Drospirenone and ethinyl estradiol

What it is

A daily tablet containing two synthetic hormones: ethinyl estradiol, a synthetic oestrogen, and drospirenone, a progestin derived from spironolactone. Marketed doses are drospirenone 3 mg with either ethinyl estradiol 0.02 mg (Yaz and generics, 24 active plus 4 inert tablets) or 0.03 mg (Yasmin and generics, 21 active plus 7 inert). Drospirenone is unlike older progestins in that it blocks the mineralocorticoid (aldosterone) receptor and the androgen receptor. Some versions also contain levomefolate calcium (a folate salt).

What the research says

The evidence that it prevents pregnancy is strong, and the trial Pearl Index for the 3 mg/0.02 mg product was 1.41 pregnancies per 100 woman-years. Two placebo-controlled trials support it for premenstrual dysphoric disorder over three cycles, and placebo-controlled trials support it for moderate acne, though the Cochrane reviews of both note the placebo effect was large and that there is little evidence it beats other combined pills. The live argument in the literature is thrombosis: registry cohorts and a Cochrane network meta-analysis put the venous clot risk roughly 1.5 to 2 times that of levonorgestrel pills, while two industry-run prospective cohorts found no difference. Absolute risk stays low either way, roughly 10 events per 10,000 woman-years in the higher-risk group by the Danish estimate.

Evidence grade: Well established.

How it works

Drug class: Combined oral contraceptive: a synthetic oestrogen (ethinyl estradiol) plus drospirenone, a spironolactone-derived progestin with anti-mineralocorticoid and anti-androgenic activity

The oestrogen and progestin together switch off the hormonal signals that trigger ovulation, so no egg is released; the label says combined pills work 'primarily by suppressing ovulation'. Drospirenone is the distinctive part: it is built from spironolactone and blocks the aldosterone receptor, which is why it does not cause the fluid retention older progestins do, and why it can push potassium up. It also blocks androgen receptors, which is the pharmacological basis for the acne effect. (Source 1)

Boxed warning

Cigarette smoking increases the risk of serious cardiovascular events from combination oral contraceptives (COC) use. This risk increases with age, particularly in women over 35 years of age, and with the number of cigarettes smoked. For this reason, COCs should not be used by women who are over 35 years of age and smoke [see Contraindications (4)].

(Source 2)

What it is used for

• A one-year open-label trial of 1,027 women completing 11,480 cycles gave a Pearl Index of 1.41 pregnancies per 100 woman-years (95% CI 0.73 to 2.47). Women with a BMI over 35 were excluded, so the trial does not speak to that group. Evidence: established. (Source 3)
• Two placebo-controlled trials of drospirenone 3 mg plus ethinyl estradiol 20 micrograms found less severe premenstrual symptoms after three months than placebo (mean difference -7.92, 95% CI -11.16 to -4.67), but the Cochrane review states the placebo effect was also large and that nothing is known beyond three cycles, in milder symptoms, or against other pills. The label itself says effectiveness beyond three cycles has not been evaluated and that it has not been evaluated for premenstrual syndrome. Evidence: limited. (Source 4)
• In two placebo-controlled trials pooled by Cochrane, investigator assessment of clear or almost clear skin favoured drospirenone (OR 3.02, 95% CI 1.99 to 4.59). The same review concluded that few important and consistent differences were found between pill types, and that how pills compare with other acne treatments is unknown because only one trial looked. Evidence: limited. (Source 5)
• A collaborative reanalysis of 45 epidemiological studies (23,257 cases) found longer oral contraceptive use was associated with greater reduction in ovarian cancer risk, with the protection persisting over 30 years after stopping. This is observational, is about oral contraceptives as a class rather than drospirenone specifically, and is not an approved indication. Evidence: limited. (Source 6)
• Three trials of drospirenone 3 mg plus ethinyl estradiol 30 micrograms in less severe symptoms did not answer the question: one placebo-controlled six-month trial had insufficient data, and a two-year trial found symptoms similar to a desogestrel comparator (OR 0.87, 95% CI 0.63 to 1.22). The label states it has not been evaluated for PMS. Evidence: unknown. (Source 4)
• The Cochrane review of 49 trials of combined contraceptives and weight found the placebo-controlled trials did not support a causal association with weight change in either direction, and concluded the available evidence was insufficient to determine an effect but that no large effect was evident. Evidence: not-supported. (Source 7)

