Ethinyl estradiol with levonorgestrel

What it is

A combined oral contraceptive pill containing two synthetic hormones: ethinyl estradiol, a synthetic oestrogen, and levonorgestrel, a second-generation progestin. In the product used as the reference label here, one pack holds 28 tablets, of which 21 active tablets each contain levonorgestrel 0.1 mg and ethinyl estradiol 0.02 mg and 7 are inactive placebo tablets. Other brands use the same pair of hormones at 30 or 20 micrograms of ethinyl estradiol and in phasic or extended-cycle arrangements.

What the research says

Its approved job is to prevent pregnancy, mainly by stopping ovulation. Perfect use is very effective and typical use much less so: Trussell's US estimates put first-year pregnancy at 0.3% with perfect use and 9% with typical use. Beyond contraception, the pill is used off-label for period pain, where a 2023 Cochrane review of 21 trials found a moderate pain reduction with high-quality evidence, and long oral-contraceptive use is associated with lower ovarian cancer risk. The costs are real too: it raises venous thrombosis risk, is contraindicated in women over 35 who smoke, and large Danish cohorts link it to small increases in breast cancer diagnoses and antidepressant starts.

Evidence grade: Well established.

How it works

Drug class: Combined hormonal contraceptive (synthetic oestrogen plus second-generation progestin)

The two hormones together suppress the pituitary signals that drive ovulation, so no egg is released. The label states this plainly as the main way the pill works. (Source 1)

Boxed warning

Cigarette smoking increases the risk of serious cardiovascular events from combined hormonal contraceptive (CHC) use. This risk increases with age, particularly in women over 35 years of age, and with the number of cigarettes smoked. For this reason, CHCs, including TYBLUME (levonorgestrel and ethinyl estradiol) tablets, are contraindicated in women who are over 35 years of age and smoke [ see Contraindications (4) and Warnings and Precautions (5.1)].

(Source 2)

What it is used for

• US estimates put first-year pregnancy at 0.3% with perfect use and 9% with typical use. In the reference product's own trial, 1,477 women over 7,720 cycles had 5 pregnancies, a rate of 0.84 per 100 woman-years, including women who did not take it correctly. Evidence: established. (Source 3)
• A 2023 Cochrane review of 21 randomised trials in 3,723 women found combined pills reduce period pain more than placebo, a moderate reduction rated high-quality evidence, at the cost of more irregular bleeding, headache and nausea. Evidence: established. (Source 4)
• A collaborative reanalysis of 45 studies in 23,257 women with ovarian cancer found risk fell by about 29% per 5 years of use in the decade after stopping, with protection lasting more than 30 years. This is observational, so it shows association with long-term use rather than proof of cause, and it is not an approved indication. Evidence: established. (Source 5)
• A Cochrane review of 49 randomised trials concluded the available evidence was insufficient to determine any effect of combination contraceptives on weight, and that no large effect was evident. Evidence: not-supported. (Source 6)

Interactions

• St John's wort (Hypericum perforatum) (pharmacokinetic study): St John's wort speeds the breakdown of the oestrogen in the pill. In a 12-woman crossover study the half-life of ethinyl estradiol roughly halved and breakthrough bleeding rose from 2 of 12 women to 7 of 12. The authors advised adding a barrier method. (Source 7)
• Enzyme-inducing drugs and St John's wort products (regulatory position) (label): The label groups St John's wort with rifampin, carbamazepine, phenytoin and other enzyme inducers that lower pill hormone levels and can cause contraceptive failure or breakthrough bleeding, and says induction potency varies widely by preparation. (Source 8)
• Grapefruit juice and other CYP3A inhibitors (label): Grapefruit juice can raise exposure to the pill's hormones by inhibiting the CYP3A enzyme, and the label notes the strength of that effect depends on brand, concentration and preparation. (Source 9)
• Vitamin C (ascorbic acid) and acetaminophen (paracetamol) (label): Both may raise blood levels of ethinyl estradiol, probably by competing for the same conjugation step that clears it. (Source 9)
• Atorvastatin and rosuvastatin (pharmacokinetic study): Taking either statin with a pill containing ethinyl estradiol raises oestrogen exposure by roughly a fifth to a quarter. (Source 9)
• Hepatitis C combinations containing ombitasvir/paritaprevir/ritonavir (label): This combination is an outright contraindication on the label because of the potential for liver enzyme elevations. Limit: The quoted line is one item in the label's bulleted list of contraindications. The sentence that governs the list, "TYBLUME is contraindicated in females who are known to have the following conditions:", sits at the head of the section and is quoted in the companion block, so this item should be read as a contraindication and not as a free-standing statement. (Source 10)

Stopping it

• Stopping the pill does not appear to delay fertility: a meta-analysis of 22 studies in 14,884 women who discontinued contraception found 83.1% were pregnant within 12 months, and duration of oral contraceptive use did not significantly change that. (Source 11)
• The clotting risk added by the pill fades after it is stopped, according to the 2026 US label; the same section says the risk is highest in the first year of use and when restarting after a break of four weeks or more, so stopping and restarting is not risk-neutral. (Source 12)
• Breast cancer risk did not immediately return to baseline on stopping in the Danish cohort: among women who had used hormonal contraception for 5 years or more, risk after discontinuation remained higher than in never-users. (Source 13)

