Estetrol is a naturally occurring human estrogen, and combined with drospirenone it is the first new estrogen introduced into hormonal contraception since 1960, with a distinct pharmacology that is believed to reduce its effect on the liver and clotting system compared with older pills.

The excitement around it for perimenopause is based mainly on markers of clotting activity that were less affected than with older pills, not on actual clot-event data, which does not yet exist for this pill. An important, often unstated limitation is that the trials establishing how well it prevents pregnancy only analyzed women up to about age 35, even though participants up to age 50 were enrolled, so its contraceptive reliability specifically in perimenopausal women has not been directly established.

What to know about this answer

This is a live and unresolved disagreement even among clinicians who are generally cautious about hormone therapy: some see estetrol as a genuine safety advance worth switching to, while the strongest case against it comes from the trial authors themselves, who caution that the safety story rests entirely on surrogate markers, not real-world clot outcomes.

What the research shows, and which source each finding rests on

Estetrol is a native human estrogen with a distinguishing pharmacology (a dissociated pattern of estrogen-receptor activation) proposed to reduce its hepatic and breast tissue effects compared with older synthetic estrogens.

E[1]

In the European phase 3 trial, women aged 18-35 had a Pearl Index (pregnancy rate) of 0.47; in the North American phase 3 trial, women aged 16-35 had a Pearl Index of 2.65; both trials enrolled women up to age 50 but restricted their efficacy analysis to younger women, so contraceptive efficacy in women aged 36-50 has not been directly established.

B[2]B[3]

In a small exploratory randomized study, a marker of clotting activity rose only 30% with the estetrol/drospirenone pill compared with 165% and 219% for two older pill formulations; the study's own authors state that further studies are needed to understand actual clot risk with this pill.

B[4]

Where the real disagreement is

Each position is shown with its own sources. A position listed here is not necessarily the accepted view.

genuine advance, worth switching to

clinicians in the source material, including a notably conservative voice on hormone therapy generally

Because the pill shows a minimal effect on clotting-related markers, some clinicians say they would consider switching an eligible woman around age 50, if covered by insurance, on the basis that it may carry a lower clotting risk than older formulations.

E[5]

the evidence is surrogate-marker-only and does not cover the women being offered it

the trial investigators' own published conclusions

The trial authors themselves wrote that large follow-up studies will be needed to confirm whether this pill actually has a better safety profile or lower clot risk in practice, one clot event did occur in the European phase 3 trial, and the efficacy analyses excluded women over 35 entirely, the exact group being offered the pill as a perimenopause option.

B[2]B[3]

What would settle it: A large, real-world follow-up study measuring actual clot events, plus a dedicated contraceptive-efficacy analysis in women aged 36-50, would settle this. Both are explicitly named as needed by the trial authors and neither exists yet.

What is really going on here

  1. Multiple authors who conducted the estetrol trials state directly that large follow-up studies are still needed to confirm whether the pill's favorable clotting-marker results translate into fewer actual clots.
  2. The phase 3 efficacy trials enrolled women up to age 50 but only analyzed pregnancy outcomes in women up to about 35, so how reliably this pill prevents pregnancy in perimenopausal women specifically is not established.
  3. Several of the papers describing estetrol's mechanism and hemostasis effects have authors employed by the pill's developer, which is worth knowing when weighing the enthusiasm around it.

Questions for your doctor

  1. Is the estetrol pill approved and appropriate for someone my age?
  2. What is actually known, versus still being studied, about this pill's clot risk?
  3. How confident can we be in its contraceptive reliability for someone in my age group?
  4. Would insurance cover it, and is there a more established alternative you would also consider?

Questions with no answer yet

Does the estetrol and drospirenone pill's favorable clotting-marker profile actually translate into fewer real-world clot events, or could it look similar to older pills once large enough numbers of women are followed?

Not directly studied yet

No research does not mean it does not work, and it does not mean it works. It means nobody has tested it yet.

What is known: The trial authors themselves wrote that large phase 4 studies will be needed to confirm whether this combination is associated with an improved adverse event profile or lower thrombosis risk; one treatment-related clot event did occur in the European phase 3 trial, and the clotting-marker data are surrogate measures, not real clot-event data.

What would test it: A large, real-world phase 4 follow-up study measuring actual clot events in estetrol and drospirenone pill users compared with users of older pill formulations.

Is the estetrol and drospirenone pill actually as effective at preventing pregnancy in women aged 36-50 as it is in the younger women who were actually analyzed for efficacy?

Not directly studied yet

No research does not mean it does not work, and it does not mean it works. It means nobody has tested it yet.

What is known: Both phase 3 trials enrolled women up to age 50 but restricted the efficacy analysis to women aged 16-35 or 18-35; contraceptive efficacy in perimenopausal women aged 36-50 has therefore not been directly established, even though the pill is recommended in field practice specifically as a perimenopausal option.

What would test it: A dedicated contraceptive-efficacy analysis in women aged 36-50, which the trial authors themselves name as needed and which does not yet exist.

Sources

  1. 1.Profile of estetrol, a promising native estrogen for oral contraception and the relief of climacteric symptoms of menopause.Gerard C, Arnal JF, Jost M, Douxfils J, et al. Profile of estetrol, a promising native estrogen for oral contraception and the relief of climacteric symptoms of menopause. Expert Rev Clin Pharmacol 2022;15(2):121-37. · Review, opinion or mechanism
  2. 2.Estetrol-Drospirenone combination oral contraceptive: a clinical study of contraceptive efficacy, bleeding pattern and safety in Europe and Russia.Gemzell-Danielsson K, Apter D, Zatik J, et al. Estetrol-drospirenone combination oral contraceptive: a clinical study of contraceptive efficacy, bleeding pattern and safety in Europe and Russia. BJOG 2022;129(1):63-71. · Randomised trial
  3. 3.Estetrol-drospirenone combination oral contraceptive: North American phase 3 efficacy and safety results.Creinin MD, Westhoff CL, Bouchard C, et al. Estetrol-drospirenone combination oral contraceptive: North American phase 3 efficacy and safety results. Contraception 2021;104(3):222-8. · Randomised trial
  4. 4.Evaluation of the effect of a new oral contraceptive containing estetrol and drospirenone on hemostasis parameters.Douxfils J, Klipping C, Duijkers I, et al. Evaluation of the effect of a new oral contraceptive containing estetrol and drospirenone on hemostasis parameters. Contraception 2020;102(6):396-402. · Randomised trial
  5. 5.Jen Gunter, MD. Update from the 2025 Menopause Society Annual Meeting (video transcript).Review, opinion or mechanism

The letter grades the type of study behind a claim, not the answer itself.

This page is general information based on published research and public sources. It is not medical advice and not a personal assessment, and it does not replace a conversation with your doctor. Peritale is a wellness product, not a medical device, and is not intended to diagnose, treat, cure or prevent any disease. For any medical question, speak with a licensed clinician.

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