Interactions

• Potassium supplements, potassium-sparing diuretics (including spironolactone), ACE inhibitors, angiotensin-II receptor antagonists, aldosterone antagonists, heparin and NSAIDs (label): Drospirenone blocks the aldosterone receptor and spares potassium, so taken with these it can push serum potassium up. The label puts the anti-mineralocorticoid effect of the 3 mg dose on a par with 25 mg of spironolactone and says potassium should be checked in the first cycle in women on long-term treatment with these drugs. (Source 8)
• Potassium (the clinical hyperkalaemia signal itself) (clinical trial): The largest comparative-safety study, 1.1 million oral contraceptive users, did not find a clinically significant hyperkalaemia signal for drospirenone against levonorgestrel, while norethindrone and norgestimate pills did show small increases. Being prescribed spironolactone alongside drospirenone was over twice as common as alongside levonorgestrel, and only 6.5 percent of those women had a potassium test. (Source 9)
• St John's wort (Hypericum perforatum) (pharmacokinetic study): St John's wort induces drug-metabolising enzymes and speeds clearance of the pill's hormones. In a 16-woman crossover study, 300 mg three times daily cut hormone exposure by 13 to 15 percent and was followed by breakthrough bleeding, follicle growth and probable ovulation - that is, loss of contraceptive reliability. (Source 10)
• Enzyme-inducing drugs and herbal products (phenytoin, barbiturates, carbamazepine, bosentan, felbamate, griseofulvin, oxcarbazepine, rifampin, topiramate, St John's wort) (label): These speed up breakdown of the pill's hormones, which can cause breakthrough bleeding or contraceptive failure. The label advises a back-up method, continued for 28 days after the inducer stops. (Source 11)
• Grapefruit juice (and moderate or strong CYP3A4 inhibitors such as ketoconazole, itraconazole, voriconazole, fluconazole, clarithromycin, erythromycin, verapamil, diltiazem) (pharmacokinetic study): These slow the breakdown of the pill's hormones, so blood levels of the oestrogen, the progestin or both can rise. In a formal interaction study, ketoconazole 200 mg twice daily for 10 days moderately raised drospirenone exposure. Because higher drospirenone exposure means more anti-mineralocorticoid effect, the label links this to potassium monitoring in high-risk women. (Source 11)
• Vitamin C (ascorbic acid) and paracetamol/acetaminophen (pharmacokinetic study): Both compete with ethinyl estradiol for the same sulphation pathway, so high doses can raise blood levels of the oestrogen. The label records the effect; a pharmacokinetics review says it could matter for women regularly taking high doses of either. (Source 12)
• Atorvastatin (pharmacokinetic study): Co-administration raised the area under the curve for ethinyl estradiol by about 20 percent in certain combined pills containing it. (Source 11)
• Broad-spectrum antibiotics (other than enzyme inducers such as rifampin) (case reports): Pregnancies have been reported in women taking both, and the belief is widespread, but formal pharmacokinetic studies have not shown a consistent effect on hormone levels. A pharmacokinetics review calls the case-report evidence real but notes no firm pharmacokinetic evidence, and suggests any at-risk individual would be unusual. (Source 12)
• Antacids and adsorbents (magnesium trisilicate, aluminium hydroxide, activated charcoal, kaolin) (theoretical): In theory these could bind the hormones in the gut and reduce absorption, but a pharmacokinetics review states there is no firm evidence they do. This is one of the interactions the literature does not support. (Source 12)
• Hepatitis C combination therapy containing ombitasvir/paritaprevir/ritonavir, and HIV/HCV protease inhibitors and non-nucleoside reverse transcriptase inhibitors (label): Plasma hormone levels can shift substantially in either direction with these antivirals; the label also carries a separate warning about liver enzyme elevations with certain hepatitis C regimens. (Source 11)
• Alcohol (theoretical): Neither the US label section on drug interactions nor the pharmacokinetics review we read documents an interaction between alcohol and this pill. The quote below is that review's own negative-findings passage, which lists what it could not substantiate (adsorbents, smoking); alcohol is not among the interactions it documents at all. We found no pharmacokinetic or outcome study of alcohol with drospirenone/ethinyl estradiol, so treat this as an absence of evidence rather than evidence of absence. (Source 12)

Stopping it

• Pooled observational data on stopping contraception found most women conceive within a year, and that neither the type of progestin nor how long the pill was taken significantly changed how quickly fertility returned. (Source 13)
• There is no dependence or withdrawal syndrome described for combined pills. What the label does say about restarting matters: the extra clot risk is greatest when a pill is first started or restarted after a break of four weeks or more, so stopping and restarting repeatedly is not risk-neutral. (Source 14)
• If a clot occurs, the label's instruction is to stop the drug rather than taper it. (Source 15)
• The protective association with ovarian cancer in pooled observational data did not vanish when women stopped: it persisted more than 30 years after use ceased, though it weakened over time. (Source 6)

What goes wrong

A Cochrane network meta-analysis of 26 studies found all combined pills raised venous thrombosis risk versus non-use, with drospirenone about 50 to 80 percent higher than levonorgestrel at the same oestrogen dose. (Source 16)

• Systematic review, Moderate certainty.
• Size: 25 publications reporting 26 studies, screened from 3,110 records.
• Who: healthy women taking combined oral contraceptives.
• How long: varies by included study.
• Result: combined pills versus non-use RR 3.5 (95% CI 2.9 to 4.3); background incidence in non-users from two cohorts 0.19 and 0.37 per 1,000 person-years; drospirenone, gestodene, desogestrel and cyproterone acetate at 30-35 micrograms ethinylestradiol about 50-80% higher than levonorgestrel.
• Funding: no specific funding; one author supported by a Netherlands Organization for Scientific Research grant, another by Capes-Nuffic Brazil; authors declared no financial conflicts.

Use of combined oral contraceptives increased the risk of venous thrombosis compared with non-use (relative risk 3.5, 95% confidence interval 2.9 to 4.3). The relative risk of venous thrombosis for combined oral contraceptives with 30-35 μg ethinylestradiol and gestodene, desogestrel, cyproterone acetate, or drospirenone were similar and about 50-80% higher than for combined oral contraceptives with levonorgestrel. A dose related effect of ethinylestradiol was observed for gestodene, desogestrel, and levonorgestrel, with higher doses being associated with higher thrombosis risk.

A Danish national registry cohort of 8 million woman-years put the absolute venous thromboembolism risk in the higher-risk progestin group at about 10 per 10,000 woman-years, and found no increase with progestogen-only pills or hormone-releasing intrauterine devices. (Source 17)

• Cohort study, Moderate certainty.
• Size: 8,010,290 woman-years of observation; 4,246 first venous thromboembolic events included, 2,847 confirmed.
• Who: non-pregnant Danish women aged 15-49 with no history of thrombotic disease.
• How long: January 2001 to December 2009.
• Result: versus non-users: levonorgestrel RR 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); drospirenone versus levonorgestrel rate ratio 2.1 (1.6 to 2.8) after adjusting for length of use; absolute risk about 10 per 10,000 woman-years; 2,000 women would need to switch to prevent one event in a year.
• Funding: Bayer Schering Pharma covered the expenses of the analysis (paid to Rigshospitalet); the lead author disclosed speaker fees including from Bayer Pharma Denmark and that he would be an expert witness for plaintiffs in a US legal case.