What goes wrong

In a Danish national cohort the crude venous thromboembolism rate on a levonorgestrel combined pill with 30-40 micrograms of ethinylestradiol was 7.5 per 10,000 user years, against 3.7 per 10,000 in non-users. (Source 14)

• Cohort study, Moderate certainty.
• Size: 8,010,290 women years; 4,246 first venous thromboembolic events included.
• Who: Non-pregnant Danish women aged 15-49 with no history of thrombotic disease, 2001-2009.
• How long: 9 years of registry follow-up.
• Result: Crude incidence per 10,000 user years: non-use 3.7; levonorgestrel combined 7.5 (adjusted RR 2.19, 95% CI 1.74 to 2.75); phasic levonorgestrel 8.4 (2.28, 1.85 to 2.83); norgestimate 6.2 (2.56, 2.18 to 3.01); desogestrel 11.8 (4.21, 3.63 to 4.87); gestodene 11.0 (4.23, 3.87 to 4.63); drospirenone 9.3 (4.47, 3.91 to 5.11); cyproterone 9.0 (4.10, 3.37 to 4.99). In the same table the progestogen-only products were not raised: progestogen-only norethisterone 2.0 (0.56, 0.29 to 1.07), progestogen-only desogestrel 2.1 (0.64, 0.29 to 1.42) and the levonorgestrel releasing intrauterine device 3.5 (0.83, 0.63 to 1.08).
• Funding: Independent (Danish registry study; the European Medicines Agency asked the team for the additional analyses)

Limit of this finding: The raised clotting risk in this table belongs to the combined, oestrogen-containing products. The same table, now quoted in full, shows the progestogen-only pills and the levonorgestrel intrauterine device at adjusted relative risks of 0.56, 0.64 and 0.83 against non-users, none of which is raised. An excerpt that stopped at the combined-pill rows would make the drug class look uniformly risky, which the paper does not say. This is also a registry cohort, so the relative risks are associations adjusted for age, year and education only.

Non-use 4 960 730 1812 3.7 1 (reference) Progestogen with 50 μg ethinylestradiol: Norethisterone 6848 11 16.1 5.66 (3.12 to 10.3) Levonorgestrel 23 691 31 13.1 3.54 (2.48 to 5.05) Progestogen with 30-40 μg ethinylestradiol: Norethisterone 27 355 10 3.7 1.57 (0.84 to 2.92) Phasic levonorgestrel 105 970 89 8.4 2.28 (1.85 to 2.83) Levonorgestrel combined 104 251 78 7.5 2.19 (1.74 to 2.75)

Relative to non-users, confirmed venous thromboembolism risk was about three-fold on levonorgestrel pills and about six-fold on desogestrel, gestodene or drospirenone pills. (Source 15)

• Cohort study, Moderate certainty.
• Size: 8,010,290 women years; 2,847 confirmed events.
• Who: Danish women aged 15-49, 2001-2009.
• How long: 9 years.
• Result: Confirmed VTE relative risk versus non-users: levonorgestrel 2.9 (95% CI 2.2 to 3.8); desogestrel 6.6 (5.6 to 7.8); gestodene 6.2 (5.6 to 7.0); drospirenone 6.4 (5.4 to 7.5).
• Funding: Independent (Danish registry study)

Compared with non-users of hormonal contraception, the relative risk of confirmed venous thromboembolism in users of oral contraceptives containing 30-40 µg ethinylestradiol with levonorgestrel was 2.9 (95% confidence interval 2.2 to 3.8), with desogestrel was 6.6 (5.6 to 7.8), with gestodene was 6.2 (5.6 to 7.0), and with drospirenone was 6.4 (5.4 to 7.5).

The US label states the venous thromboembolism rate in combined-pill users is estimated at 3 to 9 cases per 10,000 woman-years and is highest in the first year of use. (Source 12)

• Official position, Low certainty.
• Size: Not stated; a label summary of the literature.
• Who: Females using combined hormonal contraceptives.
• How long: Highest in the first year of use and when restarting after a break of four weeks or longer.
• Result: 3 to 9 cases per 10,000 woman-years in users; the label adds that 1 to 5 per 10,000 non-pregnant non-users develop a VTE in a year.
• Funding: Regulatory label text (Exeltis USA / US FDA), effective 2026-08-27.

The rate of VTE in females using COCs has been estimated to be 3 to 9 cases per 10,000 woman-years. The risk of VTE is highest during the first year of use of a CHC and when restarting hormonal contraception after a break of four weeks or longer.

