Comparing Micronized Progesterone and Norethisterone Acetate for Menopausal Hormone Therapy

Safety of Oral Micronized Progesterone Versus Norethisterone Acetate in Continuous Combination With Oral Estrogen as Menopausal Hormone Therapy - a Double-blind Randomized Study- PROBES Study (Progesterone Breast Endometrial Safety Study)

Phase 3 Interventional Karolinska University Hospital · NCT05586724

This study is testing whether micronized progesterone or norethisterone acetate works better and is safer for treating menopausal symptoms in postmenopausal women.

Quick facts

PhasePhase 3
Study typeInterventional
Enrollment520 (estimated)
Ages45 Years to 60 Years
SexFemale
SponsorKarolinska University Hospital Academic / other
Locations1 site (Stockholm)
Trial IDNCT05586724 on ClinicalTrials.gov

What this trial studies

This clinical trial aims to evaluate the effectiveness and safety of micronized progesterone (mP) versus norethisterone acetate (NETA) when combined with estrogen for treating menopausal symptoms in postmenopausal women. Participants will be randomly assigned to receive either treatment in a double-blind manner, allowing for unbiased assessment of outcomes. The study will focus on measuring changes in mammographic breast density and monitoring endometrial health over a 12-month period. A total of 520 women will be enrolled to ensure robust data collection and analysis.

Who should consider this trial

Good fit: Ideal candidates are healthy postmenopausal women aged 45-60 with climacteric symptoms that negatively impact their quality of life.

Not a fit: Patients with a history of breast or endometrial cancer, abnormal mammograms, or other significant health risks may not benefit from this study.

Why it matters

Potential benefit: If successful, this study could provide a safer hormonal therapy option for managing menopausal symptoms with reduced risks of breast and endometrial cancer.

How similar studies have performed: Previous studies have indicated potential benefits of micronized progesterone, but this specific comparison with NETA is novel and has not been extensively tested.

Eligibility criteria

Show full inclusion / exclusion criteria
Inclusion Criteria:

* Healthy and naturally postmenopausal women (more than one year since last menstruation or FSH \> 40 IE/L) with climacteric symptoms (sweating, hot flush and/or sleep problems) that adversely affect the quality of life
* Age 45-60 years
* BMI \> 19 kg/m2 and ≤ 32 kg/m2
* Intact uterus
* In case of previous MHT use, washout 8 weeks for oral MHT and 4 weeks for transdermal MHT or local estrogen treatment before screening
* Written informed consent

Exclusion Criteria:

* Previous history or risk factors for breast cancer, breast cancer in situ or abnormal mammogram at baseline as assessed clinically by a radiology expert
* Previous history or risk factors for endometrial cancer or hyperplasia or abnormal/proliferative endometrial biopsy at baseline
* Vaginal bleeding
* Any concomitant medical treatment except for well-controlled hypertension, non-insulin treated type 2 diabetes, asthma and hypothyroidism
* History or presence of or risk factor for cardiovascular disease including thromboembolic disorder or cerebrovascular disease
* History or presence of liver and gallbladder disease, familial hyperlipidemia, epilepsy or classical migraine with aura
* History or presence of clinically significant depression or other psychiatric disorder that might in anyway compromise the performance of the trial or undermine its scientific validity
* Porphyria, Systemic lupus erythematosus and otosclerosis
* Current use of MHT or local estrogen treatment
* Alcohol and/or drug abuse
* Clinically significant findings on physical and/or gynecological examination at baseline
* Hypersensitivity to any of the study treatments

Where this trial is running

Stockholm

Study contacts

How to participate

  1. Review the eligibility criteria above with your treating physician.
  2. Visit the official trial page on ClinicalTrials.gov for the most current contact information and recruitment status.
  3. Contact the listed study coordinator or principal investigator to request pre-screening. Pre-screening is free and never obligates you to enroll.
Conditions Menopausal SymptomsMenopausal hormone therapyClimacteric symptomsProgesteroneProgestogensBreast safetyEndometrial safety
Last reviewed 2026-06-15 by the Find a Trial editorial team. Information on this page is for educational purposes and is not medical advice. Always consult qualified healthcare professionals about clinical trial participation.