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). 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). The risk of confirmed venous thromboembolism was not increased with use of progestogen only pills or hormone releasing intrauterine devices. 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.

A WHO-funded systematic review and meta-analysis of 22 articles found drospirenone pills carried a significantly increased venous thromboembolism risk versus levonorgestrel pills, with pooled risk ratios in the 1.5 to 2.0 range, and called the increase small. (Source 18)

• Meta-analysis, Low certainty.
• Size: 22 articles.
• Who: healthy users of low-dose (under 50 micrograms ethinyl estradiol) combined oral contraceptives.
• How long: varies by included study.
• Result: pooled adjusted risk ratios 1.5-2.0 for cyproterone acetate, desogestrel, drospirenone or gestodene versus levonorgestrel; similar when restricted to monophasic 30 microgram formulations; estimates slightly attenuated after adjusting for study characteristics.
• Funding: World Health Organization.

Limit of this finding: The quotation reproduces the journal’s text exactly, including an unusual non-breaking space character inside "30 μg of ethinyl estradiol". That is a typesetting artefact of the source and carries no meaning.

The use of COCs containing cyproterone acetate, desogestrel, drospirenone, or gestodene was associated with a significantly increased risk of VTE compared with the use of levonorgestrel-containing COCs (pooled risk ratios 1.5-2.0). The analysis restricted to monophasic COC formulations with 30 μg of ethinyl estradiol yielded similar findings. After adjustment for study characteristics, the risk estimates were slightly attenuated. CONCLUSIONS: Compared with the use of levonorgestrel-containing COCs, the use of COCs containing other progestogens could be associated with a small increase in risk for VTE.

A Danish national cohort of over a million women found hormonal contraception associated with later antidepressant use and a first hospital diagnosis of depression, with the largest relative risks in adolescents. (Source 19)

• Cohort study, Low certainty.
• Size: 1,061,997 women and adolescents; mean follow-up 6.4 years.
• Who: women aged 15-34 living in Denmark with no prior depression diagnosis, antidepressant prescription, other major psychiatric diagnosis, cancer, venous thrombosis or infertility treatment.
• How long: followed from 1 January 2000 to December 2013.
• Result: combined oral contraceptives versus non-users, first antidepressant use rate ratio 1.23 (95% CI 1.22-1.25); adolescents aged 15-19 on combined pills 1.8 (1.75-1.84); risk ratio peaked at 1.4 (1.34-1.46) six months after starting; 1.7 (1.66-1.71) when the reference was never-users.
• Funding: not stated.

Limit of this finding: The quotation keeps two oddities of the published abstract: the patch progestin is misspelled "norgestrolmin" (the drug is norelgestromin), and the participant count is printed with narrow non-breaking spaces. Both are the journal’s, not errors of transcription. This is also an observational cohort: it shows an association between hormonal contraception and later antidepressant use, not that the contraception caused 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) and those using progestin-only pills, 2.2 (95% CI, 1.99-2.52). Six months after starting use of hormonal contraceptives, the RR of antidepressant use peaked at 1.4 (95% CI, 1.34-1.46). When the reference group was changed to those who never used hormonal contraception, the RR estimates for users of combined oral contraceptives increased to 1.7 (95% CI, 1.66-1.71). CONCLUSIONS AND RELEVANCE: Use of hormonal contraception, especially among adolescents, was associated with subsequent use of antidepressants and a first diagnosis of depression, suggesting depression as a potential adverse effect of hormonal contraceptive use.

In the manufacturer’s pooled contraception and acne trials, the commonest adverse reactions were headache or migraine in 6.7 percent, nausea or vomiting in 4.2 percent, breast pain in 4 percent and mood changes in 2.2 percent, with a 4.7 percent figure attached to menstrual irregularities. (Source 20)

• Randomized trial, Low certainty.
• Size: pooled dataset of 1,056 contraception and 536 acne participants who took at least one dose.
• Who: women aged 14-45 in the registration trials.
• How long: up to 1 year (contraception) and up to 6 cycles (acne)
• Result: headache/migraine 6.7%, menstrual irregularities 4.7%, nausea/vomiting 4.2%, breast pain/tenderness 4%, mood changes 2.2% (single-arm and placebo-controlled trials pooled, so these are not drug-minus-placebo differences)
• Funding: manufacturer trials reported in the FDA label.

Limit of this finding: The label’s own punctuation is broken here: the bracket opened at "menstrual irregularities (including vaginal hemorrhage [primarily spotting] and metrorrhagia (4.7%)," is never closed, so it is genuinely unclear whether 4.7 percent refers to metrorrhagia alone or to menstrual irregularities as a whole. The quotation reproduces the FDA text as printed. Note too that these are pooled single-arm and placebo-controlled trials, so the percentages are not drug-minus-placebo differences.

The most common adverse reactions (≥ 2% of users) were: headache/migraine (6.7%), menstrual irregularities (including vaginal hemorrhage [primarily spotting] and metrorrhagia (4.7%), nausea/vomiting (4.2%), breast pain/tenderness (4%) and mood changes (mood swings, depression, depressed mood and affect lability) (2.2%).