In a Danish cohort of 1.8 million women, current or recent hormonal contraception was associated with a 20% higher relative risk of breast cancer and 13 extra cases per 100,000 person-years. (Source 13)

• Cohort study, Moderate certainty.
• Size: 1.8 million women, 19.6 million person-years, 11,517 breast cancers.
• Who: Danish women aged 15 to 49 with no prior cancer, venous thromboembolism or infertility treatment.
• How long: Mean follow-up 10.9 years.
• Result: Relative risk 1.20 (95% CI 1.14 to 1.26), rising from 1.09 (0.96-1.23) under 1 year to 1.38 (1.26-1.51) over 10 years. Absolute increase 13 (95% CI 10 to 16) per 100,000 person-years, about 1 extra breast cancer per 7,690 women using it for a year.
• Funding: Funded by the Novo Nordisk Foundation.

The overall absolute increase in breast cancers diagnosed among current and recent users of any hormonal contraceptive was 13 (95% CI, 10 to 16) per 100,000 person-years, or approximately 1 extra breast cancer for every 7690 women using hormonal contraception for 1 year.

In a Danish cohort of over a million women, combined oral contraceptive users were more likely to start an antidepressant, with the largest relative increase in adolescents. (Source 16)

• Cohort study, Low certainty.
• Size: 1,061,997 women and adolescents aged 15 to 34.
• Who: Danish women with no prior depression diagnosis, antidepressant prescription, major psychiatric diagnosis, cancer, venous thrombosis or infertility treatment.
• How long: Mean follow-up 6.4 years, 2000-2013.
• Result: Rate ratio for first antidepressant use 1.23 (95% CI 1.22-1.25) for combined oral contraceptives overall and 1.8 (95% CI 1.75-1.84) in 15-19 year olds. Risk peaked 6 months after starting at 1.4 (1.34-1.46).
• Funding: Not stated in the abstract.

Limit of this finding: Three faults in the published abstract are reproduced here unchanged. It spells the patch progestin "norgestrolmin"; the drug's name is norelgestromin. It reports a mean age of 24.4 years with a standard deviation of 0.001 and a mean follow-up of 6.4 years with a standard deviation of 0.004, which are not credible standard deviations for a population of a million women and are probably standard errors. And it gives the patch relative risk as 2.0 with a confidence interval of 1.76 to 2.18, which is not centred on 2.0. None of this changes the study's main result, but a reader should treat the precision implied by those figures with caution, and should remember that this is an observational cohort: starting an antidepressant was associated with hormonal contraceptive use, which is not the same as the contraceptive causing depression.

Compared with nonusers, users of combined oral contraceptives had an RR of first use of an antidepressant of 1.23 (95% CI, 1.22-1.25). Users of progestogen-only pills had an RR for first use of an antidepressant of 1.34 (95% CI, 1.27-1.40); users of a patch (norgestrolmin), 2.0 (95% CI, 1.76-2.18); users of a vaginal ring (etonogestrel), 1.6 (95% CI, 1.55-1.69); and users of a levonorgestrel intrauterine system, 1.4 (95% CI, 1.31-1.42). For depression diagnoses, similar or slightly lower estimates were found. The relative risks generally decreased with increasing age. Adolescents (age range, 15-19 years) using combined oral contraceptives had an RR of a first use of an antidepressant of 1.8 (95% CI, 1.75-1.84)

Combined pills used for period pain increase irregular bleeding, headache and nausea. (Source 17)

• Systematic review, Moderate certainty.
• Size: Up to 1,025 women across 7 randomised trials for the adverse-event outcomes.
• Who: Women with primary dysmenorrhoea.
• How long: Trial durations not stated in the abstract; long-term effects were not covered.
• Result: Any adverse event RR 1.31 (95% CI 1.20 to 1.43, moderate quality); irregular bleeding RR 2.63 (2.11 to 3.28, high quality), moving an 18% baseline risk to between 39% and 60%; headache RR 1.51 (1.11 to 2.04); nausea RR 1.64 (1.17 to 2.30).
• Funding: Cochrane review; the authors declare no conflicts of interest.

Women who received OCPs had an increased risk of irregular bleeding compared to women who received placebo or no treatment (RR 2.63, 95% CI 2.11 to 3.28; I² = 29%; 7 RCTs, 1025 women; high-quality evidence). In women with a risk of irregular bleeding of 18% if using placebo or no treatment, the risk would be between 39% and 60% if using combined OCP.

St John's wort shortened the half-life of ethinyl estradiol by about half and roughly tripled the rate of breakthrough bleeding. (Source 7)

• Blood level study, Low certainty.
• Size: 12 healthy premenopausal women.
• Who: Women already using a combined oral contraceptive (ethinyl estradiol with norethindrone) for more than 3 months.
• How long: Three consecutive 28-day cycles, with St John's wort 300 mg three times daily during cycles 2 and 3.
• Result: Ethinyl estradiol half-life fell from 23.4 +/- 19.5 hours to 12.2 +/- 7.1 hours (P=.023); norethindrone oral clearance rose from 8.2 +/- 2.7 to 9.5 +/- 3.4 L/h (P=.042). Breakthrough bleeding in 2 of 12 women in the control phase versus 7 of 12 on St John's wort. FSH, LH and progesterone were unchanged.
• Funding: Not stated in the abstract.

a significant reduction in the half-life of ethinyl estradiol (23.4 +/- 19.5 hours to 12.2 +/- 7.1 hours, P =.023).

