By William Elliott, MD, FACP, and James Chan, PharmD, PhD

Dr. Elliott is Assistant Clinical Professor of Medicine, University of California, San Francisco.
Dr. Chan is Associate Clinical Professor, School of Pharmacy, University of California, San Francisco.

The FDA has approved the first combination oral contraceptive containing a naturally occurring estrogen. Estetrol (E4) is produced during human pregnancy and is synthesized from plant-derived estrone for clinical use. E4 is selective for nuclear estrogen receptor alpha and beta, with greater affinity for the receptor alpha.1,2 It is categorized as a native estrogen, with selective action in tissues (NEST). E4 is combined with a commonly used progestin, drospirenone (DRSP), with antimineralocorticoid and antiandrogen properties. This combination is manufactured in Germany and distributed as Nextstellis.


E4/DRSP can be prescribed to women of reproductive potential to prevent pregnancy.1


The recommended dose is one tablet taken orally at the same time every day.1 The E4/DRSP pill pack contains 24 active pink pills (E4 14.2 mg and DRSP 3 mg), followed by four “inactive” white inert pills.


E4 may produce a limited effect on various endocrine and metabolic parameters (e.g., gonadotropins, cortisol, angiotensinogen, cortisol-binding globulin, sex hormone-binding globulin, lipid profile, and carbohydrate parameters) compared to ethinyl estradiol (EE).3 The lower hepatic and vascular estrogenicity compared to EE/DRSP may lower the risk of venous thromboembolic events.4 E4 has 1/100 the stimulation on breast proliferation compared to natural estrogen and actually antagonizes estradiol-dependent mammary gland proliferation.2


A body mass index (BMI) ≥ 30 kg/m2 may make the drug less effective.1


E4/DRSP showed comparable complete ovulation inhibition compared to EE/DRSP.5 This was based on an assessment of follicular development and double-layer endometrial thickness. The efficacy of E4/DRSP was evaluated in a prospective, open-label, single-arm, one-year study that included 1,674 women age 16 to 35 years.1 There were 26 on-treatment pregnancies (1,524 women and 12,763 at-risk cycles).

The overall Pearl Index was 2.65 pregnancies per 100 women-years of use. The Pearl Index was higher in those with BMI ≥ 30 kg/m2 to < 35 kg/m2 (2.94; 95% CI, 1.08-6.41) compared to those < 30 kg/m2 (2.57; 95% CI, 1.57-3.97).


E4/DRSP is the first E4 containing combined oral contraceptive (COC) to be approved. While some evidence may suggest a more favorable and attractive safety profile for E4 compared to the commonly used EE, this needs to be confirmed with clinical evidence. The FDA labeling still carries the same box warning and precaution as other COCs.

There are no clinical comparisons to the corresponding EE equivalent (i.e., EE/DRSP) in terms of cycle control or safety profile, but that combination has a Pearl Index of 1.41 and no limitation based on BMI.6 Still, some women may prefer a “natural” estrogen product and the potential of less endocrine and metabolic side effects. The cost for a 28-day cycle is $190, which is more than 10 times the cost for a typical generic EE/DRSP. 


  1. Mayne Pharma. Nextstellis prescribing information. April 2021.
  2. Gérard C, Blacher S, Communal L, et al. Estetrol is a weak estrogen antagonizing estradiol-dependent mammary gland proliferation. J Endocrinol 2015;224:85-95.
  3. Klipping C, Duijkers I, Mawet M, et al. Endocrine and metabolic effects of an oral contraceptive containing estetrol and drospirenone. Contraception 2021;103:213-221.
  4. Grandi G, Del Savio MC, Lopes da Silva-Filho A, Facchinetti F. Estetrol (E4): The new estrogenic component of combined oral contraceptives. Expert Rev Clin Pharmacol 2020;13:327-330.
  5. Duijkers I, Klipping C, Kinet V, et al. Effects of an oral contraceptive containing estetrol and drospirenone on ovarian function. Contraception 2021;103:386-393.
  6. Bayer HealthCare Pharmaceuticals. Yaz prescribing information. August 2017.