In the Cochrane PMDD review the drospirenone pill produced more nausea, breakthrough bleeding and breast pain than placebo, with drug-versus-placebo odds ratios. (Source 4)

• Systematic review, Low certainty.
• Size: two placebo-controlled PMDD trials within a five-trial review.
• Who: women with PMDD.
• How long: three months.
• Result: nausea OR 3.15 (95% CI 1.90 to 5.22), intermenstrual bleeding OR 4.92 (3.03 to 7.96), breast pain OR 2.67 (1.50 to 4.78); total study-drug-related adverse events OR 2.36 (1.62 to 3.44)
• Funding: Cochrane review, NIH extramural support.

Side effects more common with the use of the drospirenone COC contraceptive were nausea, intermenstrual bleeding, and breast pain. The respective odds ratios were 3.15 (95% CI 1.90 to 5.22), 4.92 (95% CI 3.03 to 7.96), and 2.67 (95% CI 1.50 to 4.78). Total adverse events related to the study drug were more likely for the drospirenone COC group (OR 2.36; 95% CI 1.62 to 3.44).

A pharmacokinetic and pharmacodynamic trial found St John's wort increased metabolism of oral contraceptive hormones, with breakthrough bleeding, follicle growth and probable ovulation. (Source 10)

• Blood level study, Low certainty.
• Size: 16 healthy women.
• Who: healthy women on a low-dose oral contraceptive (norethindrone 1 mg / ethinyl estradiol 20 micrograms)
• How long: two control cycles then two cycles with St John's wort 300 mg three times daily.
• Result: 13-15% reduction in dose exposure from the contraceptive; increased breakthrough bleeding, follicle growth and probable ovulation in the treatment cycles.
• Funding: NIH (NCCIH and NCRR) support.

Limit of this finding: This was a 16-woman, single-blind, sequential study - two control cycles followed by two treatment cycles - not a randomised trial. The abstract reports "probable ovulation" without saying in how many women, so this should not be converted into a contraceptive failure rate.

Treatment with St. John's Wort was associated with a significant 13-15% reduction in the dose exposure from the contraceptive. Breakthrough bleeding increased in the treatment cycles, as did evidence of follicle growth and probable ovulation. CONCLUSION: St. John's Wort is associated with increased metabolism of norethindrone and ethinyl estradiol, breakthrough bleeding, follicle growth and ovulation. Women using OCs should be cautioned that St. John's Wort might interfere with contraceptive effectiveness.

Concomitant prescribing of potassium-sparing drugs alongside drospirenone/ethinyl estradiol was common in a US claims cohort. (Source 21)

• Cohort study, Low certainty.
• Size: 62,527 drospirenone/ethinyl estradiol users.
• Who: women in a US population-based pharmacy claims data set, January 2002 to March 2005.
• How long: overlapping prescription episodes over roughly three years.
• Result: 17.6% of women used drospirenone/ethinyl estradiol concomitantly with an interacting drug; 29% of concomitant use began within a month of starting; NSAIDs and diuretics were commonest; 40% of concomitant users were 35 or older versus 29% of others (p<.001)
• Funding: not stated.

Limit of this finding: The published abstract has a missing space in "35 yearsof age"; that is the source’s own typo and has been left as printed. The study counts prescriptions in a claims database, so it shows how often these drugs were prescribed together, not how often potassium actually rose.

A total of 17.6% of the women concomitantly used EE/DRSP and an interacting drug. Twenty-nine percent of concomitant use occurred within a month of EE/DRSP initiation. Nonsteroidal antiinflammatory drugs and diuretics were most frequently used concomitantly with EE/DRSP. Forty percent of the women with concomitant use were 35 yearsof age or older at EE/DRSP initiation compared with 29% without concomitant use (p<.001). Obstetricians/gynecologists and family practitioners were the most common prescribers of EE/DRSP and potassium-sparing drugs, respectively. CONCLUSIONS: Concomitant prescribing of EE/DRSP and potassium-sparing drugs occurred frequently in our study population. As EE/DRSP becomes more widely used, physicians prescribing it should monitor patients for potassium-sparing drug use.

The patient-facing part of the label names the drug classes that can push potassium up alongside drospirenone and tells women on long-term treatment with any of them to have a potassium blood test in the first month. (Source 22)

• Official position, Certainty not rated.
• Size: not applicable (FDA-approved patient labeling)
• Who: women taking daily, long-term treatment for a chronic condition with a potassium-raising medicine.
• How long: first month of taking the pill.
• Result: no rate given; the named classes are NSAIDs, potassium-sparing diuretics, potassium supplementation, ACE inhibitors, angiotensin-II receptor antagonists, heparin and aldosterone antagonists, and the label also rules the pill out in kidney, liver or adrenal disease.
• Funding: manufacturer patient labelling as approved by FDA, version effective 29 May 2025.

If you are currently on daily, long-term treatment for a chronic condition with any of the medications below, you should consult your healthcare provider about whether Yaz is right for you, and during the first month that you take Yaz, you should have a blood test to check your potassium level. •NSAIDs (ibuprofen [Motrin, Advil], naproxen [Aleve and others] when taken long-term and daily for treatment of arthritis or other problems) •Potassium-sparing diuretics (spironolactone and others) •Potassium supplementation •ACE inhibitors (Capoten, Vasotec, Zestril and others) •Angiotensin-II receptor antagonists (Cozaar, Diovan, Avapro and others) •Heparin •Aldosterone antagonists

What the evidence supports

A one-year trial of the 3 mg drospirenone / 0.02 mg ethinyl estradiol product gave a Pearl Index of 1.41 pregnancies per 100 woman-years. (Source 3)

• Randomized trial, Moderate certainty.
• Size: 1,027 subjects, 11,480 28-day cycles.
• Who: women aged 17 to 36; BMI over 35 excluded.
• How long: up to 1 year.
• Result: Pearl Index 1.41 (95% CI 0.73 to 2.47) per 100 woman-years, based on 12 pregnancies.
• Funding: manufacturer trial reported in the FDA label (Bayer)

The pregnancy rate (Pearl Index) was 1.41 (95% CI [0.73, 2.47]) per 100 woman-years of use based on 12 pregnancies that occurred after the onset of treatment and within 14 days after the last dose of Yaz in women 35 years of age or younger during cycles in which no other form of contraception was used.