The commonly reported adverse reactions of combined oral contraceptives include headache, abdominal pain, nausea, irregular bleeding, thrush, acne and vaginitis. (Source 18)

• Official position, Certainty not rated.
• Size: Not quantifiable; clinical studies plus voluntary postmarketing reports from a population of uncertain size.
• Who: Users of oral combined hormonal contraceptives.
• How long: Not stated.
• Result: No rates are given. The label lists further reported reactions including cholestatic jaundice, change in libido, mood changes, amenorrhoea, breast tenderness, melasma and Budd-Chiari syndrome.
• Funding: Regulatory label text (Exeltis USA / US FDA), effective 2026-08-27.

Common adverse reactions associated with oral CHCs are headache, abdominal pain, nausea, metrorrhagia, vaginal moniliasis and pain, acne, and vaginitis.

Combined hormonal contraceptives raise the risk of arterial events such as myocardial infarction and stroke, most of all in older women who smoke. (Source 19)

• Official position, Low certainty.
• Size: Not stated; a label summary of the literature.
• Who: Women using combined hormonal contraceptives, especially those over 35, smokers, and those with hypertension, dyslipidaemia, diabetes or obesity.
• How long: Not stated.
• Result: No rates are given. The risk is described as greater among women over 35, smokers, and women with hypertension, dyslipidaemia, diabetes or obesity.
• Funding: Regulatory label text (Exeltis USA / US FDA), effective 2026-08-27.

Arterial Events CHCs increase the risk of cardiovascular events and cerebrovascular events, such as myocardial infarction and stroke. The risk is greater among older women (> 35 years of age), smokers, and females with hypertension, dyslipidemia, diabetes, or obesity.

Some studies associate combined hormonal contraceptives with cervical cancer or intraepithelial neoplasia, but the label itself says the finding is contested. (Source 20)

• Official position, Very low certainty.
• Size: Not stated; a label summary of the literature.
• Who: Users of combined hormonal contraceptives.
• How long: Not stated.
• Result: No rates or risk estimates are given. The label records controversy about how far the association reflects differences in sexual behaviour and other factors.
• Funding: Regulatory label text (Exeltis USA / US FDA), effective 2026-08-27.

Some studies suggest that CHCs are associated with an increase in the risk of cervical cancer or intraepithelial neoplasia. There is controversy about the extent to which these findings are due to differences in sexual behavior and other factors.

The label's boxed warning contraindicates the pill in women over 35 who smoke because of serious cardiovascular events. (Source 2)

• Official position, Certainty not rated.
• Size: Not stated; a regulatory position.
• Who: Women using combined hormonal contraceptives, particularly over 35 and smokers.
• How long: Not applicable.
• Result: Risk increases with age, particularly over 35, and with the number of cigarettes smoked; the product is contraindicated in that group.
• Funding: Regulatory label text (Exeltis USA / US FDA), effective 2026-08-27.

Cigarette smoking increases the risk of serious cardiovascular events from combined hormonal contraceptive (CHC) use. This risk increases with age, particularly in women over 35 years of age, and with the number of cigarettes smoked. For this reason, CHCs, including TYBLUME (levonorgestrel and ethinyl estradiol) tablets, are contraindicated in women who are over 35 years of age and smoke [ see Contraindications (4) and Warnings and Precautions (5.1)].

What the evidence supports

First-year pregnancy with the combined pill is estimated at 0.3% with perfect use and 9% with typical use in the United States. (Source 3)

• Systematic review, Moderate certainty.
• Size: National Survey of Family Growth data plus surveys and clinical investigations; the review covers all US methods.
• Who: Women using contraception in the United States.
• How long: First year of use.
• Result: Combined pill and progestin-only pill: typical use 9%, perfect use 0.3%, 67% continuing at one year. For comparison, no method is 85%.
• Funding: Independent (NICHD grant R24 HD047879, Princeton Office of Population Research)

Limit of this finding: This is a table, and reading it needs the column order. Each row gives, in order: the method, the percentage of women who have an unintended pregnancy in the first year of typical use, the percentage who do so in the first year of perfect use, and the percentage still using the method after one year. Blank cells mean Trussell published no estimate for that cell, not zero. So "Fertility awareness-based methods | 24 | | 47" means 24% with typical use, no published perfect-use figure, and 47% still using it at a year; and "Sponge | | | 36" gives only a continuation rate of 36%, with the sponge's own failure rates appearing in the two rows beneath it for parous and nulliparous women. A reader should not read the last number in a row as a failure rate.

