Evaluation of Micronized Progesterone Versus Norethisterone Acetate with Estradiol in Menopausal Hormone Therapy: A Double-Blind, Randomized Study

The primary objective of this study is to evaluate the **breast safety** and **endometrial safety** of oral micronized progesterone (mP) versus norethisterone acetate (NETA) in continuous combination with oral estradiol as menopausal hormone therapy. Specifically, the study aims to compare the effects of one-year treatment with mP versus NETA on mammographic breast density and to assess the impact of one-year treatment with mP in combination with estradiol on endometrial pathology, including hyperplasia and cancer. These objectives are clinically relevant as they address the safety concerns associated with hormone therapy in postmenopausal women, particularly the risk of breast and endometrial cancer.

The secondary objectives include:

• Comparing the effects of one-year treatment with mP versus NETA on breast and endometrial cell proliferation.
• Assessing endometrial thickness using ultrasound.
• Evaluating the bleeding pattern.
• Investigating gene and protein expression of growth factors and apoptosis markers in breast and endometrial tissue.
• Examining symptoms of depression and anxiety using PHQ-9 and HADS scales.
• Assessing health-related quality of life using the PGWB index and the Women's Health Questionnaire (WHQ).
• Analyzing blood lipid profile, serum hormones, growth and metabolic factors, and coagulation factors.

The clinical trial focuses on **climacteric symptoms** and involves a study population of healthy, naturally postmenopausal women aged 45 to 60 years. The participants are exclusively female, with a body mass index (BMI) greater than 19 kg/m² and less than or equal to 32 kg/m². The trial does not include a vulnerable population. Participants were selected based on their experience of climacteric symptoms such as sweating, hot flushes, and sleep problems, which adversely affect their quality of life. All participants have an intact uterus and, if they have previously used menopausal hormone therapy (MHT), they underwent a washout period of 8 weeks for oral MHT and 4 weeks for transdermal MHT or local estrogen treatment before screening. The sponsor has not provided information regarding the total number of participants in the study.

The clinical trial is designed to evaluate the **safety** and efficacy of oral micronized **progesterone** compared to **norethisterone acetate** in combination with oral **estradiol** for the treatment of climacteric symptoms. This study is structured as a double-blind, randomized, controlled trial with a duration of 12 months. The trial consists of two parts: Part 1 focuses on breast safety, comparing the effects of one-year treatment on mammographic breast density, while Part 2 assesses endometrial safety through an open, single-arm design to evaluate the effect on endometrial pathology, including hyperplasia and cancer.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on criteria such as being healthy, naturally postmenopausal women aged 45-60 years with climacteric symptoms, and having an intact uterus. Follow-up visits will occur at regular intervals to monitor primary and secondary endpoints, including changes in mammographic density, endometrial proliferation, and health-related quality of life. The end-of-study visit will conclude the trial, where final assessments will be conducted.

The expected length of participant involvement is approximately 12 months, with conditions for early termination including adverse events, withdrawal of consent, or non-compliance with the study protocol. The trial aims to provide comprehensive data on the safety and efficacy of the treatment regimens, contributing valuable insights into menopausal hormone therapy.

The clinical trial involves the administration of **Utrogestan 200 mg** soft vaginal capsules, which contain **micronised progesterone** as the active substance. The pharmaceutical form is a soft vaginal capsule, and the medication is administered via the vaginal route. The maximum daily dose is 100 mg, and the treatment period extends up to 12 months. The product is manufactured by Besins Healthcare Ireland Limited and is of chemical origin. Participant compliance with the dosing schedule will be monitored throughout the study.

Another treatment used in the trial is **Estrofem 1 mg** film-coated tablets, containing **estradiol** as the active ingredient. These tablets are administered orally, with a maximum daily dose of 1 mg. The treatment duration is also set for 12 months. The product is produced by Novo Nordisk A/S and is of chemical origin. Compliance with the dosing regimen will be closely monitored to ensure adherence.

The trial also includes a placebo, which is a capsule identical in appearance to the Utrogestan capsules but contains no active substance. This placebo is administered orally and serves as a control to evaluate the effects of the active treatment. The placebo is designed to be indistinguishable from the active medication to maintain the double-blind nature of the study.

Additionally, **Activelle 1 mg/0.5 mg** film-coated tablets are used as a comparator treatment. These tablets contain a combination of **norethisterone acetate** and **estradiol**. The administration route is oral, with a maximum daily dose of 1.5 mg. The treatment period is 12 months, and the product is also manufactured by Novo Nordisk A/S. As with other treatments, participant adherence to the dosing schedule will be monitored to ensure accurate study results.

Efficacy in the clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoint is the percentage change in mammographic density compared between the groups. This will be measured to evaluate the breast safety of oral micronized **progesterone** versus norethisterone acetate in combination with estradiol as menopausal hormone therapy.

Secondary endpoints include the incidence of endometrial proliferation, assessed by the proliferation marker Ki67, and endometrial thickness measured via ultrasound. Additional secondary endpoints involve the documentation of bleeding patterns in a bleeding diary, and the analysis of gene and protein expression of growth factors and apoptosis markers in breast and endometrial tissue. Psychological assessments will be conducted using the Patient Health Questionnaire (PHQ-9), Hospital Anxiety and Depression Scale (HADS), Psychological General Well-Being Index (PGWB), and Women’s Health Questionnaire (WHQ) to evaluate depression, anxiety symptoms, and health-related quality of life.

Furthermore, the trial will monitor blood lipid profiles, serum hormones, growth and metabolic factors, and coagulation factors. These include follicle-stimulating hormone, luteinizing hormone, estradiol, **progesterone**, testosterone, sex hormone-binding globulin, IGF-I and its binding proteins, antitrombin, factor V Leiden, factor II mutation, cardiolipin antibodies, Lupus anticoagulant, Protein C activity, Protein S free, APT-time, fibrinogen, prothrombin complex, and thrombocytes. The data collection and analysis will be conducted at specified intervals throughout the trial duration, which is estimated to end on February 28, 2025.