Two placebo-controlled trials in women with PMDD found less severe premenstrual symptoms with drospirenone 3 mg plus ethinyl estradiol 20 micrograms, with a large placebo effect alongside it. (Source 4)

• Systematic review, Low certainty.
• Size: five trials, 1,920 women in total (two placebo-controlled PMDD trials drove the result)
• Who: women of reproductive age meeting DSM-IV criteria for PMDD.
• How long: three months.
• Result: mean difference in symptom score -7.92 (95% CI -11.16 to -4.67); impairment of productivity MD -0.31 (95% CI -0.55 to -0.08), social activities MD -0.29 (95% CI -0.54 to -0.04), relationships MD -0.30 (95% CI -0.54 to -0.06)
• Funding: Cochrane review supported by NIH extramural funding; review authors declared no industry interest for this review.

Two placebo-controlled trials of women with PMDD showed less severe premenstrual symptoms after three months with drospirenone 3 mg plus ethinyl estradiol 20 μg than with placebo (MD -7.92; 95% CI -11.16 to -4.67). The drospirenone group had greater mean decreases in impairment of productivity (MD -0.31; 95% CI -0.55 to -0.08), social activities (MD -0.29; 95% CI -0.54 to -0.04), and relationships (MD -0.30; 95% CI -0.54 to -0.06).

Across nine placebo-controlled trials in a 31-trial, 12,579-participant Cochrane review, combined pills reduced acne lesion counts, severity grades and self-assessed acne; the two pooled drospirenone trials favoured drospirenone on the investigators’ assessment of clear or almost clear skin. (Source 5)

• Systematic review, Low certainty.
• Size: 31 trials, 12,579 participants (two drospirenone trials pooled for the global assessment)
• Who: women with facial acne.
• How long: typically six 28-day cycles.
• Result: review size 31 trials / 12,579 participants; all nine placebo-controlled trials with analysable data favoured the pill; levonorgestrel-COC total lesion count MD -9.98 (95% CI -16.51 to -3.45); two pooled drospirenone trials, investigators’ assessment of clear or almost clear skin OR 3.02 (95% CI 1.99 to 4.59)
• Funding: Cochrane review; one review author (Grimes) declared consulting for Bayer HealthCare Pharmaceuticals and Merck.

The review includes 31 trials with 12,579 participants. Of 24 comparisons made, 6 compared a COC to placebo, 17 different COCs, and 1 compared a COC to an antibiotic. Of nine placebo-controlled trials with data for analysis, all showed COCs reduced acne lesion counts, severity grades and self-assessed acne compared to placebo. A levonorgestrel-COC group had fewer total lesion counts (MD -9.98; 95% CI -16.51 to -3.45), inflammatory and non-inflammatory lesion counts, and were more likely to have a clinician assessment of clear or almost clear lesions and participant self-assessment of improved acne lesions.

Oral contraceptive use is associated with a long-lasting reduction in ovarian cancer risk in pooled observational data, with the absolute benefit quantified. (Source 6)

• Meta-analysis, Moderate certainty.
• Size: 23,257 women with ovarian cancer and 87,303 controls from 45 studies in 21 countries.
• Who: women in 45 epidemiological studies; median year of diagnosis 1993, mean age 56.
• How long: average use 4.4 years (cases) and 5.0 years (controls); follow-up over 30 years after stopping.
• Result: proportional risk reduction per 5 years of use 29% (95% CI 23-34%) if use ceased under 10 years ago, 19% (14-24%) at 10-19 years, 15% (9-21%) at 20-29 years; 10 years of use estimated to reduce incidence before age 75 from 1.2 to 0.8 per 100 users and mortality from 0.7 to 0.5 per 100; mucinous tumours seemed little affected.
• Funding: Medical Research Council.

The longer that women had used oral contraceptives, the greater the reduction in ovarian cancer risk (p<0.0001). This reduction in risk persisted for more than 30 years after oral contraceptive use had ceased but became somewhat attenuated over time-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.

What the evidence does not support

In a two-year trial, drospirenone-containing pills were no better than a desogestrel comparator for premenstrual symptoms. (Source 4)

• Systematic review, Low certainty.
• Size: one two-year trial within a five-trial review.
• Who: women with less severe premenstrual symptoms.
• How long: two years.
• Result: premenstrual symptoms OR 0.87 (95% CI 0.63 to 1.22); treatment-related adverse events OR 1.02 (95% CI 0.78 to 1.33)
• Funding: Cochrane review, NIH extramural support.

In a two-year trial, the drospirenone COC group had similar premenstrual symptoms to the comparison group given desogestrel 150 µg plus ethinyl estradiol 30 µg (OR 0.87; 95% CI 0.63 to 1.22). The groups were also similar for adverse events related to treatment (OR 1.02; 95% CI 0.78 to 1.33).

The Cochrane acne review concluded that differences between pill types were less clear and that comparison with non-hormonal acne treatments is essentially untested. (Source 5)

• Systematic review, Low certainty.
• Size: 31 trials, 12,579 participants.
• Who: women with facial acne.
• How long: typically six cycles.
• Result: no usable comparative effect size across progestin types; only one of 24 comparisons compared a pill with an antibiotic.
• Funding: Cochrane review; author consulting disclosure for Bayer and Merck.