Method | % of women experiencing an unintended pregnancy within the first year of use | % of women continuing use at one year | Typical use | Perfect use | Column (1) | Column (2) | Column (3) | Column (4) No method | 85 | 85 | Spermicides | 28 | 18 | 42 Fertility awareness-based methods | 24 | | 47 Standard Days method | | 5 | TwoDay method | | 4 | Ovulation method | | 3 | Symptothermal method | | 0.4 | Withdrawal | 22 | 4 | 46 Sponge | | | 36 Parous women | 24 | 20 | Nulliparous women | 12 | 9 | Condom Female (fc) | 21 | 5 | 41 Male | 18 | 2 | 43 Diaphragm | 12 | 6 | 57 Combined pill and progestin-only pill | 9 | 0.3 | 67

In the reference product's own registration trial the overall pregnancy rate was 0.84 per 100 woman-years, including cycles in which tablets were missed. (Source 21)

• Randomized trial, Low certainty.
• Size: 1,477 subjects, 7,720 cycles of use, 5 pregnancies.
• Who: Women of reproductive potential taking levonorgestrel 0.1 mg with ethinyl estradiol 0.02 mg.
• How long: Up to 7,870 cycles recorded.
• Result: Overall pregnancy rate 0.84 per 100 woman-years. One or more tablets were missed in 1,479 (19%) of the 7,870 cycles.
• Funding: Manufacturer trial data reproduced in the FDA label (Exeltis USA)

1,477 subjects had 7,720 cycles of use and a total of 5 pregnancies were reported. This represented an overall pregnancy rate of 0.84 per 100 woman-years.

Long oral contraceptive use is associated with a substantial, long-lasting reduction in ovarian cancer risk. (Source 5)

• Meta-analysis, Moderate certainty.
• Size: 23,257 women with ovarian cancer and 87,303 controls from 45 studies in 21 countries.
• Who: Women in epidemiological studies, median year of diagnosis 1993.
• How long: Average duration of use 4.4 to 5.0 years; follow-up more than 30 years after stopping.
• Result: Proportional risk reduction per 5 years of use: 29% (95% CI 23-34%) if use ceased less than 10 years previously, 19% (14-24%) at 10-19 years and 15% (9-21%) at 20-29 years. Ten years of use was estimated to cut incidence before age 75 from 1.2 to 0.8 per 100 users and mortality from 0.7 to 0.5 per 100.
• Funding: Independent (Cancer Epidemiology Unit, Oxford)

the proportional risk reductions per 5 years of use were 29% (95% CI 23-34%) for use that had ceased less than 10 years previously, 19% (14-24%) for use that had ceased 10-19 years previously, and 15% (9-21%) for use that had ceased 20-29 years previously. Use during the 1960s, 1970s, and 1980s was associated with similar proportional risk reductions, although typical oestrogen doses in the 1960s were more than double those in the 1980s. The incidence of mucinous tumours (12% of the total) seemed little affected by oral contraceptives, but otherwise the proportional risk reduction did not vary much between different histological types. In high-income countries, 10 years use of oral contraceptives was estimated to reduce ovarian cancer incidence before age 75 from 1.2 to 0.8 per 100 users and mortality from 0.7 to 0.5 per 100; for every 5000 woman-years of use, about two ovarian cancers and one death from the disease before age 75 are prevented.

Combined pills reduce period pain more than placebo, with high-quality evidence for the pain-score outcome. (Source 4)

• Systematic review, High certainty.
• Size: 21 randomised trials, 3,723 women; 588 women in the 6 trials pooled for the pain score.
• Who: Women with primary dysmenorrhoea diagnosed by excluding pelvic pathology.
• How long: Not stated in the abstract; long-term effects were not covered by the review.
• Result: Standardised mean difference -0.58 (95% CI -0.74 to -0.41; I2 = 28%), described as a moderate reduction in pain, high-quality evidence. Dichotomous improvement RR 1.65 (1.29 to 2.10), low-quality evidence.
• Funding: Cochrane review; the authors declare no conflicts of interest.

the result can be interpreted as a moderate reduction in pain (standardised mean difference (SMD) -0.58, 95% confidence interval (CI) -0.74 to -0.41; I² = 28%; 6 RCTs, 588 women; high-quality evidence).

What the evidence does not support

Randomised evidence does not support the common belief that combined contraceptives cause weight gain. (Source 6)

• Systematic review, Low certainty.
• Size: 49 trials with 85 weight-change comparisons across 52 contraceptive pairs.
• Who: Women in randomised trials of at least three treatment cycles.
• How long: At least three cycles per trial.
• Result: The four trials with a placebo or no-intervention group found no evidence of a causal association; most comparisons showed no substantial difference. The review states the evidence was insufficient to determine the effect but no large effect was evident.
• Funding: Cochrane review; one author has consulted for Bayer Healthcare Pharmaceuticals and Merck, another has supervised studies sponsored by oral contraceptive manufacturers.

The four trials with a placebo or no intervention group did not find evidence supporting a causal association between combination oral contraceptives or a combination skin patch and weight change. Most comparisons of different combination contraceptives showed no substantial difference in weight. In addition, discontinuation of combination contraceptives because of weight change did not differ between groups where this was studied. AUTHORS' CONCLUSIONS: Available evidence was insufficient to determine the effect of combination contraceptives on weight, but no large effect was evident.

