or more pills needs 7 days of backup.
• Enzyme inducers: do not use.
• Body weight does not change the dose.
• Postpartum: not before 21 days if not breastfeeding; breastfeeding from 6 months.

Missed pills in 24 active and 4 inactive packs. Missed 1 or 2 active pills: take one now, continue, no backup. Missed 3 or more in the first 2 weeks: take one now, continue, backup 7 days, consider emergency contraception if sex in the last 5 days. Missed 3 or more in the last week of active tablets: finish the active tablets, discard the inactive tablets, start the next pack the next day, backup 7 days, consider emergency contraception. Missing an inactive tablet needs no action.

Dose adjustment for bleeding. After 3 months of correct use, persistent breakthrough bleeding on ethinylestradiol 20 micrograms may be managed by changing to 30 micrograms or by changing the progestin. Do not move to 50 micrograms.

Switching. Between ethinylestradiol and oestradiol-type pills no gap is needed: start the new pack the day after the last active tablet, or at the end of the usual hormone-free interval. From an injectable, start when the next dose is due. From an intrauterine device, start within 5 days of menses and remove the device then.

Follow up. Review at about 3 months and then yearly: blood pressure, weight, smoking, medicines, bleeding. For drospirenone users on interacting medicines, repeat potassium after the first cycle. Reassess from 40 years; at about 50 years a change to a progestin-only or non-hormonal method is usual practice.

Expected effects. Ethinylestradiol pills: nausea, breast tenderness, headache, fluid retention, spotting in the first 3 months. Oestradiol-type pills: unscheduled bleeding in the first 3 cycles that usually declines; shorter, lighter withdrawal bleeding and more amenorrhoea with some products. Drospirenone: acne often improves and fluid retention is uncommon.

Serious complications. Venous thromboembolism, stroke, myocardial infarction, hypertension, hyperkalaemia with drospirenone and interacting medicines, and rarely liver tumours.

Red flags. Severe abdominal pain, chest pain or breathlessness, severe or new headache, eye problems, severe calf pain. Stop and arrange urgent evaluation.

Management. Unscheduled bleeding: exclude pregnancy, infection, missed pills and interactions; reinforce timing; ibuprofen 800 mg orally three times daily for 5 days with food (maximum 2.4 g daily; avoid in renal impairment, active peptic ulcer or significant liver disease; not used in pregnancy); if bleeding persists after 3 months, change the progestin, raise ethinylestradiol from 20 to 30 micrograms, or change method. Hyperkalaemia on drospirenone: stop the pill and manage the potassium.

Referral and escalation. Suspected thrombosis, stroke or myocardial infarction needs emergency transfer. Persistent unexplained bleeding or an undiagnosed breast lump needs evaluation.