Few important and consistent differences were found between COC types in their effectiveness for treating acne. How COCs compare to alternative acne treatments is unknown since only one trial addressed this issue. The use of standardized methods for assessing acne severity would help in synthesizing results across trials as well as aid in interpretation.

In the same Danish cohort table, the rows for progestogen-only pills and hormone-releasing intrauterine devices showed no increase in confirmed venous thromboembolism. (Source 17)

• Cohort study, Moderate certainty.
• Size: 8,010,290 woman-years; 4,246 events included.
• Who: non-pregnant Danish women aged 15-49.
• How long: 2001 to 2009.
• Result: no increased risk of confirmed venous thromboembolism with progestogen-only pills or hormone-releasing intrauterine devices (the null rows of the same analysis)
• Funding: Bayer Schering Pharma funded the analysis; author disclosures as above.

The risk of confirmed venous thromboembolism was not increased with use of progestogen only pills or hormone releasing intrauterine devices. 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.

A large prospective cohort run as a post-approval safety study of the drospirenone product (EURAS) reported venous thromboembolism hazard ratios close to 1 for drospirenone pills against levonorgestrel and other pills. (Source 23)

• Cohort study, Low certainty.
• Size: 58,674 women followed for 142,475 woman-years; loss to follow-up 2.4%.
• Who: new users of drospirenone, levonorgestrel and other progestin oral contraceptives in Europe.
• How long: 142,475 woman-years of observation (semiannual follow-up)
• Result: venous thromboembolism hazard ratio for drospirenone versus levonorgestrel 1.0 and versus other pills 0.8 (upper 95% confidence limits 1.8 and 1.3); arterial thromboembolism 0.3 and 0.3 (upper limits 1.2 and 1.5)
• Funding: post-approval safety study of a drospirenone product; conducted as a Phase IV study of the manufacturer's product.

Limit of this finding: The published abstract gives only the UPPER end of each 95% confidence interval and no lower end, so there is no way to see how imprecise these estimates are. The arterial figures of 0.3 and 0.3 should not be read as drospirenone protecting against arterial clots. This was also a non-interventional cohort of new users followed by posted questionnaire, run as a phase IV study of the manufacturer’s own product, not a randomised trial, so women prescribed different pills may have differed from the start.

Cox regression analysis of cardiovascular outcomes yielded hazard ratios for DRSP-containing vs. LNG-containing and other OCs of 1.0 and 0.8 (upper 95% confidence limits, 1.8 and 1.3) for venous, and 0.3 and 0.3 (upper 95% confidence limits, 1.2 and 1.5) for arterial thromboembolism, respectively. CONCLUSIONS: Risks of adverse cardiovascular and other serious events in users of a DRSP-containing OC are similar to those associated with the use of other OCs.

The Cochrane review of combined contraceptives and weight did not support a causal link with weight change. (Source 7)

• Systematic review, Low certainty.
• Size: 49 trials, 85 weight-change comparisons across 52 contraceptive pairs or placebos.
• Who: women in randomised trials of at least three cycles.
• How long: at least three treatment cycles.
• Result: the four trials with a placebo or no-intervention group found no evidence supporting a causal association; most comparisons between pills showed no substantial difference; discontinuation for weight change did not differ.
• Funding: Cochrane review with NIH extramural support; two authors disclosed pharmaceutical consulting or sponsored studies (Bayer, Merck, 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

The Cochrane PMDD review states plainly that the placebo also had a large effect and that nothing is known about use beyond three cycles, in milder symptoms, or against other pills. (Source 4)

• Systematic review, Low certainty.
• Size: five trials, 1,920 women.
• Who: women with premenstrual symptoms.
• How long: three months to two years.
• Result: no quantitative effect; a stated limitation of the evidence base, with a call for larger, longer, higher-quality trials.
• Funding: Cochrane review, NIH extramural support.

The placebo also had a large effect. We do not know whether the combined oral contraceptive works after three cycles, helps women with less severe symptoms, or is better than other oral contraceptives. Larger and longer trials of higher quality are needed to address these issues.

The FDA label itself records the disagreement, stating epidemiological studies ranged from no increase to a three-fold increase. (Source 15)

• Official position, Certainty not rated.
• Size: two prospective cohorts, three retrospective cohorts, two case-control and two nested case-control studies, as listed in the label.
• Who: users of drospirenone 3 mg / ethinyl estradiol 0.03 mg compared with other combined pills.
• How long: not applicable.
• Result: risk estimates ranging from no increase to a three-fold increase relative to levonorgestrel or other progestins.
• Funding: label position of the manufacturer as approved by FDA; label section revised in the version effective 29 May 2025.

Epidemiologic studies that compared the risk of VTE reported that the risk ranged from no increase to a three-fold increase. Before initiating use of Yaz in a new COC user or a woman who is switching from a contraceptive that does not contain DRSP, consider the risks and benefits of a DRSP-containing COC in light of her risk of a VTE. Known risk factors for VTE include smoking, obesity, and family history of VTE, in addition to other factors that contraindicate use of COCs [see Contraindications (4)].

A retrospective cohort of 1.1 million oral contraceptive users did not find a clinically significant hyperkalaemia signal for drospirenone, while two other progestins did show one. (Source 9)

• Cohort study, Low certainty.
• Size: 1,148,183 women, 2,325 cases of hyperkalaemia; average 280 days of therapy.
• Who: new users of oral contraceptives aged 18-46 in a US health plan claims database, 1997-2009.
• How long: mean 280 days of oral contraceptive therapy.
• Result: hyperkalaemia hazard ratio for drospirenone versus levonorgestrel 1.10 (95% CI 0.95-1.26); norethindrone 1.15 (1.00-1.33); norgestimate 1.27 (1.11-1.46); other pills unassociated; odds of receiving spironolactone while on drospirenone 2.66 (2.53-2.80) times higher; only 6.5% of women on both had a potassium assay within 180 days.
• Funding: not stated in the abstract; declared as research support, non-US government.