Where the evidence is mixed

In the same Danish cohort the progestogen-only products, which contain no oestrogen, showed no raised venous thromboembolism risk, while almost every oestrogen-containing combined product in the same table did, which locates the raised risk with the oestrogen component rather than with hormonal contraception in general. (Source 14)

• Cohort study, Moderate certainty.
• Size: 8,010,290 women years; 4,246 first venous thromboembolic events included.
• Who: Non-pregnant Danish women aged 15-49 with no history of thrombotic disease, 2001-2009.
• How long: 9 years of registry follow-up.
• Result: Adjusted relative risk against non-users: progestogen-only norethisterone 0.56 (95% CI 0.29 to 1.07) at a crude 2.0 per 10,000 user years; progestogen-only desogestrel 0.64 (0.29 to 1.42) at 2.1; levonorgestrel releasing intrauterine device 0.83 (0.63 to 1.08) at 3.5. Non-use was 3.7 per 10,000 user years. Every one of those three intervals includes 1, so none is a raised risk. The oestrogen-containing combined products in the same table run from 1.57 (0.84 to 2.92) for norethisterone with 30-40 micrograms ethinylestradiol up to 5.66 (3.12 to 10.3) for norethisterone with 50 micrograms; all of them except that lowest row exclude 1.
• Funding: Independent (Danish registry study; the European Medicines Agency asked the team for the additional analyses)

Limit of this finding: One combined row is an exception: norethisterone with 30-40 micrograms ethinylestradiol has a relative risk of 1.57 with an interval of 0.84 to 2.92, which includes 1, so that one product is not shown to raise risk in this cohort either. The contrast between oestrogen-containing and progestogen-only products is a pattern across the table, not a rule without exceptions.

Progestogen only: Norethisterone 44 168 9 2.0 0.56 (0.29 to 1.07) Desogestrel 29 187 6 2.1 0.64 (0.29 to 1.42) Levonorgestrel releasing intrauterine device 155 149 55 3.5 0.83 (0.63 to 1.08)

Where the research disagrees

Whether combined oral contraceptives cause weight gain

• Gallo and colleagues, 2014 Cochrane review, systematic review of 49 randomised trials: AUTHORS' CONCLUSIONS: Available evidence was insufficient to determine the effect of combination contraceptives on weight, but no large effect was evident. (Source 6)
• Schroll and colleagues, 2023 Cochrane review of the pill for dysmenorrhoea, systematic review; a single 76-woman trial: We are uncertain of the effect of OCP on weight gain (RR 1.83, 95% CI 0.75 to 4.45; 1 RCT, 76 women; low-quality evidence). (Source 17)

How much the absolute venous thromboembolism risk differs between progestin generations

• Lidegaard and colleagues, Danish national cohort, national registry cohort: With users of oral contraceptives with levonorgestrel as reference and after adjusting for length of use, the rate ratio of confirmed venous thromboembolism for users of oral contraceptives with desogestrel was 2.2 (1.7 to 3.0), with gestodene was 2.1 (1.6 to 2.8), and with drospirenone was 2.1 (1.6 to 2.8). (Source 15)
• The same authors reporting that other studies disagreed, the authors' own absolute-risk framing of the same cohort: If oral contraceptives with desogestrel, gestodene, or drospirenone are anticipated to increase the risk of venous thromboembolism sixfold and those with levonorgestrel threefold, and the absolute risk of venous thromboembolism in current users of the former group is on average 10 per 10 000 women years, then 2000 women would need to shift from using oral contraceptives with desogestrel, gestodene, or drospirenone to those with levonorgestrel to prevent one event of venous thromboembolism in one year. (Source 15)

How much

• Reference intake: Dosing is set by the prescriber, not by the reader. As a regulatory position, the 2026 label for the reference product describes a 28-tablet pack in which 21 active tablets each contain levonorgestrel 0.1 mg and ethinyl estradiol 0.02 mg and 7 are inactive. (Source 22)
• Upper limit: No upper intake level applies to a prescription contraceptive. The label sets the regimen rather than a maximum: one active tablet a day for 21 days followed by 7 inactive tablets, and it is contraindicated outright in several groups including women over 35 who smoke. (Source 23)
• Studied: The reference product's registration trial gave levonorgestrel 0.1 mg with ethinyl estradiol 0.02 mg to 1,477 subjects over 7,720 cycles. (Source 21)
• Studied: The Danish venous thromboembolism cohort compared products containing 50, 30-40 and 20 micrograms of ethinylestradiol with different progestogens. (Source 14)
• Studied: The St John's wort interaction study used a combined pill containing ethinyl estradiol with norethindrone alongside St John's wort 300 mg three times daily. (Source 24)

A common belief, and what the research shows

The belief: The pill is 99% effective, so in practice almost nobody on it gets pregnant.

What the research shows: That figure describes perfect use. Trussell's US table gives 0.3% first-year pregnancy with perfect use but 9% with typical use, and only 67% of users are still on the method at one year: "Combined pill and progestin-only pill | 9 | 0.3 | 67" (the columns are typical use, perfect use and the percentage still using the method at one year). The reference product's own trial, which included women who missed tablets, reported 0.84 pregnancies per 100 woman-years.

