Estetrol: A New Hormonal Pathway in Menopause Treatment

I recently wrote about non-hormonal options for treating menopause symptoms for patients who can't or don't want to use hormones.

In addition to non-hormonal options, some of which are old and some are new to the market, there are new hormonal pathways being studied. One of these is estetrol.

Let’s review some of the basics about estrogen in the body.  There actually isn't just one estrogen, there are multiple forms in the body.

Our natural estrogens are:

• Estrone (E1)

  - about half as potent as E2

  - doesn’t decrease as much as E2 in menopause, therefore becomes dominant

• Estradiol (E2) 

  - most potent natural estrogen

  - decreases most with menopause (this is the lab value that is often checked)

• Estriol (E3)

  - weak estrogen

  - found in topical skin treatments

• Estetrol (E4)

  - Made in the fetal liver

  - Emerging evidence for hormonal therapy and contraception

• Estetrol

• Phase: in clinical trials

• Dose testing: different doses have been tested because higher doses show proliferation of the uterine lining (this is the reason E2 is always paired with something to protect the uterine lining) but lower doses did not

• Likely would be dosed as a daily pill

• May be a good option for endometriosis patients who want to start HRT

• How it works:

  
  

  • Estetrol appears to affect tissues differently than other estrogens (we are typically giving E2 in HRT)

  • Is more selective than E2

• Promising aspects:

  
  

  • Has been effective at treating hot flash symptoms and genitourinary symptoms (vaginal/urinary symptoms)

    
    

  • Can work as a contraceptive at certain doses

    • Suppresses ovulation (estradiol/progesterone through HRT do not)

      
      

  • Can be protective to bone

    • Superior effect on bone turnover compared with ethinyl estradiol (synthetic contraceptive estrogen)

      
      

  • May be protective to breast

    • Much weaker proliferation of breast tissue than E2 (50-2,000x weaker) in rat studies

    • The dose needed to treat menopause symptoms may not have an effect on breast tissue (in mouse studies)

• Has shown improvement in metabolic markers

  • insulin, glucose, Homa-IR improved in a study of low dose estetrol

• May have lower risk of dangerous blood clots

This is a “one to watch” novel treatment for menopause. 

Resources:

Some of the information contained in this article is the result of my training, medical knowledge, and personal experience without a specific source to be cited.

The author can earn commissions through affiliate links.

Disclaimer: This is not medical advice.  This is for educational purposes only.  Discuss with your doctor.

https://www.sciencedirect.com/topics/pharmacology-toxicology-and-pharmaceutical-science/estrone

Liao, Caiyun MD, MPH; Pal, Lubna MBBS, MS. Novel Pharmacotherapies for Menopausal Symptoms. Obstetrics & Gynecology 146(4):p 473-486, October 2025. | DOI: 10.1097/AOG.0000000000006025