Limit of this finding: The paper describes norethindrone as showing "an increased risk of hyperkalemia" at HR 1.15 with a 95% confidence interval of 1.00 to 1.33. An interval whose lower edge sits exactly on 1.00 does not establish an increase at the usual standard, so that particular claim is stronger than its own numbers support. Note also that the two "increased risk" signals here are for norethindrone and norgestimate - comparator progestins - and NOT for drospirenone, whose result in this study (HR 1.10, 0.95 to 1.26) is the null one.

The adjusted hazard ratio (HR) for hyperkalemia with drospirenone compared to levonorgestrel was 1.10 (95%CI 0.95-1.26). There was an increased risk of hyperkalemia with norethindrone HR 1.15 (95%CI: 1.00-1.33) and norgestimate HR 1.27 (95%CI: 1.11-1.46). Other OCs were unassociated with hyperkalemia. The odds of receiving spironolactone while taking drospirenone were 2.66 (95%CI 2.53-2.80) times higher than the odds of receiving spironolactone and levonorgestrel. Only 6.5% of patients taking drospirenone and spironolactone had a serum potassium assay within 180 days of starting concomitant therapy. CONCLUSIONS: A clinically significant signal for hyperkalemia with drospirenone was not demonstrated in the current study. Despite the bolded warning for hyperkalemia with joint drospirenone and spironolactone administration, physicians are actually using them together preferentially, and are not following the recommended potassium monitoring requirements in the package insert.

Where the research disagrees

Whether drospirenone-containing pills carry a higher venous thromboembolism risk than levonorgestrel-containing pills

• de Bastos and colleagues, Cochrane network meta-analysis of 26 studies (2014), network meta-analysis of 26 observational studies, unadjusted relative risks reported: Risk of venous thrombosis for combined oral contraceptives with 30-35 μg ethinylestradiol and gestodene, desogestrel, cyproterone acetate and drospirenone were similar, and about 50-80% higher than with levonorgestrel. The combined oral contraceptive with the lowest possible dose of ethinylestradiol and good compliance should be prescribed-that is, 30 μg ethinylestradiol with levonorgestrel. (Source 16)
• Lidegaard and colleagues, Danish national registry cohort 2001-2009 (BMJ 2011), national historical registry-based cohort, 8,010,290 woman-years; analysis expenses covered by Bayer Schering Pharma; lead author was to be a plaintiff expert witness in a US case: 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 17)
• Dinger and colleagues, European Active Surveillance Study (EURAS), prospective cohort (2007), multinational prospective non-interventional cohort of 58,674 new users, 142,475 woman-years, 2.4% loss to follow-up; a Phase IV post-approval safety study of the drospirenone product: Serious adverse and fatal events were rare, and rate ratios were close to unity (1.0). Cox regression analysis of cardiovascular outcomes yielded hazard ratios for DRSP-containing vs. LNG-containing and other OCs of 1.0 and 0.8 (upper 95% confidence limits, 1.8 and 1.3) for venous, and 0.3 and 0.3 (upper 95% confidence limits, 1.2 and 1.5) for arterial thromboembolism, respectively. (Source 23)
• Dragoman and colleagues for WHO, systematic review and meta-analysis (2018), random-effects meta-analysis of 22 articles with subgroup and sensitivity analyses; WHO-funded: Compared with the use of levonorgestrel-containing COCs, the use of COCs containing other progestogens could be associated with a small increase in risk for VTE. (Source 18)
• The US label (Bayer/FDA), section 5.1, version effective 29 May 2025, regulatory position summarising nine studies of several designs, including the two prospective cohorts that found no increase and the FDA-funded retrospective cohort that found hazard ratios of 1.5 to 1.8: Based on presently available information on DRSP-containing COCs with 0.03 mg ethinyl estradiol (that is, Yasmin), DRSP-containing COCs may be associated with a higher risk of venous thromboembolism (VTE) than COCs containing the progestin levonorgestrel or some other progestins. Epidemiologic studies that compared the risk of VTE reported that the risk ranged from no increase to a three-fold increase. (Source 15)

Whether drospirenone's potassium-sparing effect translates into clinical hyperkalaemia

• The US label, section 5.2, regulatory position, with a contraindication in renal, hepatic and adrenal impairment and a first-cycle potassium check in women on interacting drugs: Yaz contains 3 mg of the progestin DRSP which has anti-mineralocorticoid activity, including the potential for hyperkalemia in high-risk patients, comparable to a 25 mg dose of spironolactone. (Source 8)
• Bird, Etminan and colleagues, retrospective cohort of 1,148,183 oral contraceptive users (2011), retrospective cohort with Cox models in a US claims database; drospirenone versus levonorgestrel HR 1.10 (0.95-1.26), while norethindrone and norgestimate did show small increases: A clinically significant signal for hyperkalemia with drospirenone was not demonstrated in the current study. Despite the bolded warning for hyperkalemia with joint drospirenone and spironolactone administration, physicians are actually using them together preferentially, and are not following the recommended potassium monitoring requirements in the package insert. (Source 9)