Questions and answers

What is it?

It is a daily tablet containing two synthetic hormones: ethinyl estradiol, a synthetic oestrogen, and levonorgestrel, a progestin. A typical pack has 21 active tablets and 7 inactive ones. In the reference product each active tablet holds levonorgestrel 0.1 mg and ethinyl estradiol 0.02 mg. Its only approved use in the United States is preventing pregnancy. (Source 22)

What does it do in the body?

The two hormones suppress the signals that trigger ovulation, so no egg is released. The label states this is the main way the pill works. Secondary effects on cervical mucus and the womb lining are often described, but ovulation suppression is what the label names. (Source 1)

Is it good or bad for you?

Both, and which dominates depends on who is taking it. For contraception it is highly effective when taken consistently, 0.3% first-year pregnancy with perfect use against 9% with typical use, and long use is associated with substantially less ovarian cancer. Against that, it raises venous thrombosis risk from about 3.7 to about 7.5 events per 10,000 user years for a levonorgestrel pill, is linked to a small rise in breast cancer diagnoses and antidepressant starts, and carries a boxed warning making it contraindicated in women over 35 who smoke. (Source 14)

How do you get more of it?

It is a prescription medicine, not a nutrient, so the only route is a prescription and the schedule is set by the prescriber. No food or supplement contains it. Some drugs raise its hormone levels: atorvastatin or rosuvastatin raise ethinyl estradiol exposure by about 20 to 25 percent, and vitamin C and paracetamol may raise it too. This is description, not advice. (Source 9)

If it is harmful, what reduces it?

Levels fall when the tablets stop, and the added clotting risk fades after discontinuation according to the label. Several substances lower the hormones while they are still being taken, which reduces contraceptive protection rather than being a benefit: enzyme inducers including St John's wort products, rifampin, carbamazepine and topiramate, and colesevelam, which should be separated by four or more hours. (Source 8)

Why might someone be low in it or missing it?

Nobody is deficient in it, because it is a medicine rather than something the body makes. What the literature covers is why someone cannot or should not take it. The label contraindicates it in women over 35 who smoke, in current or past deep vein thrombosis or pulmonary embolism, cerebrovascular or coronary artery disease, inherited or acquired clotting disorders, uncontrolled hypertension, migraine with aura, current or past breast cancer, and several liver conditions. (Source 23)

Which whole foods contain it or feed it?

No whole food contains these hormones. The only food-related entries in the label are grapefruit juice, which can raise exposure by inhibiting CYP3A, and vitamin C, which may raise ethinyl estradiol levels by competing for conjugation. There is no documented food that supplies or substitutes for the pill. (Source 9)

What happens if you do not have it?

Without contraception the first-year pregnancy rate in the same US table is 85%. Stopping also removes the non-contraceptive effects in both directions: the ovarian cancer protection fades slowly over decades rather than vanishing, and period pain treated with the pill would be expected to return. Fertility itself is not harmed: 83.1% of women who stopped contraception were pregnant within 12 months. (Source 11)

How can you test for it?

There is no routine blood test to check whether the pill is working; effectiveness is judged by whether pregnancy occurs, which is how the trials measured it. The label does warn that the pill changes several laboratory results, so tests taken while on it need interpreting with that in mind: coagulation factors, lipids, glucose tolerance and binding proteins can all shift. (Source 25)