How much

• Reference intake: No reference intake exists; this is a prescription medicine and the dose is set by the prescriber. As a position, the label (effective 29 May 2025) states the regimen for the 3 mg drospirenone / 0.02 mg ethinyl estradiol product as one tablet daily at the same time each day, in the order of the blister pack, without interruption. (Source 24)
• Upper limit: There is no upper limit in the nutritional sense. As a position, the label's stated maximum is one tablet in 24 hours - the product is a fixed-dose daily tablet and the label instructs taking the tablets in the order directed, every day, at the same time. (Source 24)
• Studied: The pivotal contraceptive trial gave drospirenone 3 mg plus ethinyl estradiol 0.02 mg daily in 28-day cycles to 1,027 women for up to one year (11,480 cycles). (Source 3)
• Studied: The two PMDD trials gave drospirenone 3 mg plus ethinyl estradiol 20 micrograms for three menstrual cycles (384 evaluable women in the parallel-group study; 64 in a crossover study terminated early). (Source 25)
• Studied: The Cochrane review of combined oral contraceptives for acne pooled 31 trials in 12,579 participants, of which nine were placebo-controlled. The recorded passage gives no participant count, age range or cycle count for the drospirenone with ethinyl estradiol trials specifically, so none is stated here. (Source 5)
• Studied: Trials of the less severe premenstrual-symptom question used drospirenone 3 mg plus ethinyl estradiol 30 micrograms, over six months to two years. (Source 4)

A common belief, and what the research shows

The belief: The pill makes you put on weight.

What the research shows: The Cochrane review of 49 randomised trials of combined contraceptives and weight found that the trials with a placebo or no-treatment arm gave no support for a causal link, and that most head-to-head comparisons showed no substantial difference. Its own summary of the state of play is quoted here: Available evidence was insufficient to determine the effect of combination contraceptives on weight, but no large effect was evident. Note that two of the review's authors disclosed pharmaceutical consulting or sponsored work. A separate misconception runs the other way: because drospirenone blocks the aldosterone receptor it was marketed as avoiding fluid retention, and a pharmacology review of the hormone-replacement combination reports mean weight falling 1.2 kg versus baseline over a year - but that was a different product, dose and population from the contraceptive pill.

Questions and answers

What is it?

A daily tablet holding two synthetic hormones: ethinyl estradiol, a synthetic oestrogen, and drospirenone, a progestin built from spironolactone. The common versions are drospirenone 3 mg with ethinyl estradiol 0.02 mg (sold as Yaz and generics) or 0.03 mg (Yasmin and generics). Drospirenone is the unusual ingredient: unlike older progestins it blocks the aldosterone receptor and the androgen receptor. (Source 22)

What does it do in the body?

It mainly stops ovulation, so no egg is released. The drospirenone part also blocks the aldosterone receptor, which is why it does not cause the fluid retention older progestins do and why it can raise potassium, and blocks androgen receptors, which is the basis for its effect on acne. A pharmacology review of the drospirenone molecule describes both effects. (Source 1)

Is it good or bad for you?

Both, depending on who is taking it. It reliably prevents pregnancy, and pooled observational data link oral contraceptive use to a lasting reduction in ovarian cancer risk. Against that, all combined pills raise the risk of a venous clot - the Cochrane network meta-analysis put combined pills at 3.5 times non-use, and drospirenone pills about 50 to 80 percent above levonorgestrel pills at the same oestrogen dose. The absolute numbers stay small: the Danish cohort estimated about 10 events per 10,000 woman-years in the higher-risk group, against a background of roughly 2 to 4 per 10,000 in non-users. It is a bad choice for anyone who smokes and is over 35, who has had a clot, or who has kidney, liver or adrenal disease. (Source 16)

How do you get more of it?

There is no way to get more of it other than a prescription, and no food or supplement contains it. Dose is fixed by the product and set by the prescriber; the label's stated regimen is one tablet daily in the order of the pack. Taking more does not make it work better - the registration trial gave one tablet a day and nothing else is studied. (Source 3)

If it is harmful, what reduces it?

Stopping the tablets is what clears it; the hormones are short-acting and the ovulation suppression lifts, which is why pooled data put the rate of pregnancy at 83.1 percent within twelve months of stopping any contraception. Note that the same paper describes this measure as a pooled rate of conception in its methods and a pooled rate of pregnancy in its results, using the two words interchangeably. The label’s instruction when a clot occurs is to stop the drug outright, not taper. There is no antidote or washout procedure in the literature we found. (Source 13)

Why might someone be low in it or missing it?

Not applicable in the sense this question usually means - nobody is naturally low in a synthetic drug. What does happen is that blood levels fall below the level needed for contraception. The documented causes are enzyme-inducing drugs and herbal products, including St John's wort, phenytoin, carbamazepine, rifampin and topiramate; vomiting or diarrhoea; and missed tablets. In the St John's wort study, exposure fell 13 to 15 percent and probable ovulation returned. (Source 11)

Which whole foods contain it or feed it?

No whole food contains ethinyl estradiol or drospirenone; they are synthetic and only come in the tablet. Food matters in the other direction: grapefruit juice inhibits CYP3A4 and can raise levels of the oestrogen, the progestin or both, and high doses of vitamin C or paracetamol compete for the same sulphation pathway as ethinyl estradiol and can raise its blood level. (Source 11)

What happens if you do not have it?

Nothing is lost physiologically, because it is not a nutrient. What changes is that pregnancy becomes possible again - the trial pregnancy rate on the drug was 1.41 per 100 woman-years, against far higher rates without contraception - and, for women taking it for PMDD or acne, those symptoms can return, since the PMDD trials only ran three cycles and the label says effectiveness beyond that has not been evaluated. (Source 26)

How can you test for it?

There is no routine blood test to check the drug itself or whether it is working; the practical test of contraceptive effect is not becoming pregnant. One test does get recommended: a serum potassium measurement during the first treatment cycle in women also on long-term drugs that raise potassium. In practice it is often skipped - in a claims cohort only 6.5 percent of women taking drospirenone with spironolactone had a potassium assay within 180 days, and in an earlier study only 40 percent of at-risk initiators were tested. (Source 8)

References

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