References

1. Exeltis USA, Inc. / DailyMed (U.S. FDA Structured Product Label, effective 2026-08-27). TYBLUME (levonorgestrel and ethinyl estradiol) tablets - 12.1 Mechanism of Action (Full Prescribing Information). 2026. Read the source
2. Exeltis USA, Inc. / DailyMed (U.S. FDA Structured Product Label, effective 2026-08-27). TYBLUME (levonorgestrel and ethinyl estradiol) tablets - BOXED WARNING: CIGARETTE SMOKING AND SERIOUS CARDIOVASCULAR EVENTS (Full Prescribing Information). 2026. Read the source
3. Contraception. Contraceptive failure in the United States. Table 1 (label, caption, column headings and all body rows).. 2011. PMID 21477680, DOI 10.1016/j.contraception.2011.01.021. Read the source
4. Cochrane Database of Systematic Reviews. Combined oral contraceptive pill for primary dysmenorrhoea.. 2023. PMID 37523477, DOI 10.1002/14651858.CD002120.pub4. Read the source
5. The Lancet. Ovarian cancer and oral contraceptives: collaborative reanalysis of data from 45 epidemiological studies including 23,257 women with ovarian cancer and 87,303 controls.. 2008. PMID 18294997, DOI 10.1016/S0140-6736(08)60167-1. Read the source
6. Cochrane Database of Systematic Reviews. Combination contraceptives: effects on weight.. 2014. PMID 24477630, DOI 10.1002/14651858.CD003987.pub5. Read the source
7. Clinical Pharmacology and Therapeutics. The interaction between St John's wort and an oral contraceptive. [RESULTS]. 2003. PMID 14663455, DOI 10.1016/j.clpt.2003.08.009. Read the source
8. Exeltis USA, Inc. / DailyMed (U.S. FDA Structured Product Label, effective 2026-08-27). TYBLUME (levonorgestrel and ethinyl estradiol) tablets - 7.1 Effects of Other Drugs on Combined Hormonal Contraceptives, Table 3 metabolic enzyme inducers. 2026. Read the source
9. Exeltis USA, Inc. / DailyMed (U.S. FDA Structured Product Label, effective 2026-08-27). TYBLUME (levonorgestrel and ethinyl estradiol) tablets - 7.1 Effects of Other Drugs on Combined Hormonal Contraceptives, substances increasing the systemic exposure of CHCs. 2026. Read the source
10. Exeltis USA, Inc. / DailyMed (U.S. FDA Structured Product Label, effective 2026-08-27). TYBLUME (levonorgestrel and ethinyl estradiol) tablets - 4 CONTRAINDICATIONS, remaining conditions including hepatitis C combinations. 2026. Read the source
11. Contraception and Reproductive Medicine. Return of fertility after discontinuation of contraception: a systematic review and meta-analysis. [RESULTS]. 2018. PMID 30062044, DOI 10.1186/s40834-018-0064-y. Read the source
12. Exeltis USA, Inc. / DailyMed (U.S. FDA Structured Product Label, effective 2026-08-27). TYBLUME (levonorgestrel and ethinyl estradiol) tablets - 5.1 Thromboembolic Disorders and Other Vascular Problems, Venous Events. 2026. Read the source
13. New England Journal of Medicine. Contemporary Hormonal Contraception and the Risk of Breast Cancer.. 2017. PMID 29211679, DOI 10.1056/NEJMoa1700732. Read the source
14. BMJ. Risk of venous thromboembolism from use of oral contraceptives containing different progestogens and oestrogen doses: Danish cohort study, 2001-9. Table 2.. 2011. PMID 22027398, DOI 10.1136/bmj.d6423. Read the source
15. BMJ. Risk of venous thromboembolism from use of oral contraceptives containing different progestogens and oestrogen doses: Danish cohort study, 2001-9. Abstract.. 2011. PMID 22027398, DOI 10.1136/bmj.d6423. Read the source
16. JAMA Psychiatry. Association of Hormonal Contraception With Depression.. 2016. PMID 27680324, DOI 10.1001/jamapsychiatry.2016.2387. Read the source
17. Cochrane Database of Systematic Reviews. Combined oral contraceptive pill for primary dysmenorrhoea. Adverse events reported in MAIN RESULTS.. 2023. PMID 37523477, DOI 10.1002/14651858.CD002120.pub4. Read the source
18. Exeltis USA, Inc. / DailyMed (U.S. FDA Structured Product Label, effective 2026-08-27). TYBLUME (levonorgestrel and ethinyl estradiol) tablets - 6 ADVERSE REACTIONS (Full Prescribing Information). 2026. Read the source
19. Exeltis USA, Inc. / DailyMed (U.S. FDA Structured Product Label, effective 2026-08-27). TYBLUME (levonorgestrel and ethinyl estradiol) tablets - 5.1 Thromboembolic Disorders and Other Vascular Problems, Arterial Events (Warnings and Precautions). 2026. Read the source
20. Exeltis USA, Inc. / DailyMed (U.S. FDA Structured Product Label, effective 2026-08-27). TYBLUME (levonorgestrel and ethinyl estradiol) tablets - 5.10 Cervical Cancer (Warnings and Precautions). 2026. Read the source
21. Exeltis USA, Inc. / DailyMed (U.S. FDA Structured Product Label, effective 2026-08-27). TYBLUME (levonorgestrel and ethinyl estradiol) tablets - 14 CLINICAL STUDIES (Full Prescribing Information). 2026. Read the source
22. Exeltis USA, Inc. / DailyMed (U.S. FDA Structured Product Label, effective 2026-08-27). TYBLUME (levonorgestrel and ethinyl estradiol) tablets - 3 DOSAGE FORMS AND STRENGTHS (Full Prescribing Information). 2026. Read the source
23. Exeltis USA, Inc. / DailyMed (U.S. FDA Structured Product Label, effective 2026-08-27). TYBLUME (levonorgestrel and ethinyl estradiol) tablets - 4 CONTRAINDICATIONS (Full Prescribing Information). 2026. Read the source
24. Clinical Pharmacology and Therapeutics. The interaction between St John's wort and an oral contraceptive. [METHODS]. 2003. PMID 14663455, DOI 10.1016/j.clpt.2003.08.009. Read the source
25. Exeltis USA, Inc. / DailyMed (U.S. FDA Structured Product Label, effective 2026-08-27). TYBLUME (levonorgestrel and ethinyl estradiol) tablets - 7.3 Effect on Laboratory Tests (Drug Interactions). 2026. Read the source